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
Phase: PHASE2
Conditions: Kidney Transplantation
Sponsor: ITB-Med LLC

Clinical Protocol TCD601B101 
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 Recipient 
 
NCT Number: NCT06365437 
 
Release Date: 06-Mar-2024 

Clinical Study Protocol 
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06 March 2024 Amendment 02 (v3.0) 
CONFIDENTIAL 
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TCD601 (siplizumab) 
CLINICAL PROTOCOL TCD601B101 
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 
 
 
 
EU CT Number: 
2023-507895-36 
Current Version: 
Amendment 02 (v3.0) dated 06 March 2024 
Protocol History: 
Amendment 01 (v2.0) dated 18 January 2021 
Original Protocol (v1.0) dated 28 August 2020 
Clinical Trial Phase: 
2a 
Sponsor: 
ITB-MED AB 
Sonja Kovalevskys Gata 4 
113 65 Stockholm 
Sweden 
Contact: alan.slade@itb-med.com 
 
 
 
 
 
 
 
 
 
Confidential Property of ITB-MED LLC 
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 
CLINICAL PROTOCOL TCD601B101 .......................................................................................... 1 
TABLE OF CONTENTS ................................................................................................................. 2 
LIST OF ABBREVIATIONS .......................................................................................................... 9 
PROTOCOL SYNOPSIS ............................................................................................................... 14 
STUDY SCHEMA ......................................................................................................................... 23 
1. 
INTRODUCTION....................................................................................................... 24 
1.1. 
Background ................................................................................................................. 24 
1.1.1. 
Transplant Induction Therapy ..................................................................................... 25 
1.1.2. 
CD2 Biology ............................................................................................................... 26 
1.1.3. 
Siplizumab (TCD601): Mechanism of Action ............................................................ 26 
1.1.4. 
Siplizumab Data Summary ......................................................................................... 27 
1.1.4.1. 
In Vitro Pharmacology ................................................................................................ 27 
1.1.4.2. 
Toxicology Data .......................................................................................................... 27 
1.1.4.3. 
Teratogenicity and Reproductive Toxicology Data .................................................... 28 
1.1.4.4. 
Human Safety and Tolerability Data........................................................................... 28 
1.1.4.5. 
Human Pharmacokinetic Data ..................................................................................... 28 
1.1.4.6. 
Human Pharmacodynamic Data .................................................................................. 29 
1.2. 
Study Purpose ............................................................................................................. 30 
2. 
OBJECTIVES AND ENDPOINTS ............................................................................ 31 
3. 
STUDY DESIGN ........................................................................................................ 32 
3.1. 
General Overview ....................................................................................................... 32 
3.1.1. 
Screening Period ......................................................................................................... 32 
3.1.2. 
Treatment Period ......................................................................................................... 32 
3.1.2.1. 
Cohort Assignment/Randomization ............................................................................ 32 
3.1.2.2. 
Investigational Product (IP) Administration (Siplizumab/rATG) ............................... 33 
3.1.2.3. 
Background Immunosuppressive Therapy .................................................................. 33 
3.1.2.4. 
Post-Transplant Study Visits ....................................................................................... 33 
3.2. 
Dose Escalation Review .............................................................................................. 33 
3.3. 
Safety Stopping Rules ................................................................................................. 34 
4. 
STUDY DESIGN RATIONALE ................................................................................ 35 
4.1. 
Dose/Regimen and Treatment Duration Rationale ..................................................... 36 

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4.1.1. 
Siplizumab Tissue Distribution/Effect Compartment ................................................. 38 
4.2. 
Rationale for Active Control ....................................................................................... 40 
4.3. 
Rationale for Background Immunosuppression .......................................................... 41 
4.4. 
Risks and Benefits ....................................................................................................... 41 
4.4.1. 
Risks of Siplizumab .................................................................................................... 41 
4.4.1.1. 
Infusion and Inflammatory Reactions and Cytokine Release ..................................... 42 
4.4.1.2. 
Immunosuppression and Infections ............................................................................. 43 
4.4.1.3. 
Other Hypothetical Risks ............................................................................................ 44 
4.4.2. 
Risks of ATG Induction Therapy ................................................................................ 46 
4.4.3. 
Risks of MMF Concomitant Immunosuppression ...................................................... 47 
4.4.4. 
Risks of TAC Concomitant Immunosuppression ........................................................ 48 
4.4.5. 
Risks of SARS-CoV-2 (COVID-19) ........................................................................... 48 
4.4.6. 
Risk Mitigation Strategy ............................................................................................. 49 
5. 
POPULATION ............................................................................................................ 51 
5.1. 
Inclusion Criteria ......................................................................................................... 51 
5.2. 
Exclusion Criteria ....................................................................................................... 51 
6. 
TREATMENTS .......................................................................................................... 54 
6.1. 
Method of Treatment Assignment .............................................................................. 54 
6.2. 
Investigational Product (IP) ........................................................................................ 54 
6.2.1. 
Identification of Investigational Product ..................................................................... 54 
6.2.2. 
Management of Investigational Product ..................................................................... 54 
6.2.3. 
Investigational Product Dosing Regimen .................................................................... 55 
6.2.4. 
Preparation of Siplizumab ........................................................................................... 55 
6.2.5. 
Premedication for Siplizumab Infusion ...................................................................... 56 
6.2.6. 
Siplizumab Administration ......................................................................................... 56 
6.2.7. 
Provisional Dose Levels.............................................................................................. 57 
6.2.8. 
Dose Escalation Guidelines ......................................................................................... 57 
6.3. 
rATG (Standard of Care Control) ............................................................................... 58 
6.3.1. 
rATG Dose and Duration ............................................................................................ 58 
6.3.2. 
Preparation of rATG ................................................................................................... 58 
6.3.3. 
Premedication for rATG Infusion ............................................................................... 59 
6.3.4. 
Administration of rATG Infusion ............................................................................... 59 
6.3.5. 
Management of rATG Therapy ................................................................................... 59 

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6.4. 
Background Immunosuppression ................................................................................ 59 
6.4.1. 
MMF Administration .................................................................................................. 60 
6.4.2. 
TAC Administration .................................................................................................... 60 
6.4.3. 
Corticosteroid Administration ..................................................................................... 61 
6.5. 
Infectious Disease Prophylaxis and Treatment ........................................................... 61 
6.6. 
Other Concomitant Treatments ................................................................................... 62 
6.7. 
Treatment of Adverse Events ...................................................................................... 63 
6.7.1. 
Treatment of Acute Rejection Episodes ...................................................................... 63 
6.7.2. 
Management of BK Viremia ....................................................................................... 63 
6.7.3. 
Management of Delayed Graft Function (DGF) ......................................................... 64 
6.7.4. 
Primary Graft Non-Function (PGNF) ......................................................................... 64 
6.7.5. 
Epstein-Barr Virus-Post-Transplant Lymphoproliferative Disorder 
(EBV-PTLD) ............................................................................................................... 64 
6.8. 
Prohibited Treatment ................................................................................................... 65 
6.9. 
Treatment Exposure and Compliance ......................................................................... 65 
7. 
INFORMED CONSENT PROCEDURES ................................................................. 66 
8. 
VISIT ASSESSMENTS .............................................................................................. 67 
8.1. 
Subject Identification .................................................................................................. 67 
8.2. 
Screen Failure Assessments ........................................................................................ 67 
8.3. 
Efficacy/Pharmacodynamic Assessments ................................................................... 67 
8.4. 
Safety Assessments ..................................................................................................... 68 
8.4.1. 
Physical Examination .................................................................................................. 68 
8.4.2. 
Vital Signs ................................................................................................................... 68 
8.4.3. 
Height and Weight ...................................................................................................... 68 
8.4.4. 
Laboratory Evaluations ............................................................................................... 68 
8.4.4.1. 
Hematology ................................................................................................................. 69 
8.4.4.2. 
Clinical Chemistry ...................................................................................................... 69 
8.4.4.3. 
Lipid Panel .................................................................................................................. 69 
8.4.4.4. 
Urine Dipstick ............................................................................................................. 69 
8.4.4.5. 
Pregnancy .................................................................................................................... 69 
8.4.4.6. 
Renal Function ............................................................................................................ 69 
8.4.4.7. 
Coagulation Studies .................................................................................................... 70 
8.4.4.8. 
EBV-DNA PCR .......................................................................................................... 70 

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8.4.4.9. 
Cytomegalovirus (CMV) DNA PCR .......................................................................... 70 
8.4.4.10. 
Donor-Specific Antibodies (DSA) .............................................................................. 70 
8.4.4.11. 
Immunogenicity .......................................................................................................... 70 
8.4.4.12. 
Viral Testing and Surveillance .................................................................................... 70 
8.4.5. 
EBV-PTLD Surveillance ............................................................................................ 70 
8.4.6. 
Imaging: PTLD Surveillance ...................................................................................... 72 
8.4.7. 
Renal Biopsies ............................................................................................................. 72 
8.4.8. 
Treated Biopsy-Proven Acute Rejection (tBPAR) ..................................................... 72 
8.4.9. 
Graft Loss .................................................................................................................... 72 
8.4.10. 
Death ........................................................................................................................... 73 
8.5. 
Pharmacokinetic Assessments .................................................................................... 73 
8.6. 
Assessment of Treatment Exposure and Compliance ................................................. 73 
8.7. 
Exploratory Biomarker Assessments .......................................................................... 73 
9. 
STUDY DISCONTINUATION AND COMPLETION ............................................. 74 
9.1. 
Discontinuation ........................................................................................................... 74 
9.1.1. 
Safety Stopping Rules ................................................................................................. 74 
9.1.2. 
Discontinuation of Study Treatment ........................................................................... 75 
9.1.3. 
Withdrawal of Informed Consent ............................................................................... 75 
9.1.4. 
Lost to Follow-up ........................................................................................................ 76 
9.1.5. 
Early Study Termination by the Sponsor .................................................................... 76 
9.2. 
Study Completion ....................................................................................................... 76 
9.3. 
Subject Replacement ................................................................................................... 76 
10. 
SAFETY MONITORING AND REPORTING .......................................................... 77 
10.1. 
Definition of Adverse Events and Reporting Requirements ....................................... 77 
10.1.1. 
Adverse Events ........................................................................................................... 77 
10.1.2. 
Serious Adverse Events .............................................................................................. 78 
10.1.3. 
Adverse Events of Special Interest ............................................................................. 78 
10.1.4. 
SAE Reporting ............................................................................................................ 79 
10.1.5. 
Pregnancy Reporting ................................................................................................... 79 
10.1.6. 
Early Phase Safety Monitoring ................................................................................... 80 
10.1.7. 
Reporting of Study Treatment Errors .......................................................................... 80 
11. 
DATA MONITORING COMMITTEE (DMC) ......................................................... 81 
12. 
DATA ANALYSIS AND STATISTICAL METHODS ............................................. 82 

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12.1. 
Analysis Sets ............................................................................................................... 82 
12.2. 
Baseline ....................................................................................................................... 82 
12.3. 
Subject Demographics and Other Baseline Characteristics ........................................ 82 
12.4. 
Treatments ................................................................................................................... 83 
12.4.1. 
Concomitant Immunosuppressants .............................................................................. 83 
12.4.2. 
Other Co-Medications ................................................................................................. 83 
12.5. 
Analysis of the Primary Endpoint(s) ........................................................................... 83 
12.5.1. 
Definition of Primary Endpoint(s) .............................................................................. 83 
12.5.2. 
Safety Endpoints ......................................................................................................... 84 
12.5.2.1. 
Adverse Events ........................................................................................................... 84 
12.5.2.2. 
Vital Signs ................................................................................................................... 85 
12.5.2.3. 
Clinical Laboratory Evaluations ................................................................................. 85 
12.5.2.4. 
Immunogenicity .......................................................................................................... 85 
12.5.2.5. 
Other Safety Evaluations ............................................................................................. 85 
12.5.3. 
Statistical Model, Hypothesis, and Method of Analysis ............................................. 86 
12.5.4. 
Handling of Missing Values/Censoring/Discontinuations........................................... 86 
12.5.5. 
Pharmacokinetics ........................................................................................................ 86 
12.5.6. 
PK/PD Relationships ................................................................................................... 87 
12.6. 
Analysis of Secondary Endpoints ............................................................................... 88 
12.6.1. 
Efficacy and/or Pharmacodynamic Endpoint(s) ......................................................... 88 
12.7. 
Analysis of Exploratory Endpoints ............................................................................. 88 
12.8. 
Interim Analysis .......................................................................................................... 89 
12.9. 
Sample Size Calculation ............................................................................................. 89 
13. 
STUDY CONDUCT ................................................................................................... 90 
13.1. 
Sponsor Responsibilities ............................................................................................. 90 
13.2. 
Investigator Responsibilities ....................................................................................... 90 
13.3. 
Site Initiation ............................................................................................................... 90 
13.4. 
Data Quality Control ................................................................................................... 91 
13.4.1. 
Data Collection ........................................................................................................... 91 
13.4.2. 
Data Management ....................................................................................................... 91 
13.4.3. 
Monitoring Procedures ................................................................................................ 91 
13.4.4. 
Protocol Adherence and Amendments ........................................................................ 92 
13.4.5. 
Quality Assurance ....................................................................................................... 93 

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13.5. 
Study Site Closure ....................................................................................................... 93 
13.5.1. 
Records Retention ....................................................................................................... 93 
14. 
ETHICAL CONSIDERATIONS ................................................................................ 94 
14.1. 
Regulatory and Ethical Compliance ............................................................................ 94 
14.2. 
Publication of Study Protocol and Results .................................................................. 94 
15. 
REFERENCES ............................................................................................................ 95 
16. 
APPENDICES ............................................................................................................ 98 
APPENDIX 1. 
SCHEDULE OF ASSESSMENTS (SOA) ......................................................... 99 
SOA: Screening through Day 4 ...................................................................................................... 99 
SOA: Day 5 through Day 70/Week 10......................................................................................... 100 
SOA: Day 84/Week 12 through Day 336/Week 48 ..................................................................... 101 
SOA: Abbreviations and Footnotes .............................................................................................. 102 
APPENDIX 2. 
AMENDMENT NO. 01 – SUMMARY OF CHANGES ................................. 104 
APPENDIX 3. 
INVESTIGATOR AGREEMENT PAGE ........................................................ 105 
APPENDIX 4. 
US-SPECIFIC CELLCEPT® PREGNANCY AND SAFETY 
INFORMATION ....................................................................................................... 106 
APPENDIX 5. 
GUIDELINES FOR MMF DOSE REDUCTION ............................................ 108 
APPENDIX 6. 
TACROLIMUS DRUG-DRUG INTERACTIONS ......................................... 109 
APPENDIX 7. 
BANFF CLASSIFICATION ............................................................................ 111 
 
LIST OF TABLES 
Table 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 ................................................................................. 30 
Table 2: 
Objectives and Related Endpoints ............................................................................. 31 
Table 3: 
Dosing Cohorts .......................................................................................................... 33 
Table 4: 
Renal Transplantation Pooled Analysis: Opportunistic Infections ............................. 44 
Table 5: 
Provisional Dose Levels.............................................................................................. 57 
Table 6: 
Non-Compartmental Pharmacokinetic Parameters ..................................................... 87 
LIST OF FIGURES 
Figure 1: 
Mean CD3 Lymphocyte Profile Following Siplizumab (MEDI-507) 
Administration in Study MI-CP027 ........................................................................... 29 

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Figure 2: 
Mean Predicted Serum Concentrations Following Siplizumab Doses of 0.2 
and 0.6 mg/kg in Study TCD601B101 ....................................................................... 36 
Figure 3: 
Mean Predicted Serum Concentrations Following Siplizumab Doses of 1.7 
and 5.0 mg/kg in Study TCD601B101 ....................................................................... 37 
Figure 4: 
Mean Predicted, Log-Transformed, Siplizumab Serum Concentrations 
Following 0.2 and 0.6 mg/kg Siplizumab Administration in Study 
TCD601B101 ............................................................................................................. 39 
Figure 5: 
Mean Predicted, Log-Transformed, Siplizumab Serum Concentrations 
Following 1.7 or 5.0 mg/kg Siplizumab Administration in Study 
TCD601B101 ............................................................................................................. 40 

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LIST OF ABBREVIATIONS 
 
Abbreviation 
Definition 
ABC 
antibody biodistribution coefficient 
ADCC 
antibody-dependent cell-mediated cytotoxicity 
ADCP 
antibody-dependent cellular phagocytosis 
AE 
adverse event 
AESI 
adverse event of special interest 
aGvHD 
acute graft-versus-host disease 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AMR 
antibody-mediated rejection 
APC 
antigen-presenting cell 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
ATG 
anti-thymocyte globulin 
AUC 
area under the concentration-time curve 
AUCinf 
area under the concentration-time curve from time zero to infinity 
AxMP 
Auxiliary Medicinal Product 
BID 
twice a day/twice daily 
BKV 
BK polyomavirus 
BMI 
body mass index 
BMT 
bone marrow transplantation 
BPAR 
biopsy-proven acute rejection 
BUN 
blood urea nitrogen 
CDC 
complement-dependent cytotoxicity 
CDR 
complementarity-determining region 
CIT 
cold ischemia time 
CL/F 
total body clearance of drug from the plasma 
Cmax 
maximum observed concentration 
CMV 
cytomegalovirus 
CNI 
calcineurin inhibitor 
CRS 
cytokine release syndrome 
CS 
corticosteroid(s) 

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Abbreviation 
Definition 
CsA 
cyclosporine 
COVID-19 
coronavirus disease 2019 
CSR 
clinical study report 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTS 
chimeric transition syndrome 
CV 
coefficient of variation 
CV% 
percent coefficient of variation 
DGF 
delayed graft function 
DLT 
dose-limiting toxicity 
DMC 
Data Monitoring Committee 
DSA 
donor-specific antibody 
EBV 
Epstein-Barr virus 
EC50 
half-maximal effective concentration 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
ELISA 
enzyme-linked immunosorbent assay 
EMA 
European Medicines Agency 
EOS 
End of Study 
EU 
European Union 
FACS 
fluorescence-activated cell sorting 
FAS 
Full Analysis Set 
Fc 
fragment crystallizable 
FcRn 
fragment crystallizable neonatal receptor 
FcγR 
fragment crystallizable gamma receptor 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GvHD 
graft-versus-host disease 
HBsAg 
hepatitis B surface antigen 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 

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Abbreviation 
Definition 
HLA 
human leukocyte antigen 
HIV 
human immunodeficiency virus 
HSCT 
hematopoietic stem cell transplantation 
IAR 
infusion-associated reaction 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG 
immunoglobulin G 
IL 
interleukin 
IL-2RA 
interleukin-2 receptor antagonist 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
IP 
investigational product 
IV 
intravenous 
IWRS 
interactive web response system 
IVIG 
intravenous immunoglobulin 
KDIGO 
Kidney Disease Improving Global Outcomes 
KM 
Michaelis constant 
LFA 
leukocyte function antigen 
LGL 
large granular lymphocytic 
LLOQ 
lower limit of quantitation 
LOCF 
last-observation-carried-forward 
LPD 
lymphoproliferative disorder 
mAb 
monoclonal antibody 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMF 
mycophenolate mofetil 
MPA 
mycophenolic acid 
MRI 
magnetic resonance imaging 
mTOR 
mechanistic target of rapamycin 
NCI 
National Cancer Institute 

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Abbreviation 
Definition 
NK 
natural killer 
PCP 
Pneumocystis jirovecii (Pneumocystis carinii) pneumonia 
PCR 
polymerase chain reaction 
PD 
pharmacodynamic(s) 
PET 
positron-emission tomography 
PGNF 
primary graft non-function 
PK 
pharmacokinetic(s) 
p.o. 
orally 
PT 
Preferred Term 
PT 
prothrombin time 
PTLD 
post-transplant lymphoproliferative disorder 
PVAN 
polyomavirus-associated nephropathy 
rATG 
rabbit anti-thymocyte globulin 
RO 
receptor occupancy 
REMS 
Risk Evaluation and Mitigation Strategy 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
s.c. 
subcutaneous 
SD 
standard deviation 
SID 
subject identification number 
SmPC 
Summary of Product Characteristics 
SMQ 
Standardized MedDRA Query 
SoC 
standard of care 
SOC 
System Organ Class 
SOP 
standard operating procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TAC 
tacrolimus 
TB 
tuberculosis 
tBPAR 
treated biopsy-proven acute rejection 
TCMR 
T-cell mediated rejection 
TCR 
T-cell receptor 

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Abbreviation 
Definition 
TEAE 
treatment-emergent adverse event 
Tmax 
time to reach maximum observed concentration 
TMDD 
target-mediated drug disposition 
t½ 
half-life 
ULOQ 
upper limit of quantitation 
US 
United States 
VL 
viral load 
WBC 
white blood cell 
WHO 
World Health Organization 
WOCBP 
women of childbearing potential 

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study visits, up to and including Week 10, and then monthly through Month 12 
or EOS (all enrolled subjects will be followed for a minimum of 12 months), 
as indicated in the Schedule of Assessments (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, or are otherwise 
considered non-evaluable, will be replaced. 
Dose Escalation Review 
A review of safety/tolerability (e.g., AEs, SAEs, clinical laboratory assessments, 
vital signs), PD (immunophenotyping), receptor occupancy, and PK (if available) 
data will be conducted by ITB-MED and an independent Data Monitoring 
Committee (DMC) at least 28 days following the last IP administration in the 
4th siplizumab-treated subject in each cohort prior to dose escalation to the next 
dose level cohort. This 28-day safety period allows sufficient time for subjects to 
reach full receptor occupancy, maximum PD activity, and for presentation of acute, 
drug-related toxicities. 
Upon completion of the review by the DMC, if there is no evidence of acute, 
dose-limiting toxicities (DLTs), the DMC may recommend escalation to the next 
dose level cohort. Alternatively, a decision to terminate the dosing arm could be 
reached, or the study could be amended to add additional and/or intermediate dose 
levels or cohorts below the maximum tolerated dose to further evaluate safety, PK, 
or PD. 
If escalation to the next dose level cohort is recommended by the DMC and opened 
for enrollment prior to existing dose level cohorts being filled, the Interactive Web 
Response System (IWRS) will randomize subjects to either the newly opened dose 
level cohort or a prior cohort. This will ensure that all cohorts are backfilled to 
achieve the sample size of 10 subjects (8 siplizumab: 2 placebo). 
Data Monitoring Committee (DMC) 
In addition to the dose escalation review process described above, the independent 
Data Monitoring Committee (DMC) will convene as described in the DMC Charter 
to conduct ongoing review of cumulative PK, PD, and safety data (including DLTs, 
AEs, SAEs, EBV viral load, post-transplant lymphoproliferative disorder (PTLD) 
surveillance results, clinical laboratory assessments, and ad hoc imaging). 
Safety Stopping Rules 
If at any time the observed AEs meet or exceed the a priori defined stopping 
criteria (safety stopping rules), the study will be placed on hold pending further 
review from the Sponsor and DMC. 
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 grade scale, the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0. 

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The following stopping rules based on potential toxicities will serve as the basis for 
placing enrollment and dose escalation on hold: 
• 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 (CRS) 
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/mm3 [0.2 to <0.5 × 109/L]) considered drug-related 
as determined by the Investigator. 
• Two (2) or more subjects presenting with Grade 3 or higher toxicity 
considered drug-related (including infusion reactions) as determined by the 
Investigator, 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. 
Population 
Up to 40 moderate immunological risk, adult, de novo renal transplant patients 
Planned Study 
Sites 
Up to 10 study sites within Europe (EU) 
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-human leukocyte antigen (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. 
Exclusion 
Criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this 
study: 
1. Transplant recipients seronegative 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. 

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6. Subjects at high immunological risk for rejection as determined by local 
practice (e.g., presence of pre-existing donor-specific antibodies [DSA], 
recipient of high Kidney Donor Profile Index ≥85 kidney [where assessed]). 
7. Subjects with anti-HLA donor-specific antibody as measured by 
complement-dependent cytotoxicity (CDC) assay, 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. 
11. Subjects with clinically significant laboratory abnormality that would 
preclude participation in the study. 
For example: 
>2.5 × upper limit of normal (ULN) values for: 
- Liver function chemistries (alanine aminotransferase [ALT], 
aspartate aminotransferase [AST], alkaline phosphatase [ALP]) 
- Bilirubin 
- Coagulation studies (International Normalized Ratio [INR]/ 
prothrombin time [PT], activated partial thromboplastin time 
[aPTT]). 
12. Subjects with any of the following: 
• Hemoglobin (Hgb) <8 mg/dL 
• White blood cell (WBC) count ≤2,000/mm3 
• Platelet count ≤75,000/mm3 
13. Seropositive for human immunodeficiency virus (HIV) or hepatitis B surface 
antigen (HBsAg). Subjects who are seropositive 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/ 
hepatitis B core antigen (HBcAg) positive, or HCV. 
15. History of hypersensitivity to any of the study drugs or to drugs of similar 
chemical classes (e.g., siplizumab, anti-thymocyte globulin [ATG], 
tacrolimus [TAC], mycophenolate mofetil [MMF], corticosteroids [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 tuberculosis (TB) infection (after anti-TB treatment, patients 
with history of latent TB may become eligible according to national 
guidelines). 
18. Subjects with severe systemic infections, current or within the 2 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. 

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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 childbearing 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 confirmed by follow up 
hormone level assessment is she considered not of childbearing potential. 
• 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. 
Withdrawal and period abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) are not acceptable forms of contraception. 
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 is considered 
not of childbearing potential. 

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• Tacrolimus trough concentrations on Days 0, 1, 7, 14, 21, 28; on Months 3, 
6, 12, and as clinically indicated. Sample collection should be taken before 
the next dose is administered. 
• PD: 
o PD sampling times to be linked with relevant PK time points 
o Peripheral lymphocyte immunophenotyping (FACS analysis) – CD2, 
CD3, CD4, CD5, CD8, CD19, CD25, CD27, CD38, CD45RA, CD45RO, 
CD59, CD127, CD138, CD154, FoxP3, HLA-DR 
o Peripheral CD2 receptor occupancy 
Safety 
Assessments 
• AEs and SAEs 
• Clinically significant changes in clinical chemistry, hematology, vital signs, 
and serology 
• Renal function 
Data Analysis 
All information obtained on AEs will be displayed by treatment and subject. 
The number and percentage of subjects with treatment-emergent adverse events 
(TEAEs) will be tabulated by body system (i.e., System Organ Class [SOC]) and 
Preferred Term (PT) with a breakdown by treatment arm. A subject with multiple 
TEAEs within a PT or SOC is only counted once towards the total. No formal 
statistical analysis will be conducted 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. 
The magnitude and duration of PD effect of siplizumab will be characterized by 
measuring the change in peripheral immunophenotype, including all subsets of 
T-, B-, and natural killer (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 for all PD and biomarker data. 
The relationship between siplizumab concentration (PK) and PD variables will be 
explored graphically. 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 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. 
Study Duration 
All subjects enrolled will be followed for a minimum of 12 months. 

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STUDY SCHEMA 
 
 
 

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1. 
INTRODUCTION 
1.1. 
Background 
Since the first successful human kidney transplantation by Murray et al. in 1954 (Murray 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 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 2 or 3 immunosuppressive 
drugs with or without induction. Optimal combinations of therapies must be individualized based 
on the risk and benefit for each individual recipient (Bia 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 CNIs include 
antiproliferative agents such as mycophenolic acid (MPA)-based drugs (mycophenolate mofetil 
[MMF], CellCept or Myfortic) which block inosine monophosphate dehydrogenase (IMPDH) 
or mechanistic target of rapamycin [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 SoC regimen. 
Calcineurin inhibitor-based SoC regimens have resulted in excellent 1-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 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 (rATG, Thymoglobulin) and nondepleting monoclonal antibodies such 
as basiliximab (Simulect) and formerly daclizumab (Zenapax; withdrawn from US in 2009) that 
inhibit T-cell activation (Hardinger 2013). In the past, the lymphocyte depleting murine 
anti-human CD3 monoclonal antibody, 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 
interleukin-2 receptor antagonists (IL-2RAs; 20.6%) (Hart 2020) whereas almost an inverse use 
of ATG and IL-2RA 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 (mAb) that 
specifically targets CD25, or the interleukin (IL)-2 receptor, 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 (CS)-based 
immunosuppression regimen clinically relevant suppression of IL-2 receptor activity following 
basiliximab administration is approximately 59 ±17 days (Simulect® Prescribing Information 
2020). 
Anti-thymocyte globulin (ATG) is a polyclonal mixture of chimeric (rabbit/human) immuno-
globulins 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 et al 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 major histocompatibility 
complex (MHC) class I (Popow 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-dependent cytotoxicity (CDC) of 
various immune cells (Andress 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 2004). Mechanistic side effects such as infusion reactions, cytokine release syndrome 
(CRS), 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 IL-2 receptor antagonists (IL-2RA) and induction-free regimens are 
primarily utilized in patients with low immunologic risk (e.g., living donor renal transplant) 
(Hardinger 2013). The current Kidney Disease Improving Global Outcomes (KDIGO) 
Transplant Work Group guidelines recommend IL-2RA 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 et al assessed the use of induction therapy in living donor renal recipients on 

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immunosuppression with TAC/MPA ± prednisolone (assessment period 2000–2012). Their 
conclusions were there was no benefit from use of IL-2RA induction versus no induction 
in patients maintained on TAC/MPA/ prednisolone with respect to acute rejection or graft 
survival; and 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 2015). 
Overall, antibodies with a high specificity for single T-cell receptors (TCRs) 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 leukocyte function antigen (LFA)-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, natural killer (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 (Seed 1987, 
Springer 1987, Davis 1996). 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 (Leitner 2015, Rölle 2016). In addition, CD2 is upregulated 
on both activated and memory T cells (Tmems) 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 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. 
Siplizumab (TCD601): 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 fragment crystallizable (Fc) portion of the siplizumab 
antibody binds to fragment crystallizable gamma receptors (FcγR) 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 Tmems (high CD2 expression) and sparing of regulatory T cells (Treg; low CD2 expression) 

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in vitro and in vivo based on the differential expression of 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. 
Siplizumab Data Summary 
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 
Siplizumab only cross-reacts with one non-human primate species, the chimpanzee 
(Damschroder 2004). Toxicology studies with single and multiple doses of siplizumab 
were conducted in primate (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, 1 single and 3 repeated 
dose toxicology studies were conducted in chimpanzees. All animals were administered one 
(0.143 mg/kg) to three, intravenous (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 recur 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. 
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 

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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. 
1.1.4.4. 
Human Safety and Tolerability Data 
The safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (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. 
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 Epstein-Barr virus (EBV)-lymphoproliferative disorder (LPD). In renal 
transplant and psoriasis patients, a total of 59 SAEs were reported in 47 patients. There was 
1 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 fragment crystallizable neonatal receptor (FcRn) (a high-capacity 
receptor responsible for immunoglobulin G [IgG] homeostasis by recycling/salvage), and (ii) 
through the complementarity-determining regions (CDRs), 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 

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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 elimination. 
Siplizumab binds to FcRn receptors in vitro with a half-maximal effective concentration (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 (Michaelis 
constant [KM] EC50 0.34 μg/mL), TMDD elimination 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 (t½) 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 t½ 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 
t½ of 14–49 hours and loss of PD activity (rapid lymphocyte recovery) and around Day 8 as 
illustrated below (Figure 1). 
Figure 1: 
Mean CD3 Lymphocyte Profile Following Siplizumab (MEDI-507) 
Administration in Study MI-CP027 
 
 
Note: N = 4 (0.012 and 0.06 mg/kg); N = 5 (0.12). 
Source: MI-CP027; Mean (± standard error) CD3 lymphocyte phenotypes by dose level at Day 1 pre-infusion, and at Day 2 
(p = 0.027), Day 3 (p = 0.016), Day 8 (p = 0.17), Day 33 (p = 0.21), and Day 60 (p = 0.20). 
 
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. 

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3. 
STUDY DESIGN 
3.1. 
General Overview 
This is a 12-month, randomized, controlled, open-label, dose escalation study evaluating safety, 
tolerability, PK, and PD of siplizumab, an anti-CD2 monoclonal antibody, compared to rabbit 
polyclonal anti-thymocyte globulin (rATG), as induction therapy in de novo renal transplant 
recipients. All subjects will receive triple regimen 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 40 moderate 
immunological risk, adult, de novo renal transplant candidates will be enrolled in the study. 
3.1.1. 
Screening Period 
The screening period is defined as Day -28 to Day -1; Day 0 is defined as the day of 
transplant/day of first dose of investigational product (IP). If the screening and Day 0 visits occur 
in close proximity (i.e., within a 24-hour timespan), screening assessments are not required to be 
repeated. 
During the screening period 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 chronic kidney disease [CKD], end stage renal disease 
[ESRD], and dialysis history) and current medical conditions at screening, a physical 
examination, vital signs, laboratory assessments, and a pregnancy test (for women of 
childbearing potential [WOCBP]) will also be obtained. 
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. 
3.1.2. 
Treatment Period 
3.1.2.1. 
Cohort Assignment/Randomization 
Upon confirmation of eligibility for the study, and no later than Day 0, subjects 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 
subjects on Day 0, but when logistical considerations prevent this from occurring (e.g., central 
pharmacy requirements), randomization may occur up to 24 hours pre-transplant. 
Eligible subjects will be sequentially assigned to 1 of 4 cohorts (A–D) using a time-lagged dose 
escalation methodology (see Study Schema). Within each cohort, 10 subjects will be randomized 
in an 8:2 ratio to receive either siplizumab (Arms 1, 2, 3, or 4) or rATG (Control Arm 5), as 
shown in Table 3. 

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safety period allows sufficient time for subjects to reach full receptor occupancy, maximum PD 
activity, and for the presentation of acute, drug-related toxicities. See Section 6.2.8 (Dose 
Escalation Guidelines) for details. 
Upon completion of the review by the DMC, if there is no evidence of acute, dose-limiting 
toxicities (DLTs), the DMC may recommend escalation to the next dose level cohort. 
Alternatively, a decision to terminate the dosing arm could be reached, or the study could be 
amended to add additional and/or intermediate dose levels or cohorts below the maximum 
tolerated dose to further evaluate safety, PK, or PD. 
If escalation to the next dose level cohort is recommended by the DMC and opened for 
enrollment prior to existing dose level cohorts being filled, the IWRS will randomize subjects to 
either the newly opened dose level cohort or a prior cohort. This will ensure that all cohorts are 
enrolled to achieve the sample size of 10 subjects (8 siplizumab: 2 placebo). 
Dose escalation will be based on a priori defined criteria outlined in Section 6.2.8. 
3.3. 
Safety Stopping Rules 
If at any time the observed AEs meet or exceed the a priori defined stopping criteria (safety 
stopping rules), the study will be placed on hold pending further review from the Sponsor and 
DMC (Section 9.1.1). 

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4. 
STUDY DESIGN RATIONALE 
The goal of induction therapy is to prevent acute rejection during the early post-transplant 
period by providing a high degree of immunosuppression at the time of transplant surgery 
and 1–2 months thereafter. CD2 represents a unique target for induction considering the broad 
expression and function in T-cell activation, co-stimulation, and alloantigen recognition. 
Escalating doses of siplizumab (0.2 mg/kg, 0.6 mg/kg, 1.7 mg/kg, and 5.0 mg/kg) will be 
administered in place of 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 along with an assessment of safety, tolerability, PK, and PD 
activity of siplizumab. 
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) and is to be completed prior to revascularization and rereperfusion of the 
allograft to ensure 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 study and the Population PK/PD model may be 
revised after each dose escalation to predict the concentration-response/exposure-response for 
the next dose, as appropriate. Overall, the dose 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 an 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 SoC 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 employ an 
open-label design. This open-label design will not only minimize the risks for subjects during the 
initial investigation of TCD601 (siplizumab) should the need for rapid intervention arise, such as 
emergent SAEs, but also avoids the additional difficulties associated with placebo infusions in 
a control group. It is recognized that Investigator bias can affect the management of subjects 
receiving investigational treatment; especially in an open-label study setting. In general, such 
scrutiny biases the study in favor of the control arm. As such, efforts to minimize bias for 
or against the 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 of siplizumab, this study will enroll a moderate 
immunological risk de novo patient population who would typically be treated with T-cell 
depleting induction. This population was selected as 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 

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marrow transplantation (BMT), 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 2 and Figure 3, it is anticipated that 2 doses of 0.6 mg/kg will result in 
 
 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 PD 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, it is expected 
that doses of 1.7 to 5.0 mg/kg will be needed to achieve the PK/PD target. PK/PD modeling 
planned prior to each dose escalation step will allow for a near real-time exposure-response 
analysis during the study 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 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 (percent coefficient of variation [CV%] 
±3.10) was reported, whereas the ABC for lymph nodes is 8.46 ±11.4% (Shah 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 renal 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 
 are required for adequate T and NK cell modulation and depletion, 
target siplizumab trough (C0) siplizumab concentrations of 
 and 
 would 
result in adequate CD2 engagement and lymphocyte suppression in renal tissue and lymph 
nodes, respectively. 
As discussed in Section 1.1.4.5, population pharmacokinetics modeling suggests that 
concentrations of siplizumab above the KM of 
, which represents the EC50 
concentration, is necessary to maintain saturation of the TMDD pathway and linear clearance in 
renal transplant patients. Practically, to maintain full CD2 RO, target engagement and saturation 
of clearance a target concentration 3–5 fold the KM (
) is necessary. This 
concentration is represented by the inflection point and transition from linear- to non-linear 
clearance, occurring around the 
 concentration range in the simulations. This 
concentration also represents a key threshold 
 for T-cell engagement and depletion, 
where maintenance of trough concentrations above the threshold in the periphery are expected 

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4.3. 
Rationale for Background Immunosuppression 
In adult de novo kidney transplant recipients, the use of a ‘triple drug regimen’ consisting of 
concentration-controlled TAC, MMF, and CS is the current SoC used in more than 90% of 
kidney transplants globally. 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. In this study, 
immediate-release generic or equivalent medications for TAC and MMF are allowed, however, 
substitution is not permitted for the first 12 months post-transplant. All subjects who start on a 
brand or a specific generic TAC and MMF should be maintained on the same brand or generic 
for the duration of this study. TAC will be administered at a dose and frequency that maintains 
target trough concentrations in a per label range of 4–11 ng/mL. Similarly, MMF will be 
administered with a target daily dose of 2000 mg, divided BID (see Section 6.4 for further 
details). 
4.4. 
Risks and Benefits 
The risks and benefits of siplizumab in combination with SoC immunosuppression 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. In all subjects, infection risk will be 
mitigated by following applicable national vaccination guidelines and by use of infection 
prophylaxis (see Section 6.5). Similarly, the risks of severe acute respiratory syndrome 
coronavirus 2 (SARS-CoV-2) will be minimized by following local, national, and international 
guidelines for immunosuppressed and solid organ transplant patients (see Section 4.4.4). 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. 
For further details regarding risks related to siplizumab see Section 7 of the current IB. 
It is not expected that treatment with siplizumab will result in any direct benefit to the subject. 
Subjects randomized to receive siplizumab may incidentally receive the benefit of closer clinical 
care due to the frequency of study visits and monitoring. Subjects randomized to Control Arm 5 
will receive the contemporary SoC with a similar potential benefit of close clinical care during 
the first year post-transplant. Overall, information gained from this study may help other renal 
transplant patients in the future. 
4.4.1. 
Risks of 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. 

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Assays to detect a putative antibody response to siplizumab are included in the study design. 
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 
• Other hypothetical risks 
These risks and an overall risk mitigation strategy are discussed below. 
4.4.1.1. 
Infusion and Inflammatory Reactions and Cytokine Release 
Cytokine Release 
Cytokine release syndrome (CRS) 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. 
No severe CRS events have been reported in any subjects receiving siplizumab alone or in 
combination with other immunosuppressants to date. Siplizumab is a non-activating humanized 
monoclonal antibody (mAb) that binds to CD2+ immune cells and rapidly eliminates them via 
ADCC and ADCP. As a result, any CRS events would not be related to direct T cell activation 
but rather to depletion of CD2-expressing cells. Across all subjects that have received 
siplizumab, self-limiting infusion reactions have been observed, including fever and chills, which 
although not meeting the full presentation of CRS could be associated with a milder release of 
cytokines during ADCC and ADCP. 
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 
been managed with warm blankets. 
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 

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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 CRS 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. 
4.4.1.2. 
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 Infection Disease Prophylaxis and Treatment [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 studies with siplizumab there is no clear evidence for a higher rate 
of infections associated with treatment administration. Infections were common in post- 
hematopoietic stem cell transplantation (HSCT) patients with Grade 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 patients (MI-CP099), with 5 (26%) 
patients testing positive for cytomegalovirus (CMV) antigen; 3 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%) 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 4.4.1.3 for details. 

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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 below: 
Table 4: 
Renal Transplantation Pooled Analysis: Opportunistic Infections 
 
Standard or Custom MedDRA Query 
Preferred Term, n (%) 
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) 
Abbreviations: CMQ = Custom MedDRA Query; SMQ = Standardized MedDRA Query. 
Note: MedDRA Version 22.1. 
Source: Table 2.1.5.5 (Listing ADVERSE_EVENTS in CP027 study, Listing AE_LAA in NKD03 study, Listing 16_2_7_1 
in ITN036 study. 
 
4.4.1.3. 
Other Hypothetical Risks 
Renal Dysfunction 
In 2 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 2 weeks 
post-transplant and is better described as chimeric transition syndrome (CTS). Patients in these 
2 studies 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 with onset around 
post-transplant Day 10–14 that peaked (range 3.5–15.4 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, 7/9 (78%) 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 2 remaining patients 
failed to recover full renal function; this included 1 patient who lost their graft at Day 10 due to 
severe antibody mediated rejection, as well as a patient who presented with subsequent CNI 

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toxicity, and later progressed to graft loss associated with thrombotic microangiopathy at Month 
7. 
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. 
Lymphoproliferative Disorders and other Malignancies 
Prolonged and sustained immunosuppression may result in an increased risk of developing 
certain types of cancer. 
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 aGvHD 
following BMT, EBV-associated 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 (LGL) leukemia (n = 2), cutaneous T-cell lymphoma 
(n = 1), peripheral T-cell lymphoma (n = 1), and adult T-cell lymphoma (n = 1). One patient with 
LGL leukemia developed a secondary leukemia (M4 type leukemia) 1 year after completing 
MEDI-507 therapy. In the GvHD studies EBV-LPD (n = 1), PTLD (n = 1), and EBV-related 
lymphoma (n = 2) has been reported (4/48 [8.3%] patients). A case of acute myeloid leukemia 
relapse was also reported. In addition, three cases of LPD have been reported in Investigator-
initiated and compassionate use studies of MEDI-507 in patients following BMT. 
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). 
All of the LPD cases reported with MEDI-507 have been limited to 2 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 from 2–15% based on patient age, ethnicity, and immune status (Dojcinov 2018). In the 
setting of HSCT, especially in patients who present with multiple risk factors (Curtis 1999, 
Uhlin 2014), PTLD, rates of 8% up to 40% have been reported (Juvonen 2003). Hence, in the 
setting of broad T-cell depletion, the reported rates are within the range expected and are not in 
excess of that anticipated with the use of ATG in the same patient populations. 
In the setting of renal transplantation, siplizumab use is not expected to increase the risk 
of EBV-LPD/PTLD over rATG-based induction in combination with background 

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immunosuppression. Independent adjudication of all 9 reported 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 as 1.03% (Hart 2020) and as high as high as 2.4% with ATG 
induction (Thymoglobulin SmPC 2023). 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 2011). Therefore, all recipients will be screened prior to administration of siplizumab, 
and EBV-seronegative subjects excluded from participating in the TCD601B101 clinical study. 
In addition, clinicians who specialize in transplant immunosuppression are aware of the risks for 
EBV-LPD will be managing patients enrolled in this study. Regular assessments of hematology 
and EBV-viral load per local practice as well as monitoring of clinical signs and symptoms will 
be conducted during the 12-month study. 
Adjunct Immunosuppression 
The combination of escalating doses of siplizumab in the presence of adjunct immuno-
suppression 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. 
4.4.2. 
Risks of ATG Induction Therapy 
The following summary is taken from the most recent Swedish Medical Products Agency-
approved Summary of Product Characteristics (SmPC) and labelling of rATG (Thymoglobulin 
SmPC 2023). 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 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. 
Infusion-Associated Reactions (IARs; including Cytokine Release Syndrome [CRS]) 
Cases consistent with 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 WBC and 
platelet counts should be monitored. 

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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 outcomes. 
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. 
4.4.3. 
Risks of MMF Concomitant Immunosuppression 
The following summary is taken from the most European Medicines Agency (EMA)-approved 
SmPC and labeling of mycophenolate mofetil (MMF) (CellCept SmPC 2023). For the most 
recent guidance, refer to the most recently approved local labeling from the appropriate 
authority. 
MMF is a teratogen associated with an increased rate of spontaneous abortion and congenital 
malformation compared with other immunosuppressants. MMF-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. 
WOCBP must be counseled regarding pregnancy prevention and planning. Mycophenolate 
should not be used in WOCBP unless they are using highly effective contraception. Some local 
labels for MMF 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. 
Please refer to local labeling and guidelines for the use of MMF in WOCBP, including use of 
contraception and wash-out periods following discontinuation of MMF-containing products. 

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4.4.4. 
Risks of TAC Concomitant Immunosuppression 
The following summary is taken from the most recent Swedish Medical Products Agency-
approved SmPC and labeling of TAC (Adoport SmPC 2022). For the most recent guidance, refer 
to the most recently approved local labeling from the appropriate authority. 
Malignant Neoplasms 
Use of immunosuppressive agents, including TAC, may increase the incidence of malignancies, 
including lymphoma or lymphoproliferative disorders. These events have been associated with 
fatal outcomes. 
Serious Infections and Reactivation of Pre-Existing Infections 
TAC is routinely used in combination with other immunosuppressive agents. Infections 
(bacterial, fungal, viral, and protozoal), reactivation of infection (particularly cytomegalovirus 
and BK polyomavirus [BKV]) have been reported after TAC administration in combination with 
multiple immunosuppressive agents. These infections can be fatal. 
Interaction with Other Medication and Herbal Drugs 
Inhibitors or inducers of CYP3A4 (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, 
voriconazole, itraconazole, telithromycin or clarithromycin, rifampicin, rifabutin) should only be 
co-administered with care. This may result in a change in TAC metabolism and subsequent 
change in TAC trough level, requiring an adjustment of TAC dose. 
Ventricular Hypertrophy and Cardiomyopathies 
Ventricular hypertrophy or hypertrophy of the septum, reported as cardiomyopathies, have been 
observed in patients treated with TAC. Risk factors observed to increase the risk of these clinical 
conditions included pre-existing heart disease, corticosteroid usage, hypertension, renal or 
hepatic dysfunction, infections, fluid overload, and edema. Accordingly, high-risk patients 
receiving substantial immunosuppression should be monitored, using such procedures as 
echocardiography or electrocardiogram (ECG) pre- and post-transplant (e.g., initially at 3 months 
and then at 9–12 months). 
Use During Pregnancy or Lactation 
Use of immunosuppressants, including TAC, is a potential risk to the fetus in utero, and neither 
pregnancy nor breast-feeding are recommended while receiving TAC. 
4.4.5. 
Risks of SARS-CoV-2 (COVID-19) 
The novel coronavirus, SARS-CoV-2, can spread rapidly within healthcare settings and 
communities and poses a special challenge for organ transplantation. Coronavirus disease 2019 
(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 2020). Transmission via droplet spread can occur 
from both symptomatic and asymptomatic individuals (Arons 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 

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infection; consideration of symptoms and exposure history, including PCR-based testing per 
local practice, may be employed. 
4.4.6. 
Risk Mitigation Strategy 
With initial administration of any biologic drug, 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 2007). No cytokine release has been 
detected with IV or s.c. siplizumab (MEDI-507) administration in clinical studies. A mild 
infusion reaction has been described following the first dose in primates as well as human 
subjects treated with siplizumab. 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 (paracetamol) and antihistamine (i.e., 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 TCD601B101 study, all subjects will receive premedication prior to each dose of 
siplizumab to mitigate any infusion reactions. 
Safety assessments will include vital signs, physical examinations, clinical laboratory evaluations 
(hematology, blood chemistry, and urinalysis), AE and SAE monitoring, and PK/PD collections, 
as outlined in the Schedule of Assessments (Appendix 1). 
Infections are a common risk for all transplant recipients. In this study all subjects will be 
regularly evaluated while hospitalized and following discharge for signs and symptoms which 
might indicate a severe infection (i.e., fever, nausea, myalgia, headache, arthralgia, chills, 
diarrhea, stiff neck, and malaise). Appropriate treatment will be administered per local practice. 
Subjects will be instructed to report any of the aforementioned symptoms to the clinical staff to 
assure proper assessment and care can be administered in a timely manner. Further, considering 
the expected immunosuppressive nature of the compound, subjects will be screened for a history 
of latent infections prior to enrollment. Viral reactivation will be assessed for CMV and BKV 
according to local practice on a regular basis. Prophylaxis for CMV and Pneumocystis 
pneumonia (PCP) will be administered to all subjects during the study according to local 
practice. Subjects at-risk for, or with a history of exposure to active/latent tuberculosis (TB) 
disease, will be assessed per local institutional practice and excluded from participation 
(exclusion criterion #17) in the study. This assessment will be at the discretion of the Investigator 
based on subject history and local practice, and in accordance with contemporary local, national, 
and international guidelines. 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 study 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. 
Guidelines on the risks and management of SARS-CoV-2 in the setting of clinical trials as well 
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5. 
POPULATION 
This multicenter study will be conducted in up to 10 centers in Europe. The study population 
will consist of approximately 40 male and female de novo adult renal transplant patients. The 
Investigator must ensure that all subjects meet the following eligibility criteria. Subject selection 
is to be established by checking all inclusion/exclusion criteria at screening and confirming 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-human leukocyte antigen (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. 
5.2. 
Exclusion Criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Transplant recipients seronegative 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 donor-specific antibodies [DSA], recipient of high Kidney 
Donor Profile Index ≥85 kidney [where assessed]). 
7. Subjects with anti-HLA donor-specific antibody as measured by complement-dependent 
cytotoxicity (CDC) assay, 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. 
For example: 
>2.5 × upper limit of normal (ULN) values for: 
- Liver function chemistries (alanine aminotransferase [ALT], aspartate 
aminotransferase [AST], alkaline phosphatase [ALP]) 
- Bilirubin 
- Coagulation studies (International Normalized Ratio [INR]/prothrombin time 
[PT], activated partial thromboplastin time [aPTT]). 
12. Subjects with any of the following: 
• Hemoglobin (Hgb) <8 mg/dL 
• White blood cell (WBC) count ≤2,000/mm3 
• Platelet count ≤75,000/mm3 
13. Seropositive for human immunodeficiency virus (HIV) or hepatitis B surface antigen 
(HBsAg). Subjects who are seropositive 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/hepatitis B core 
antigen (HBcAg) positive, or HCV. 
15. History of hypersensitivity to any of the study drugs or to drugs of similar chemical 
classes (e.g., siplizumab, anti-thymocyte globulin [ATG], tacrolimus [TAC], 
mycophenolate mofetil [MMF], corticosteroids [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 tuberculosis (TB) infection (after anti-TB treatment, patients with history of 
latent TB may become eligible according to national guidelines). 
18. Subjects with severe systemic infections, current or within the 2 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. 

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23. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during dosing and for 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 confirmed by follow up hormone level assessment is she considered not 
of childbearing potential. 
• 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. Withdrawal and period 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) are not 
acceptable forms of contraception. 
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 is considered not of 
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6. 
TREATMENTS 
6.1. 
Method of Treatment Assignment 
Approximately 40 subjects will be sequentially assigned to 1 of 4 cohorts (A–D) using 
a time-lagged dose escalation methodology (see Study Schema). Within each cohort, 10 subjects 
will be randomized in an 8:2 ratio to receive either siplizumab (Arms 1, 2, 3, or 4) or rATG 
(Control Arm 5), as shown in Table 3. 
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 Electronic Data Capture (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 the IWRS to execute each randomization after a subject 
has met all prerequisites for randomization 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 for each 
subject. 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 IP. 
6.2. 
Investigational Product (IP) 
6.2.1. 
Identification of Investigational Product 
Siplizumab is a humanized IgG1κ class monoclonal antibody, supplied as a 
 
 concentrate for solution. Siplizumab 
will be supplied in 6 mL vials containing 60 mg at a concentration of 10 mg/mL. 
6.2.2. 
Management of Investigational Product 
Investigational product will be provided as open-label, bulk medication. Detailed instructions for 
the receipt, storage, accountability, and return or destruction will be described in the ITB-MED 
provided Pharmacy Manual, as well as expectations for reporting temperature excursions to 
ITB-MED. 
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 IP 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 IP 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. 

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The Investigator must maintain an accurate record of the dispensing of all IP 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, IP accountability will be 
noted by the Monitor during site visits and/or at the completion of the study. 
All IP 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 IP supply. 
Only after receiving a written authorization by ITB-MED, the Investigator/designee will: 
• Send all the unused and partly used drug supplies (as well as the empty containers) to the 
address provided at the time of authorization for destruction 
OR 
• Destroy the unused and partly used drug supplies (as well as the empty containers) by the 
site’s pharmacist or designee, who will provide a drug destruction certificate 
6.2.3. 
Investigational Product Dosing Regimen 
The initial siplizumab dose to be investigated will be 0.2 mg/kg (Cohort A/Arm 1) with planned 
escalation to 0.6, 1.7, and 5.0 mg/kg in subsequent cohorts (see Table 3). Subjects will receive 
2 siplizumab IV doses. The first dose will be administered on Day 0, pre- or intra-operatively, 
and must be completed prior to revascularization and reperfusion of the allograft. The second 
dose of siplizumab will be administered on Day 4 post-transplant. 
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. Subjects may be 
discontinued from treatment earlier at the discretion of the Investigator or upon request of the 
subject. 
Detailed instructions on the preparation and administration of the IP will be provided in the 
Pharmacy Manual and must be referenced prior to administration to any study subject. 
6.2.4. 
Preparation of Siplizumab 
As per the treatment assigned upon randomization, the Investigator or his/her designee will 
obtain the IP to be administered to the subject. The dose of siplizumab must be prepared by 
and administered either by the Investigator or a 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 (each siplizumab vial contains 60 mg): 
Dose (mg) = [subject weight (kg) × dose level (mg/kg)] 
Example 1: 
A subject whose weight is 70 kg in Cohort A (0.2 mg/kg) should receive 14 mg of 
siplizumab (70 kg × 0.2 mg/kg = 14 mg) and would require 1 vial of siplizumab. 

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Example 2: 
A subject whose weight is 70 kg in Cohort B (0.6 mg/kg) should receive 42 mg of siplizumab 
(70 kg × 0.6 mg/kg = 42 mg) and would require 1 vial of siplizumab. 
Example 3: 
A subject whose weight is 70 kg in Cohort C (1.7 mg/kg) should receive 119 mg of 
siplizumab (70 kg × 1.7 mg/kg = 119 mg) and would require 2 vials of siplizumab. 
Example 4: 
A subject whose weight is 70 kg in Cohort D (5 mg/kg) should receive 350 mg siplizumab 
(70 kg × 5 mg/kg = 350 mg) and would require 6 vials of siplizumab. 
Upon confirmation of subject dose, the product will be prepared from vial(s), using aseptic 
technique. 
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. 
6.2.6. 
Siplizumab Administration 
Siplizumab will be administered by IV infusion (using a syringe pump) to the subject by 
authorized site personnel. 
The first dose of siplizumab will be administered on Day 0 over 60 (±5) minutes by IV infusion. 
The infusion should be administered pre- or intra-operatively and timed so that completion of the 
infusion is no earlier than 4 hours prior to revascularization and reperfusion 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 dose will be administered by IV infusion over 
60 (±5) minutes on Day 4. 
The compatibility of siplizumab with other IV medications is not known and must not be 
combined with other infusions or medications in the same syringe. 
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 
using the same line. 
The date, start time, completion time, and volume of siplizumab administration must be recorded 
in the subject’s source documentation and applicable electronic case report form (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 
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• A maximum single dose of 15 mg/kg has been administered in subjects; therefore, this 
dose will not be exceeded in this study 
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 AEs 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 
• Administration of an intermediate dose strength between the current and next planned 
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 Reactions 
(SUSARs) and study changes. 
6.3. 
rATG (Standard of Care Control) 
6.3.1. 
rATG 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 3 doses. rATG dose 
adjustments and/or interruptions for a given subject are not permitted unless warranted (see 
below). rATG will be administered per applicable local label. 
6.3.2. 
Preparation of rATG 
As per the treatment assigned upon randomization, the dose of rATG must be prepared 
and administered by the Investigator and/or a 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 
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6.3.3. 
Premedication for rATG 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 rATG Infusion 
rATG will be administered on Day 0, Day 1, and Day 2 per local label or as outlined in the 
Pharmacy Manual. 
Important Note for rATG Administration – Per the Thymoglobulin Data Sheet 
(Section 4.5 Interaction with Other Medicinal Products and Other Forms of Interaction): 
• Blood or blood products must not be administered together with Thymoglobulin. 
6.3.5. 
Management of rATG Therapy 
Subjects should be monitored for adverse reactions during and after infusion. The total white 
blood cell (WBC) and platelet counts should be monitored during and after rATG therapy. 
The rATG dose should be reduced by one-half if: 
• WBC count is between 2,000 and 3,000 cells/mm3 
OR 
• Platelet count is between 50,000 and 75,000 cells/mm3 
rATG treatment may need to be stopped if: 
• WBC count falls below 2,000 cells/mm3 
OR 
• Platelet count falls below 50,000 cells/mm3. 
6.4. 
Background Immunosuppression 
The following background immunosuppression medications will be used in this study, supplied 
locally, and administered in accordance with this protocol, SoC practices at the institution, and 
where applicable, current local labeling: 
• Immediate-release TAC as 0.5 mg, 1.0 mg, or 5.0 mg capsules 
Note: If oral administration is not feasible or practical, IV TAC (containing the 
equivalent of 5 mg/mL TAC) administration by continuous infusion may be substituted 
per label) 
• 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 
Not all dosage forms listed are available in each country, dependent on local approval status 
and regulations. All doses of background immunosuppression medication, along with dose 
changes during the study, must be recorded with the reason for administration in the 

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corresponding eCRF, as per the eCRF completion guidelines. At enrollment all subjects must 
follow the assigned regimen. 
The use of immediate-release generic TAC and MMF are permitted in this study. Subjects 
should remain on the same concomitant immunosuppression medication throughout the duration 
of the 12-month study (i.e., if the subject starts with brand Prograf® or CellCept®, the subject 
should 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). 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. 
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 6. 
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 to keep the subject on study treatment. 
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 2000 mg will be administered orally (p.o.) in divided doses (1000 mg per dose) twice 
a day (BID): 
• 2 × 500 mg tablets, or 
• 4 × 250 mg capsules, or 
• 1000 mg via IV administration (2 × 500 mg vials for IV administration), if oral 
administration is not feasible. † 
† For subjects who remain intubated >24 hours post-transplant and/or are otherwise 
unable to swallow oral medication, IV MMF may be substituted until oral 
conversion is possible. 
The first dose of MMF will be administered no later than 24 hours after 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 eCRF. 
6.4.2. 
TAC Administration 
TAC will be administered 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 TAC) administration by continuous infusion may be 
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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 study, 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 TAC trough concentration falls outside the required target, 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 
Corticosteroids should be administered at a minimum of 5.0 mg/day (prednisone or equivalent) 
from Day 0 until Month 12 per local standard practice in a manner consistent for all subjects 
enrolled at the site. 
6.5. 
Infectious Disease Prophylaxis and Treatment 
Cytomegalovirus (CMV) 
CMV prophylaxis, with IV ganciclovir or oral valganciclovir, will be used in subjects 
(CMV positive and CMV negative) as per local practice. 
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 site. 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 permitted and will be 
administered at the discretion of the Investigator. 

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BK Polyomavirus 
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, or fluconazole) will not be permitted unless subjects are 
systemically infected since azole antifungal agents may increase blood concentrations of TAC. 
Systemic therapy will be based on study site practice and at the Investigator’s discretion. 
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 2019). 
Vaccination during treatment with siplizumab and prior to clearance of the antibody and PD 
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. 
6.6. 
Other Concomitant Treatments 
The Investigator should instruct the subject to notify the study site of any new medications taken 
after enrollment into the study. All medications, clinically relevant concomitant 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 treatment 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, ITB-MED should be contacted to determine if the subject should 
continue participation in the study. No other immunosuppressive medications should be 
administered, other than as permitted per protocol. 
† Relevant is defined as: any procedure that is performed due to or to evaluate an AE, to confirm 
specific medical history, or to provide further information that the Investigator considers 
relevant, in accordance with his/her own judgement. 

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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 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 (e.g., sirolimus or everolimus), IVIG, or 
costimulatory blockade (i.e., belatacept) have not been investigated and may result in 
overlapping pharmacology. In the event 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 polyomavirus (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 cells or urine BKV loads over 7-log geq/mL) is adequate for screening; 
if negative, the risk for polyomavirus-associated nephropathy (PVAN) is low. 
Quantitative cutoffs for presumptive diagnosis of BKV nephropathy include plasma DNA 
VL >10,000 copies/mL (whole blood PCR VL >1500–3500 copies/mL), urine VP1 mRNA 
load >6.5 × 105 copies/ng total RNA, or urine DNA load >107 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 
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6.7.3. 
Management of Delayed Graft Function (DGF) 
Delayed graft function (DGF) for this study is defined as the need for dialysis performed within 
7 days of transplant. 
Note: Patients who require dialysis (up to 2 sessions), with the purpose of correcting 
electrolyte abnormalities in the immediate post-transplant time period (i.e., during the 
first 36 hours post-transplant), would not meet the definition of DGF for purposes of this 
study. 
In the event DGF is reported as an AE, the end of DGF is the date the last dialysis session ends. 
For all other subjects, the end of DGF is the date renal dysfunction is considered resolved by the 
Investigator. 
If a subject experiences DGF, the DGF is by definition starting at reperfusion after the 
transplantation procedure. If the graft dysfunction starts later according to the Investigator, the 
condition is considered secondary graft dysfunction. 
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 ATG is used prior to 
Day 4, the IP must be discontinued, and the subject will be placed on SoC per local practice. 
6.7.4. 
Primary Graft Non-Function (PGNF) 
Primary graft non-function (PGNF) is defined as dialysis starting after transplantation with 
a continuous record of post-transplant dialysis until either transplantectomy, retransplantation, 
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 Adverse 
Event eCRFs should be completed, and an SAE of graft loss reported. 
6.7.5. 
Epstein-Barr Virus-Post-Transplant Lymphoproliferative Disorder 
(EBV-PTLD) 
Epstein-Barr virus (EBV)-post-transplant lymphoproliferative disorder (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 subjects diagnosed with EBV-PLTD, therapy must be individualized. rATG and siplizumab 
doses planned for this study 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 labeling 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 (Parker 2010, 
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6.8. 
Prohibited Treatment 
Immunosuppressants and induction treatment other than those specified in the protocol are NOT 
permitted from the signing of informed consent through EOS. 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 TAC levels should be avoided (refer to 
Appendix 6 and local prescribing information). 
6.9. 
Treatment Exposure and Compliance 
Following discharge from the hospital, the Investigator or designee will assure the appropriate 
amount of concomitant study treatment is dispensed 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 study drugs exactly as prescribed and emphasize 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 concomitant 
study treatment as prescribed. 
All drug trough concentrations assessed in this study (siplizumab, TAC) will be measured per the 
Schedule of Assessments (Appendix 1) 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 IP 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. 

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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), Independent Ethics Committee (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 Council for 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 IEC. 
A copy of the approved version of all consent forms must be provided to ITB-MED after IEC 
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8. 
VISIT ASSESSMENTS 
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 7 and Study Month 2 is considered to start on Week 5/ 
Day 28. 
Following is a description of study assessments/procedures. The full Schedule of Assessments is 
located in Appendix 1 and lists all study assessments and timing of when they are to be 
performed. All data obtained from these assessments must be supported in the subject’s source 
documentation. 
8.1. 
Subject Identification 
Each subject is identified 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 study. 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 
eCRF 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 
an 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 collected 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. 

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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 include the examination 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 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. 
Information for all physical examinations must be included in the source documentation at the 
study site but are not required to be included in the 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 eCRF that captures medical history. Significant 
findings discovered after the start of study procedures, which meet the definition, must be 
recorded as an AE. 
8.4.2. 
Vital Signs 
Vital signs include radial pulse rate, blood pressure, and body temperature. 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 5 minutes. Body temperature should be measured per local practice – the same method 
should be used consistently for all subjects at each study 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 
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regarding the timing of central laboratory specimen collection along with the handling, 
processing, storage, and shipping of samples. 
If a laboratory assessment 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 will be excluded from the study. 
The Investigator must document in the source documents the clinical considerations and medical 
relevance of any values outside 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 AE criteria 
reported 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/Adverse Event eCRF page as appropriate. 
8.4.4.1. 
Hematology 
Hemoglobin, hematocrit, red blood cells (RBCs), mean corpuscular volume (MCV), mean 
corpuscular hemoglobin (MCH), platelet count, WBCs with differential (percent and absolute). 
8.4.4.2. 
Clinical Chemistry 
Albumin, total bilirubin, calcium, creatinine, glucose, phosphorus, magnesium, potassium, ALT, 
AST, ALP, gamma-glutamyl transferase (GGT), amylase, sodium, uric acid, and urea/blood urea 
nitrogen (BUN) will be measured. 
8.4.4.3. 
Lipid Panel 
Cholesterol, triglycerides, low-density lipoprotein (LDL), and high-density lipoprotein (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 WOCBP, at time points designated in the 
Schedule of Assessments (Appendix 1). A serum or urine pregnancy test must be obtained up to 
72 hours prior to the time of transplant and the result must be available and negative prior to 
administration of IP. 
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. 

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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 WHO 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. 
Suspicion of PTLD in the setting of increasing EBV viral load should be further evaluated as 
outlined in Section 6.7.5. 
8.4.4.9. 
Cytomegalovirus (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, 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 BKV per local 
center practice unless more rigorous testing is required for EBV and CMV monitoring, as noted 
in Section 8.4.4.8 and Section 8.4.4.9. Results of these assessments are to be recorded in the 
applicable 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 
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Any diagnostic procedures or additional laboratory assessments that result in the diagnosis of 
EBV-PTLD must be captured in 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. Computed tomography (CT), magnetic resonance imaging 
(MRI), and/or positron-emission tomography (PET) imaging may be considered for staging and 
monitoring of biopsy-confirmed PTLD. 
8.4.7. 
Renal Biopsies 
Biopsies will be read by the local pathologist according to local practice and scored according to 
the Banff Classification of Renal Allograft Pathology (Appendix 7). Results of biopsies read by 
the local pathologist must be recorded in the applicable eCRF. 
Preimplantation 
Pre-implantation renal biopsies must be collected unless the collection is contraindicated or not 
possible (e.g., fully robotic-assisted donor nephrectomy). Allograft tissue is to be stored for the 
purpose of baseline comparison in the event of a for-cause renal biopsy during the course of the 
study. The immediate processing and histological analysis of pre-implantation renal biopsies is 
not required. 
For-Cause 
For all suspected rejection episodes, regardless of initiation of anti-rejection treatment, a renal 
biopsy must be performed within 48 hours. The results will be used for subject management and 
assessment of acute rejection (See Section 8.4.8). 
Other/Local Practice 
Any biopsies performed according to local practice must be recorded in the applicable eCRF. 
8.4.8. 
Treated Biopsy-Proven Acute Rejection (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 Banff 
Classification of Renal Allograft Pathology (Appendix 7), including borderline rejections. 
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 
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 Adverse Event eCRF (as serious) and the SAE reported to ITB-MED Safety 
within 24 hours. 

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9. 
STUDY DISCONTINUATION AND COMPLETION 
9.1. 
Discontinuation 
9.1.1. 
Safety Stopping Rules 
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. 
The following stopping rules based on potential toxicities will serve as the basis for placing 
enrollment and dose escalation on hold: 
• 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 (CRS) 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/mm3; 0.2 to <0.5 × 109/L) considered drug-related as determined by the 
Investigator. 
• Two (2) or more subjects presenting with Grade 3 or higher toxicity considered 
drug-related (including infusion reactions) as determined by the Investigator, 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 
(Section 11). 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. 

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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., CRS, 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. 
Subjects should remain in the study, if possible, and receive SoC 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 determine their health status, evaluate safety (SAEs), and 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 in 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 permitted unless safety findings 
require communication 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. 

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For subjects enrolled within the European Union (EU), all biological samples collected at the 
time of withdrawal but not yet analyzed will not be used unless permitted by applicable law. 
Sample storage will be according to applicable legal requirements. 
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). A subject should not be considered 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 to ensure adequate 
consideration is given to the protection of the subject’s interests. The Investigator will be 
responsible for informing IECs of the early termination of the study. 
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 
of that decision. 
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 the 
Month 12/EOS 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 
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. 

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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 
assessments. 
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 
version 5.0. 
• 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 study 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. 

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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 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 
• 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: 
• Opportunistic Infections 
• Malignancies 

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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 AESIs, 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) occurring with Investigational Medicinal 
Products (IMPs) and Auxiliary Medicinal Products (AxMPs) is collected and entered in the 
eCRF(s). If necessary, relevant safety information on AxMPs may be addressed in the Annual 
Safety Report (ASR) of the IMP. 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. 
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. 

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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 its 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. 

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11. 
DATA MONITORING COMMITTEE (DMC) 
This study will include a Data Monitoring Committee (DMC), which will function independently 
of all other individuals associated with the conduct of this clinical study, including the 
participating site investigators. The DMC will convene as described in the DMC Charter to 
conduct ongoing review of cumulative PK, PD, and safety data (including DLTs, AEs, SAEs, 
EBV viral load, PTLD surveillance results, clinical laboratory assessments, and ad hoc imaging). 
The DMC will make recommendations to ITB-MED with regard to dose escalation, as well as 
modification or termination of the study. 
Specific details regarding composition, responsibilities, data monitoring, meeting frequency, 
and documentation of DMC reports, minutes, and recommendations will be described in 
a separate charter established between ITB-MED and the DMC. 

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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 to which they have been assigned during the randomization procedure. 
The Safety Analysis Set includes all subjects who received at least 1 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 1 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 who received any study drug with at least 
1 available valid PK concentration measurement (i.e., not flagged for exclusion), and 
experienced no protocol deviations with relevant impact on PK data. 
The PD Analysis Set will include all subjects in the FAS with available PD data and no protocol 
deviations with relevant impact on PD data. Summary statistics will also be provided such as 
mean, standard deviation (SD), median, minimum, and maximum by treatment and visit/time for 
all PD and biomarker data. 
For PK and PD analysis sets, subjects will be analyzed according to the study treatment(s) 
received. 
12.2. 
Baseline 
Baseline is defined as the last observation before the first study treatment administration. 
Baseline for renal function analysis will be based on the nadir post-transplant serum creatinine. 
12.3. 
Subject Demographics and Other Baseline Characteristics 
All data for background and demographic variables will be listed by treatment and subject. 
Summary statistics will be provided by treatment. 
Subject demographics will include age, sex, race, ethnicity, height, weight, and BMI. 
Other baseline disease characteristics include relevant medical history, current medical 
conditions, results of laboratory evaluations, transplant history, donor characteristics (e.g., age, 
sex, race, type, cold ischemia time [CIT]), and any other relevant information. 

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Summary statistics will be presented for the subjects in the FAS. Continuous variables will be 
presented with mean, SD, median, 25th percentile, 75th percentile, minimum, maximum, and the 
number of non-missing observations. 
Categorical data will be displayed via absolute and relative frequencies for each category 
(including a category labeled as “missing” when appropriate). 
12.4. 
Treatments 
The duration (days) of IP administration will be summarized. This will be calculated by 
subtracting the date of the last administration of IP 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 IP 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 IP for any reason. 
The number and percentage of subjects who prematurely discontinued IP 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. 
12.4.1. 
Concomitant Immunosuppressants 
The average daily dose of administered TAC, MMF, and CS will be summarized by treatment 
arm. The dose of the induction agent will be summarized for each of the days when it was 
administered. TAC exposure will be summarized by trough concentration and visit. 
The dose of antibodies or CS used for the treatment of acute rejection episodes will be recorded 
as well. 
12.4.2. 
Other Co-Medications 
Concomitant medications, other than immunosuppressants and CS mentioned above, will be 
summarized by therapeutic class and Preferred Term (PT) and presented by treatment with the 
number and percentage of subjects using each concomitant medication. 
12.5. 
Analysis of the Primary Endpoint(s) 
12.5.1. 
Definition of Primary Endpoint(s) 
All safety data, including AEs, SAEs, clinically significant changes in clinical chemistry, 
hematology, vital signs, and serology, as well as siplizumab PK, immunophenotyping, CD2 
receptor occupancy, eGFR, and anti-siplizumab antibodies are considered primary endpoints. 
Pharmacokinetics, anti-siplizumab antibodies, and CD2 receptor occupancy and PD 
(immunophenotyping) will be summarized by treatment and visit as described in Section 12.5.5, 
Section 12.5.2.4, and Section 12.6.1, respectively. 

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12.5.2. 
Safety Endpoints 
For all safety analyses, the Safety Analysis Set will be used. All listings and tables will be 
presented by treatment. 
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 
adverse events [TEAEs]). 
The on-treatment period lasts from the date of first administration of study treatment through the 
Month 12/EOS visit. 
12.5.2.1. Adverse Events 
All information obtained on AEs will be displayed by treatment and subject. 
The number and percentage of subjects with TEAEs (events started after the first dose of study 
treatment, or events present prior to start of treatment but increased in severity based on PT) will 
be summarized in the following ways: 
• TEAEs by primary System Organ Class (SOC) and PT 
• TEAEs considered related to study drug by SOC and PT 
• TEAEs by primary SOC, PT, and maximum severity 
• SAEs by SOC and PT 
• SAEs considered related to study drug by SOC and PT 
• Deaths by SOC and PT 
• TEAEs leading to discontinuation of a study drug by SOC and PT 
• TEAEs leading to dose adjustment or interruptions of a study drug by SOC and PT 
• Infections by type (viral, bacterial, fungal, and others) and microorganism of infection 
• Serious infections by type and micro-organism of infection 
• TEAEs by standardized Medical Dictionary for Regulatory Activities (MedDRA) query 
(SMQ) 
• TEAEs by SMQ and PT (broad and narrow search) 
Separate summaries will be provided for study treatment-related TEAEs, death, SAEs, other 
significant TEAEs leading to discontinuation, and TEAEs leading to dose adjustment. 
The number (and proportion) of subjects with adverse events of special interest (AESIs)/related 
to identified and potential risks (i.e., serious infections, opportunistic infections, CRS, 
malignancies) will be summarized by treatment. 

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Multiple Occurrences for Tables 
In all tables about incidence rates of TEAEs/infections, if a subject has multiple occurrences 
of a TEAE, the subject will be counted only once in the corresponding TEAE category. A subject 
with multiple TEAEs within an SOC is only counted once towards the total of the SOC. A 
subject with multiple severity ratings for a TEAE while on treatment is only counted once under 
the maximum rating. 
Adverse events will be listed by subject, including the verbatim term given by the Investigator, 
the PT and SOC given by the MedDRA dictionary, start and end date, causality, grade, and 
relationship to study drug as assessed by the Investigator. 
Adverse events which will be counted for the treatment period are those which are treatment-
emergent (i.e., TEAEs). 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. 
12.5.2.2. 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. 
12.5.2.3. Clinical Laboratory Evaluations 
Abnormalities according to clinically notable criteria will be identified. A listing of individual 
subject laboratory data will be generated. Values outside of the clinically notable limits will be 
flagged. Shift tables describing changes from baseline based on the clinical notable criteria will 
be presented. 
Descriptive statistics (mean, SD, median, minimum, and maximum) of quantitative laboratory 
variables, including change from baseline, will be generated by visit. 
Estimated GFR Using the MDRD Formula 
Renal function as assessed by eGFR (MDRD formula) will be evaluated at Months 3, 6, and 12 
(EOS/ET) by comparing the mean eGFR values between groups. 
12.5.2.4. Immunogenicity 
Anti-siplizumab antibodies will be determined at specified time points. Immunogenicity data 
consisting of qualitative and quantitative assessment of anti-siplizumab antibodies information 
will be listed by subject and visit. 
12.5.2.5. Other Safety Evaluations 
BKV Viremia and Nephropathy 
The following variables will be analyzed descriptively: 
• Occurrence of BKV viremia any time post-transplantation 
• Occurrence of BKV 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, median, minimum, and maximum as 
well as change from baseline/previous assessment including shift tables will be provided by 
treatment and visit/time. 
12.5.3. 
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. 
12.5.4. 
Handling of Missing Values/Censoring/Discontinuations 
The analysis will be performed using the FAS. 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 the Schedule of Assessments (Appendix 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. 
12.5.5. 
Pharmacokinetics 
Siplizumab concentrations will be determined by a validated enzyme-linked immunosorbent 
assay (ELISA) method. 
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 quantitation 
(LLOQ). Concentrations below the LLOQ will be reported as “zero” and missing data will be 
labeled as such in the Bioanalytical Data Report. 
Summary statistics will include mean (arithmetic and geometric), SD, coefficient of variation 
(CV; arithmetic and geometric), median, minimum, and maximum. The anticipated LLOQ is 
10 ng/mL and concentrations expressed in mass per volume units. Concentrations below LLOQ 

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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 
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 study, the Investigator/institution must obtain approval/favorable opinion 
from the IEC for the study protocol, written ICF, consent form updates, subject recruitment 
procedures (e.g., advertisements), and any other written information to be provided to subjects. 
Prior to study start, the Investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to provide access to all relevant data 
and records to ITB-MED monitors, auditors, ITB-MED Quality Assurance representatives, 
designated agents of ITB-MED, IECs, and regulatory authorities as required. 
If an inspection of the study 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 to 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 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. 

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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. 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 received training. 
The Investigator/designee is responsible for assuring 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 
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, 
accuracy of data capture/data entry, the adherence to the protocol and GCP, 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 Council for Harmonisation 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 

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a clinical study necessary for the reconstruction and evaluation of the study. 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 GCP 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 designee 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, study procedures, and data to be collected on study 
subjects. Additional assessments required to ensure safety of subjects should be administered as 
deemed necessary on a case-by-case basis. Under no circumstances, including incidental 
collection, is an investigator permitted to collect additional data or conduct additional procedures 
for any purpose involving the 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 subjects. 
Investigators should exercise due diligence to avoid protocol deviations; however, should 
a deviation occur, the Principal Investigator or 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, the 
deviation must be considered a protocol amendment, and unless such an amendment is agreed 
upon by ITB-MED and approved by the 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 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 IEC per the 
IEC’s protocol deviation reporting requirements. 

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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 IP 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 
Investigator wishes to assign the study records to another party or move them to another location, 
ITB-MED must be notified in advance. 

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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, and with the ethical principles laid down in the Declaration of Helsinki. 
Personal data collection, storage, protection, and record keeping will be conducted according to 
applicable local regulations (e.g., General Data Protection Regulation). 
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 study 
will be submitted for publication and posted in a publicly accessible database of clinical trial 
results, such as the ITB-MED clinical study results website and all required Health Authority 
websites (e.g., clinicaltrials.gov, EudraCT, etc.). 

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15. 
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Andress L, Gupta A, Siddiqi N, Marfo K (2014). Rabbit anti-thymocyte globulin induction in 
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Arons MM, Hatfield KM, Reddy SC, Kimball A, James A, Jacobs JR, et al. Presymptomatic 
SARS-CoV-2 infections and transmission in a skilled nursing facility. N Engl J Med. 2020; 
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Bia M, Adey DB, Bloom RD, Chan L, Kulkarni S, Tomlanovich S. KDOQI US commentary on 
the 2009 KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J 
Kidney Dis. 2010; 56(2): 189–218. 
Branco L, Barren P, Mao SY, Pfarr D, Kaplan R, Postema C, et al. Selective deletion of antigen-
specific, activated T cells by a humanized MAB to CD2 (MEDI-507) is mediated by NK 
cells. Transplantation. 1999; 68(10): 1588–1596. 
CELLCEPT® (mycophenolate mofetil) [Summary of Product Characteristics]. Roche 
Registration GmbH; 2023. 
Curtis RE, Travis LB, Rowlings PA, Socié G, Kingma DW, Banks PM, et al. Risk of 
lymphoproliferative disorders after bone marrow transplantation: a multi-institutional 
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Damschroder MM, Kozhich AA, Woods RM, Cheng L, Mullikin BA, Wilson SD, et al. Analysis 
of human and primate CD2 molecules by protein sequence and epitope mapping with anti-human 
CD2 antibodies. Mol Immunol. 2004; 41(10): 985–1000. 
Danziger-Isakov L, Kumar D. Vaccination of solid organ transplant candidates and recipients: 
Guidelines from the American society of transplantation infectious diseases community of 
practice. Clin Transplant. 2019; 33(9): e13563. 
Davis SJ, van der Merwe PA. The structure and ligand interactions of CD2: implications for 
T-cell function. Immunol Today. 1996; 17(4): 177–187. 
Dojcinov SD, Fend F, Quintanilla-Martinez L. EBV-Positive Lymphoproliferations of B- T- and 
NK-Cell Derivation in Non-Immunocompromised Hosts. Pathogens. 2018; 7(1): 28. 
Fishman JA. Infection in Organ Transplantation. Am J Transplant. 2017; 17(4): 856–879. 
Green M, Michaels MG. Epstein-Barr virus infection and posttransplant lymphoproliferative 
disorder. Am J Transplant. 2013; 13 Suppl 3: 41–54. 
Guirado L. Does Rabbit Antithymocyte Globulin (Thymoglobuline®) Have a Role in Avoiding 
Delayed Graft Function in the Modern Era of Kidney Transplantation? J Transplant. 2018; 
2018:4524837. 

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Haas M, Loupy A, Lefaucheur C, Roufousse C, Glotz D, Seron D, et al. 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. 2018; 18(2): 293–307. 
Hardinger KL, Schnitzler MA, Miller B, Lowell JA, Shenoy S, Koch MJ, et al. Five-year follow 
up of thymoglobulin versus ATGAM induction in adult renal Transplantation. Transplantation. 
2004; 78(1): 136–141. 
Hardinger KL, Brennan DC, Klein CL. Selection of induction therapy in kidney transplantation. 
Transpl Int. 2013; 26(7): 662–672. 
Hart A, Smith JM, Skeans MA, Gustafson SK, Wilk AR, Castro S, et al. OPTN/SRTR 2018 
Annual Data Report: Kidney. Am J Transplant. 2020; 20 Suppl s1: 20–130. 
Juvonen E, Aalto SM, Tarkkanen J, Volin L, Mattila PS, Knuutila S, et al. High incidence of 
PTLD after non-T-cell-depleted allogeneic haematopoietic stem cell transplantation as a 
consequence of intensive immunosuppressive treatment. Bone Marrow Transplant. 2003; 32(1): 
97–102. 
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO 
clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009; 
9 Suppl 3: S1–S155. 
Leitner J, Herndler-Brandstetter D, Zlabinger GJ, Grubeck-Loebenstein B, Steinberger P. 
CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28-CD8+ T Cells. J Immunol. 
2015; 195(2): 477–487. 
Lo DJ, Weaver TA, Stempora L, Mehta AK, Ford ML, Larsen CP, et al. Selective targeting of 
human alloresponsive CD8+ effector memory T cells based on CD2 expression. Am J 
Transplant. 2011; 11(1): 22–33. 
Marks WH, Ilsley JN, Dharnidharka VR. Posttransplantation lymphoproliferative disorder in 
kidney and heart transplant recipients receiving thymoglobulin: a systematic review. Transplant 
Proc. 2011; 43(5): 1395–1404. 
Murray JE, Merrill JP, Harrison JH. Kidney transplantation between seven pairs of identical 
twins. Ann Surg. 1958; 148(3): 343–359. 
Parker A, Bowles K, Bradley JA, Emery V, Featherstone C, Gupte G, et al. Diagnosis of post-
transplant lymphoproliferative disorder in solid organ transplant recipients - BCSH and BTS 
Guidelines. Br J Haematol. 2010; 149(5): 675–692. 
Popow I, Leitner J, Grabmeier-Pfistershammer K, Majdic O, Zlabinger G-J, Kindi M, et al. 
A comprehensive and quantitative analysis of the major specificities in rabbit antithymocyte 
globulin preparations. Am J Transplant. 2013; 13(12): 3103–3113. 
PROGRAF® (tacrolimus) [Prescribing Information]. Northbrook, IL: Astellas Pharma Inc.; 2023. 
Rölle A, Halenius A, Ewen EM, Cerwenka A, Hengel H, Momburg F. CD2-CD58 interactions 
are pivotal for the activation and function of adaptive natural killer cells in human 
cytomegalovirus infection. Eur J Immunol. 2016; 46(10): 2420–2425. 

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Roufosse C, Simmonds N, Clahsen-van Groningen M, Haas M, Henriksen KJ, Horsfield C, et al. 
A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology [published 
correction appears in Transplantation. 2018;102(12): e497]. Transplantation 2018; 102(11): 
1795–1814. 
Seed B, Aruffo A. Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a 
rapid immunoselection procedure. Proc Natl Acad Sci USA. 1987; 84(10): 3365–3369. 
Shah DK, Betts AM. Antibody biodistribution coefficients: inferring tissue concentrations of 
monoclonal antibodies based on the plasma concentrations in several preclinical species and 
human. Mabs. 2013; 5(2): 297–305. 
SIMULECT® (basiliximab) for injection [Prescribing Information]. East Hanover, NJ: Novartis 
Pharmaceuticals Corporation; 2020. 
Song T, Yin S, Li X, Jiang Y, Lin T. Thymoglobulin vs. ATG-Fresenius as Induction Therapy in 
Kidney Transplantation: A Bayesian Network Meta-Analysis of Randomized Controlled Trials. 
Front Immunol. 2020; 11: 457. 
Springer TA, Dustin ML, Kishimoto TK, Marlin SD. The lymphocyte function-associated 
LFA-1, CD2, and LFA-3 molecules: cell adhesion receptors of the immune system. Annu Rev 
Immunol. 1987; 5: 223–252. 
Tabrizi MA, Roskos LK. Preclinical and clinical safety of monoclonal antibodies. Drug Discov 
Today. 2007; 12(13-14): 540–547. 
Tanriover B, Zhang S, MacConmara M, Gao A, Sandikci B, Ayvaci MUS, et al. Induction 
Therapies in Live Donor Kidney Transplantation on Tacrolimus and Mycophenolate With or 
Without Steroid Maintenance. Clin J Am Soc Nephrol. 2015; 10(6): 1041–1049. 
Tanriover B, Jaikaransingh V, MacConmara MP, Parekh JR, Levea S-L, Ariyamuthu VK, et al. 
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. 2016; 11(9): 1650–1661. 
THYMOGLOBULIN® (anti-thymocyte globulin [rabbit]) for injection, for intravenous use 
[Summary of Product Characteristics]. Sanofi B.V.; 2023. 
Uhlin M, Wikell H, Sundin M, Blennow O, Maeurer M, Ringden O, et al. Risk factors for 
Epstein-Barr virus-related post-transplant lymphoproliferative disease after allogeneic 
hematopoietic stem cell transplantation. Haematologica. 2014; 99(2): 346–352. 
Zou L, Ruan F, Huang M, Liang L, Huang H, Hong Z, et al. SARS-CoV-2 viral load in upper 
respiratory specimens of infected patients. N Engl J Med. 2020; 382(12): 1177–1179. 

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16. 
APPENDICES 

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SOA: Abbreviations and Footnotes 
Abbreviations: A = Austria; aPTT = activated partial thromboplastin time; BKV = BK polyomavirus; 
CDC = complement-dependent cytotoxicity; CMV = cytomegalovirus; ConMeds = concomitant medications; 
D = day; D&R = donor and recipient; DSA = donor-specific antibodies; EBV = Epstein-Barr virus; EOS = End 
of Study; ET = early termination; FACS = fluorescence-activated cell sorting; HBsAg = hepatitis B surface 
antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; 
INR = International Normalized Ratio; M = month; MMF = mycophenolate mofetil; PCR = polymerase chain 
reaction; PK = pharmacokinetic(s); Pre = pre-dose; PT = prothrombin time; rATG = rabbit anti-thymocyte 
globulin; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2; SD = noted in source document; 
TAC = tacrolimus; TMP/SMX = trimethoprim/sulfamethoxazole; V = visit; W = week. 
 
†  Eligibility must also be confirmed on Day 0 prior to randomization and treatment. 
‡  Medical history, including disease and procedure background for recipient/donor. 
a. All screening procedures may occur on the day of transplant for deceased donors. 
b. Vitals collected pre-dose, immediately following the end of infusion, and 6 hours after completion of infusion 
with siplizumab or rATG. Other time points captured as indicated. Weight is captured pre-dose on Day 0 and 
Day 4 for siplizumab-treated subjects and on Days 0, 1, and 2 for rATG. 
c. Results obtained within the past 6 months acceptable; panel reactive antibodies (PRAs) when available. 
d. Results obtained within the past 6 months are acceptable for the initial assessment of EBV (donor and 
recipient) and CMV; serological testing for BKV is not required at screening (BKV monitoring 
post-transplant will be performed per local center practice). EBV, CMV, and BKV viral testing via PCR 
should be conducted thereafter. 
e. Daily while in hospital, thereafter as noted above; see protocol for panel analytes. 
NOTE: Screening urinalysis not required for anuric recipients. 
f. A negative pregnancy test must be available prior to randomization. Assessments designated with A/SD are to 
be conducted in Austria only and may be documented in source. 
g. DSA collected as noted, and additional collection with each kidney biopsy. 
h. Tacrolimus trough concentrations on Days 0, 1, 7, 14, 21, 28; on Months 3, 6, 12, and as clinically indicated. 
Sample collection should be taken before the next dose is administered. 
i. Subjects randomized to siplizumab: First dose administered pre- or intra-operatively, infused over 
60 (±5) minutes, and timed so that completion of the infusion is no earlier than 4 hours prior to 
revascularization and reperfusion of the allograft. The Day 4 dose should be infused over 60 (±5) minutes, 
between 08:00 and 10:00 to facilitate future sample collections/visits. 
Subjects randomized to rATG control: Administration will occur on Day 0, Day 1, and Day 2, per standard 
of care. 
Important Note for rATG Administration – Per the Thymoglobuline Data Sheet (Section 4.5 Interaction 
with Other Medicinal Products and Other Forms of Interaction): 
• Blood or blood products must not be administered together with Thymoglobuline. 
j. Must be started within 24 hours post-transplantation. 
k. CMV/Pneumocystis prophylaxis per local medical practice. 
l. Pre-implantation biopsy on Day 0; for-cause and/or protocol biopsies as indicated, per local practice 
(see Section 8.4.7). 
m. Siplizumab PK sampling: All post-dose sample collections are relative to the START time of the infusion. 
• Day 0 dosing (pre-dose; and at 1, 3, 6, and 24 hours post-dose) and Day 4 dosing (pre-dose; and at 1, 3, 
and 6 hours post-dose). 
• Post-operative Days 2, 3, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, and 84. 
n. CD2 receptor occupancy collection times to coincide with PK collection. 
o. Collect pre-dose when sample collection falls on dosing Day 0 or Day 4. 
p. Renal injury markers; clean catch morning void urine collection. 

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q. Sampling to coincide with PK collections. All post-dose sample collections are relative to the START time of 
the infusion. 
• Day 0 dosing (pre-dose; and at 1, 3, 6, and 24 hours post-dose) and Day 4 dosing (pre-dose; and at 1, 3, 
and 6 hours post-dose). 
• An additional sample is to be collected on Day 5. 
r. Blinded EBV surveillance will be conducted bi-weekly through Month 3; monthly through Month 6; 
thereafter, bi-monthly though EOS. 

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APPENDIX 2. AMENDMENT NO. 01 – SUMMARY OF CHANGES 
[Appendix removed] 

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APPENDIX 3. INVESTIGATOR AGREEMENT PAGE 
 
INVESTIGATOR AGREEMENT 
 
 
Protocol Number: TCD601B101 
Version: 3.0 
 
I have read the Investigator’s Brochure and protocol TCD601B101, “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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Appendix 4. 
US-SPECIFIC CELLCEPT® PREGNANCY AND SAFETY 
INFORMATION 
The US mycophenolate REMS can be accessed at www.mycophenolaterems.com. 
• 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 MMF products and must be 
counseled regarding pregnancy prevention and planning. 
• For those females using Cellcept® at any time during pregnancy and those becoming 
pregnant within 6 weeks of discontinuing therapy, the Investigator or healthcare 
practitioner should report the pregnancy to the Mycophenolate Pregnancy Registry 
(1-800-617-8191). The Investigator or healthcare practitioner should strongly 
encourage the 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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APPENDIX 7. BANFF CLASSIFICATION 
Category 1: Normal biopsy or nonspecific changes 
Category 2: Antibody-mediated changes 
 Active Antibody-Mediated Rejection (ABMR): 
 
All 3 features must be present for diagnosis. Biopsies showing histological features plus 
evidence of current/recent antibody interaction with vascular endothelium or donor-specific 
antibody (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 (glomerulitis [g] >0 in the absence of recurrent or 
de novo glomerulonephritis, and/or peritubular capillaritis [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 
immunofluorescence [IF] on frozen sections or C4d >0 by immunohistochemistry 
[IHC] on paraffin sections) 
o At least moderate microvascular inflammation ([g + ptc] ≥2), although in the 
presence of acute T-cell mediated rejection (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 (human leukocyte antigen [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 3 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: 
1. Morphologic evidence of chronic tissue injury, including one or more of the 
following: 

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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 4 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 
 
• 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 
 No intimal or transmural arteritis (v = 0) 
 
Category 4: TCMR 
 Acute TCMR 
 
• 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 
• 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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• Grade IIA:1 
Mild to moderate intimal arteritis (v1) with or without interstitial inflammation and 
tubulitis 
• Grade IIB:1 
Severe intimal arteritis (v2), with or without interstitial inflammation and/or tubulitis 
• Grade III:1 
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 
 
• 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 
• 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 
• Grade II:1 
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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Abbreviations: 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 2018, Roufosse 2018).