Clinical trial NCT02921789
Conditions: Kidney Transplantation Primary Focal Segmental Glomerulosclerosis (FSGS)
Keywords: Bleselumab ASKP1240 Efficacy and Safety
Sponsor: Astellas Pharma Global Development, Inc.
Start date: 2017-05-22; Completion date: 2021-05-18
Enrollment: 67 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to assess the efficacy of the bleselumab regimen (basiliximab induction, tacrolimus, steroids and bleselumab) compared with the Standard of Care (SOC) regimen (basiliximab induction, tacrolimus, steroids and mycophenolate mofetil \[MMF\]) in the prevention of recurrent Focal Segmental Glomerulosclerosis (rFSGS) defined as nephrotic range proteinuria with protein-creatinine ratio (≥ 3.0 g/g) through 3 months post-transplant. Death, graft loss or lost to follow-up were imputed as rFSGS.

Detailed description:
The study consisted of the following periods: Screening (Days -21 to -1), Transplant (Day 0), Post-Transplant (Day 0/post-skin closure through 12 months post-transplant). All subjects entered into a Screening Period (Days -21 to -1 prior to transplant), and underwent a Transplant (Day 0 \[zero\]), and then followed for up to 12 months in the Post-Transplant Period (Day 0 through 12 months post-transplant).

Arms: arm 1: Participants received SOC regimen (basiliximab induction, MMF, Tacrolimus, Methylprednisone, Prednisolone). Basiliximab 20 milligrams (mg) administered by intravenous injection prior to transplantation or intra- operatively before revascularisation as induction therapy and 20mg on day 3 or 4 or 5 post-transplant. MMF 1 gram (g) administered orally or intravenously twice daily until 12 months post transplant. Tacrolimus 0.1 milligram per kilogram per day (mg/kg/day) (two equally divided doses at 0.05 mg/kg/day every 12 hours with a target trough level of 4 - 11 nanogram per milliliter (ng/mL) administered orally within 48 hours post-transplant until 12 months post transplant. Methylprednisone 500, 250, 125 and 60mg administered orally or intravenously on days 0, 1, 2 and 3 respectively and continue through 12 months post transplant. Prednisolone administered orally by tapered doses of 20-30 mg on days 4-14, 10-20mg on days 15-28, 5-10mg on days 29 through 12 months post transplant. arm 2: Participants received bleselumab regimen (basiliximab induction, bleselumab, Tacrolimus, Methylprednisone, Prednisolone). Basiliximab 20mg administered by intravenous injection prior to transplantation or intra - operatively before revascularisation as induction therapy and 20mg on day 3 or 4 or 5 post-transplant. Bleselumab 200mg administered by intravenous infusion on day 0, 7, 14, 28, 42, 56, 70, 90 and once per month until month 12. Tacrolimus 0.1 mg/kg/day (two equally divided doses at 0.05 mg/kg/day every 12 hours with a target trough level of 4 - 11 ng/mL) administered orally within 48 hours post transplant until 12 months post transplant. Methylprednisone 500, 250, 125 and 60mg administered orally or intravenously on days 0, 1, 2 and 3 respectively and continue through 12 months post transplant. Prednisolone administered orally by tapered doses of 20-30 mg on days 4-14, 10-20mg on days 15-28, 5-10mg on days 29 through 12 months post transplant.
Interventions: intervention 1: Bleselumab intervention 2: Basiliximab intervention 3: Mycophenolate Mofetil (MMF) intervention 4: Tacrolimus Capsules intervention 5: Methylprednisone intervention 6: Prednisone
Intervention descriptions: intervention 1: Intravenous infusion intervention 2: Bolus injection intervention 3: Oral Intravenous intervention 4: Oral Capsule intervention 5: Oral or Intravenous intervention 6: Oral Tablet

Protocol documents:
Prot_000.pdf: 
Sponsor: APGD
ISN/Protocol 7163-CL-3201
- CONFIDENTIAL -
02 Feb 2018
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Version 3.1 Incorporating Nonsubstantial Amendment 2
A Phase 2a, Randomized, Open-Label, Active Control, 
Multi-Center Study to Assess the Efficacy and Safety of 
Bleselumab in Preventing the Recurrence of Focal Segmental 
Glomerulosclerosis in de novo Kidney Transplant Recipients
Protocol for Phase 2a Study of Bleselumab (ASKP1240)
ISN/Protocol 7163-CL-3201
Version 3.1
Incorporating Nonsubstantial Amendment 2 [See Attachment 1]
02 February 2018
IND 100686
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
Protocol History:
Version 1.0 [08Jul2016]
Version 1.1 [16Dec2016]
Version 2.0 [10May2017]
Version 3.0 [23Jan2018]
Investigator:
Investigator information is on file at Astellas
This confidential document is the property of the Sponsor. No unpublished information contained in this 
document may be disclosed without prior written approval of the Sponsor.


Sponsor: APGD
ISN/Protocol 7163-CL-3201
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Table of Contents
I.
SIGNATURES ······················································································ 8
II.
CONTACT DETAILS OF KEY SPONSOR’S PERSONNEL····························11
III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS ··················12
IV.
SYNOPSIS··························································································17
V.
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································30
1
INTRODUCTION·················································································35
1.1
Background ····················································································35
1.2
Non-clinical and Clinical Data ······························································35
1.2.1
Mechanism of Action ···································································35
1.2.2
Summary of Nonclinical Pharmacology··············································36
1.2.3
Summary of Toxicology································································37
1.2.4
Clinical Data ·············································································41
1.2.4.1
Study 7163-CL-0101 ······························································41
1.2.4.2
Study 7163-CL-0103 ······························································41
1.2.4.3
Study 7163-CL-0107 ······························································42
1.2.4.4
Study 7163-CL-0108 ······························································42
1.3
Summary of Key Safety Information for Study Drugs ···································44
1.4
Risk-Benefit Assessment·····································································46
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS ··································48
2.1
Study Objectives ··············································································48
2.1.1
Primary Objective ·······································································48
2.1.2
Secondary Objectives ···································································48
2.1.3
Exploratory Objectives ·································································49
2.2
Study Design and Dose Rationale···························································49
2.2.1
Study Design·············································································49
2.2.2
Dose Rationale···········································································51
2.3
Endpoints·······················································································52
2.3.1
Primary Endpoint········································································52
2.3.2
Secondary Endpoints····································································52
2.3.3
Exploratory Endpoints ··································································52
3
STUDY POPULATION··········································································53
3.1
Selection of Study Population ·······························································53


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3.2
Inclusion Criteria··············································································53
3.3
Exclusion Criteria ·············································································54
4
TREATMENT(S)··················································································56
4.1
Identification of Investigational Product(s) ················································56
4.1.1
Test Drug(s)··············································································56
4.1.2
Comparative Drug(s)····································································56
4.1.2.1
Basiliximab·········································································56
4.1.2.2
Tacrolimus··········································································56
4.1.2.3
Mycophenolate Mofetil ···························································57
4.1.2.4
Corticosteroids ·····································································58
4.2
Packaging and Labeling ······································································58
4.3
Study Drug Handling ·········································································58
4.4
Blinding ························································································59
4.5
Assignment and Allocation ··································································59
5
TREATMENTS AND EVALUATION························································60
5.1
Dosing and Administration of Study Drug(s) and Other Medication(s)················60
5.1.1
Dose/Dose Regimen and Administration Period ····································60
5.1.2
Increase or Reduction in Dose of the Study/Drug(s)································61
5.1.2.1
Bleselumab ·········································································61
5.1.2.2
Basiliximab·········································································61
5.1.2.3
Tacrolimus··········································································61
5.1.2.4
Mycophenolate Mofetil ···························································61
5.1.3
Previous and Concomitant Treatment (Medication and Non-medication 
Therapy) ··················································································61
5.1.3.1
Other Immunosuppressant Medications·········································62
5.1.3.2
Cytomegalovirus Prophylaxis····················································62
5.1.3.3
Pneumocystis jiroveci Pneumonia Prophylaxis ································62
5.1.3.4
Fungal Prophylaxis ································································62
5.1.3.5
Bacterial Prophylaxis······························································62
5.1.4
Treatment Compliance··································································62
5.1.5
Restrictions During the Study··························································63
5.2
Demographics and Baseline Characteristics ···············································63
5.2.1
Demographics············································································63
5.2.2
Medical History··········································································63


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5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease··············64
5.3
Efficacy | Pharmacokinetics | Immunogenicity Assessment ·····························64
5.3.1
Efficacy···················································································64
5.3.1.1
Recurrence of Focal Segmental Glomerulosclerosis ··························64
5.3.1.2
Blinded, Central Read for Recurrence of Focal Segmental 
Glomerulosclerosis ································································64
5.3.1.3
Biopsy-proven Acute Rejection··················································64
5.3.2
Exploratory Efficacy Variables························································65
5.3.3
Pharmacokinetics········································································65
5.3.3.1
Bleselumab ·········································································65
5.3.3.2
Anti-Bleselumab and Bleselumab Bi-Specific Antibodies ···················66
5.3.3.3
Auto-Anti-CD40 Antibody ·······················································66
5.4
Safety Assessment ············································································66
5.4.1
Vital Sign Measurements·······························································66
5.4.2
Adverse Events ··········································································66
5.4.2.1
Adverse Events of Possible Hepatic Origin ····································67
5.4.3
Laboratory Assessments································································67
5.4.3.1
Local Laboratory Testing·························································67
5.4.3.2
Central Laboratory Testing·······················································68
5.4.4
Physical Examination···································································68
5.4.5
Electrocardiogram·······································································69
5.4.6
Imaging ···················································································69
5.5
Adverse Events and Other Safety Aspects ·················································70
5.5.1
Definition of Adverse Events (AEs) ··················································70
5.5.1.1
Definitions of Specific Adverse Events·········································71
5.5.2
Definition of Serious Adverse Events)················································72
5.5.3
Criteria for Causal Relationship to the Study Drug ·································73
5.5.4
Criteria for Defining the Severity of an Adverse Event ····························74
5.5.5
Reporting of Serious Adverse Events (SAEs) ·······································74
5.5.6
Follow-up of Adverse Events··························································75
5.5.7
Monitoring of Common Serious Adverse Events ···································76
5.5.8
Procedure in Case of Pregnancy·······················································76
5.5.9
Emergency Procedures and Management of Overdose ·····························77
5.5.10
Supply of New Information Affecting the Conduct of the Study··················77
5.6
Test Drug Concentration ·····································································77


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5.6.1
Blood Sampling and Processing for Bleselumab ····································77
5.7
Other Measurements, Assessments or Methods ···········································77
5.7.1
Patient-reported Outcomes ·····························································77
5.7.1.1
Short Form 36-Item Health Survey Score ······································77
5.7.1.2
European Quality of Life – 5 - Dimensions - 5 Levels························78
5.7.1.3
Kidney Transplant Questionnaire················································78
5.7.2
Blood Sample for Future Pharmacogenetic Analysis (Retrospective PGx 
Analysis)··················································································78
5.8
Total Amount of Blood·······································································79
6
DISCONTINUATION············································································79
6.1
Discontinuation of Individual Subject(s)···················································79
6.2
Discontinuation of the Site···································································80
6.3
Discontinuation of the Study·································································80
7
STATISTICAL METHODOLOGY ···························································81
7.1
Sample Size····················································································81
7.2
Analysis Set····················································································83
7.2.1
Full Analysis Set ········································································83
7.2.2
Per Protocol Set··········································································83
7.2.3
Safety Analysis Set······································································83
7.2.4
Pharmacokinetic Analysis Set ·························································83
7.3
Demographics and Other Baseline Characteristics········································83
7.4
Analysis of Efficacy ··········································································83
7.4.1
Analysis of Primary Endpoint ·························································84
7.4.1.1
Primary Analysis···································································84
7.4.1.2
Subgroup Analysis·································································84
7.4.2
Analysis of Secondary Endpoints ·····················································84
7.4.2.1
Recurrence of Focal Segmental Glomerulosclerosis through 6 and 12 
Months ··············································································84
7.4.2.2
Biopsy-Proven Acute Rejection determined by Local Review···············84
7.4.2.3
Efficacy Failure ····································································85
7.4.2.4
Biopsy-Proven Recurrence of Focal Segmental Glomerulosclerosis 
through 3,  6 and 12 Months determined by Central Blinded Review of 
the Biopsy Slides ··································································85
7.4.3
Analysis of Exploratory Endpoints····················································85
7.4.3.1
Graft and Patient Status (Graft and Patient Survival) ·························85


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7.4.3.2
Estimated Glomerular Filtration Rate ···········································86
7.4.3.3
Time to rFSGS; Time to rFSGS or Initiation of Plasmapheresis; Time 
to Death, Graft Loss or Lost to Follow-up Imputed as rFSGS; Time to 
Biopsy-Proven rFSGS·····························································86
7.4.3.4
Time to First BPAR ·······························································86
7.4.3.5
Urine Protein-Creatinine Ratio···················································86
7.4.3.6
Urine Albumin-Creatinine Ratio·················································87
7.4.3.7
Auto-anti-CD40 antibodies·······················································87
7.4.3.8
Patient-Reported Outcomes ······················································87
7.5
Analysis of Safety·············································································88
7.6
Analysis of Pharmacokinetics ·······························································88
7.7
Protocol Deviations and Other Analyses···················································88
7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)····················89
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········89
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS ····················89
8.1
Procedure for Clinical Study Quality Control ·············································89
8.1.1
Data Collection ··········································································89
8.1.2
Specification of Source Documents···················································90
8.1.3
Clinical Study Monitoring······························································90
8.1.4
Direct Access to Source Data/Documents············································90
8.1.5
Data Management ·······································································91
8.1.6
Protocol Deviations ·····································································91
8.1.7
End of Trial in All Participating Countries···········································92
8.2
Ethics and Protection of Subject Confidentiality··········································92
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA) ···························································92
8.2.2
Ethical Conduct of the Study···························································92
8.2.3
Informed Consent of Subjects ·························································92
8.2.3.1
Subject Information and Consent················································92
8.2.3.2
Supply of New and Important Information Influencing the Subject’s 
Consent and Revision of the Written Information ·····························93
8.2.4
Subject Confidentiality ·································································93
8.3
Administrative Matters ·······································································94
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study ·····94
8.3.2
Documents and Records Related to the Clinical Study ·····························94


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8.3.3
Protocol Amendment and/or Revision················································94
8.3.4
Signatory Investigator for Clinical Study Report····································95
9
QUALITY ASSURANCE········································································95
10
STUDY ORGANIZATION······································································95
10.1
Data Monitoring Committee·································································95
10.2
Other Study Organization ····································································95
11
REFERENCES ····················································································96
12
APPENDICES ·····················································································98
12.1
List of Excluded Concomitant Medications················································98
12.1.1
List of known Drug-Induced Hepatotoxicity·········································98
12.2
Liver Safety Monitoring and Assessment ················································ 100
12.3
Common Serious Adverse Events························································· 103
12.4
Retrospective Pharmacogenetic Sub-Study ·············································· 104
12.5
List of Secondary Causes of Focal Segmental Glomerulosclerosis ··················· 106
12.6
Definition of Cytomegalovirus Disease in Solid Organ Transplant Recipients ····· 107
12.7
Categories of Post-transplant Lymphoproliferative Disorders························· 109
12.8
Grading of Acute Kidney Allograft Rejection··········································· 110
12.9
Short-Form 36 Item Health Survey Score Version 2.0 ································· 111
12.10
European Quality of Life 5 Dimensions - 5 Levels Questionnaire···················· 112
12.11
Kidney Transplant Questionnaire ························································· 113
13
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 2·························· 114
14
SPONSOR’S SIGNATURES·································································· 116


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I.
SIGNATURES
1. SPONSOR’S SIGNATURE
Required signatures (e.g., Protocol authors, Sponsor’s reviewers and contributors, etc.) are 
located in Section 13, Sponsor Signatures; e-signatures (when applicable) are located at the 
end of this document.


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2. COORDINATING INVESTIGATOR’S SIGNATURE 
A Phase 2a, Randomized, Open-Label, Active Control, Multi-Center Study to 
Assess the Efficacy and Safety of Bleselumab in Preventing the Recurrence of Focal 
Segmental Glomerulosclerosis in de novo Kidney Transplant Recipients
ISN/Protocol 7163-CL-3201
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02 February 2018
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree that it 
contains all the information required to conduct this study.
Coordinating Investigator:
Signature:
<Insert name, department/affiliation, name of institution>
Date (DD Mmm YYYY)
Printed Name:
Address:


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3. INVESTIGATOR’S SIGNATURE
A Phase 2a, Randomized, Open-Label, Active Control, Multi-Center Study to 
Assess the Efficacy and Safety of Bleselumab in Preventing the Recurrence of Focal 
Segmental Glomerulosclerosis in de novo Kidney Transplant Recipients
ISN/Protocol 7163-CL-3201
Version 3.1
Incorporating Nonsubstantial Amendment 2
02 February 2018
I have read all pages of this clinical study protocol for which Astellas is the Sponsor. I agree to 
conduct the study as outlined in the protocol and to comply with all the terms and conditions set out 
therein. I confirm that I will conduct the study in accordance with ICH GCP guidelines and applicable 
local regulations. I will also ensure that sub-Investigator(s) and other relevant members of my staff 
have access to copies of this protocol and the ICH GCP guidelines to enable them to work in 
accordance with the provisions of these documents.
Principal Investigator:
Signature:
<Insert name and qualifications of the Investigator>
Printed Name:
Date (DD Mmm YYYY)
Address:




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III.
LIST OF ABBREVIATIONS AND DEFINITION OF KEY TERMS
Abbreviations
Description of abbreviations
ABO
Blood group system (A, AB, B, O)
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (SGPT)
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
APC
Antigen-presenting cell
APGD
Astellas Pharma Global Development, Inc.
AST
Aspartate aminotransferase (SGOT)
AUC
Area under the plasma concentration–time curve
AUCinf
Area under the concentration-time curve from time 0 to infinity
AUC336
Area under the concentration-time curve at 336 hours
AUC0-168h
Area under the concentration-time curve from baseline to 168 hours
AU 0-336h
Area under the concentration-time curve from baseline to 336 hours
AUST
Astellas US Technologies, Inc.
BKV
BK virus
BKVAN
BK virus associate nephropathy
BPAR
Biopsy-proven acute rejection
BUN
Blood urea nitrogen
CD
Cluster of differentiation 
CD40L
CD40 ligand (CD154)
CI
Confidence interval
CIT
Cold ischemia time
Cmax
Maximum concentration
CMV
Cytomegalovirus
CNI
Calcineurin inhibitor
CNS
Central nervous system
CRO
Contract research organization
cPRA
Calculated panel reactive antibody
DCD
Donation after cardiac death
DILI
Drug-induced liver injury
DMC
Data Monitoring Committee
EBV
Epstein-Barr virus
ECD
Extended Criteria Donor
eCRF
Electronic case report form
ECG
Electrocardiogram
eGFR
Estimated glomerular filtration rate
e/PRO
Electronic/Patient Reported Outcomes
EOT
End of Treatment
EQ-5D-5L
European quality of life – 5 dimensions – 5 levels


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Abbreviations
Description of abbreviations
ESRD
End stage renal disease
FcR
Fc receptor
FIH
First-in-human
FSGS
Focal segmental glomerulosclerosis
GC
Germinal centers
GCP
Good clinical practice
GFR
Glomerular filtration rate
GMP
Good manufacturing practice
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus 
HIPAA
Health Insurance Portability and Accountability Act
HIV
Human Immunodeficiency Virus
IC50
Half-maximal inhibitory concentration
ICF
Informed consent form
ICH 
International Conference on Harmonization 
IEC
Independent ethics committee
IgG
Immunoglobulin G
IL
Interleukin
INR
International normalized ratio
IRB
Institutional review board
IRT
Interactive response technology
IVIG
Intravenous immunoglobulin
KTQ
Kidney transplant questionnaire
LA-CRF
Liver abnormality case report form
LDH
Lactate dehydrogenase
LFT
Liver function test 
MCS
Mental component summary 
MDRD
Modification of Diet in Renal Disease
MFI
Mean fluorescence intensity
MMF
Mycophenolate mofetil
MST
Mean survival time
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NHP
Non-human primate
NOAEL
No-observed-adverse-effect level
PBMC
Peripheral blood mononuclear cell
PCR
Polymerase chain reaction
PCS
Physical component summary 
pFSGS
Primary focal segmental glomeruloscerosis
PGx
Pharmacogenetics
PKAS
Pharmacokinetic analysis set
PTLD
Post-transplant lymphoproliferative disorder


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Abbreviations
Description of abbreviations
rFSGS
Recurrent focal segmental glomerulosclerosis
rTAC
Reduced tacrolimus
SAE
Serious adverse event
SAF
Safety analysis set
sCD154
Soluble CD154
SF-36s
Short form 36-item health survey score version 2.0
SOC
Standard of care
SOP
Standard operating procedure
SPC
Summary of product characteristics
Tac
Tacrolimus
tmax
Time to attain Cmax
t1/2
Terminal elimination half-life
TB
Tuberculosis
TBL
Total bilirubin
TEAE
Treatment-emergent adverse event
TLF
Tables, listings and figures
TNF
Tumor necrosis factor
ULN
Upper limit of normal
VAS
Visual analogue scale
WFI
Water for injection


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Definition of Key Study Terms
Terms
Definition of terms
Assigned Treatment 
Regimen
Arm 1 - Standard of Care regimen (basiliximab induction, tacrolimus, steroids 
and mycophenolate mofetil [MMF]).
Arm 2 – Bleselumab regimen (basiliximab induction, tacrolimus, steroids and 
bleselumab).
In this study, when a subject permanently discontinues or replaces any 
treatment within the assigned regimen, he/she has reached end of treatment 
(EOT). See EOT term.
Baseline
Time when ‘baseline’ parameters are observed.
The last protocol-defined assessment prior to first dose of study drug in the 
assigned treatment regimen (days -21 to -1, prior to transplant) is considered 
the baseline measurement.
Biopsy-proven 
Acute Rejection
Acute rejection episode of which the diagnosis is supported by renal allograft 
histologic evaluation.
Clinically Treated 
Acute Rejection
Any acute rejection episode that is treated with supplemental 
immunosuppressive agents.
Cold Ischemia 
Time
Time between initiation of cold preservation to final unclamping in the 
recipient.
De novo
First line therapy after kidney transplantation. This differentiates the “de novo” 
transplant recipient from a stable transplant recipient that is converted from 
one regimen to another (conversion study).
End of Study (EOS)
End of study (EOS) for each subject has occurred when the final, protocol-
defined assessment has been completed. The last protocol-defined assessment 
is approximately 30 days after the last study drug dose.
If a subject permanently discontinues with the assigned treatment regimen 
AND discontinues participation in the study, he/she is considered to have 
reached EOS.
Electronic Patient-
Reported Outcomes
(ePRO)
An electronic patient-reported outcome (ePRO) is a subject-reported outcome 
that is collected by electronic methods.
End of Treatment 
(EOT)
Subjects that permanently discontinue or replace bleselumab, tacrolimus or 
MMF in the post-transplant period will be considered to have reached end of 
treatment (EOT) and are to continue with the protocol-defined visit schedule
(Table 1: Schedule of Assessments – Screening through 12 months Post-
transplant), for the collection of safety and clinical assessment information.
Enroll
The point in time when a subject signs the informed consent.
Hepatic enzymes
Also called Liver enzymes: Aspartate aminotransferase, (AST), alanine 
aminotransferase (ALT) and alkaline phosphatase (ALP).
Interim Analysis
Analysis comparing intervention groups at any time before the formal 
completion of the trial.
Intervention
The drug, device, therapy or process under investigation in a clinical trial,
which has an effect on outcome of interest in a study (e.g., health-related 
quality of life, efficacy and/or safety).


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Terms
Definition of terms
Liver Function Test
Includes aspartate aminotransferase, (AST), alanine aminotransferase (ALT) 
and/or alkaline phosphatase (ALP) and/or total bilirubin, and/or prothrombin 
time (PT/INR).
Post-transplant 
Period
Period of time starting on the day of transplant (day 0/post-skin closure)
through visit 20/month 12 when a subject is on the assigned treatment regimen 
and fully participating in the study.
Randomization
Action to allocate a subject to the treatment group or treatment cohort. 
Randomization is to occur after consent has been obtained and the subject has 
met entry criteria, but prior to giving initial dose of study drug in any assigned 
treatment regimen.
Screening
The process for identifying a candidate for the study and for evaluation of 
his/her eligibility to participate in the study.
Screen failure
A subject who signs the informed consent and undergoes the protocol-specific 
screening procedures, but does not fulfill the protocol inclusion and/or 
exclusion criteria. This subject should not be randomized.
Screening Period
The period of time after a subject is enrolled (signs the informed consent form) 
until randomization (assigned to a treatment regimen).
Study period
The study will consist of the following study periods: screening, transplant and 
post-transplant.
The entire Study Period includes the time from screening (visit 1/days -21 to 0) 
through post-transplant (visit 21/month 12/EOS). See EOS term.
Total ischemia time
Time from circulatory arrest in donor to final unclamping of the kidney in the 
recipient.
Warm Ischemia 
Time
Time between circulatory arrest in donor to initiation of cold preservation.


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IV.
SYNOPSIS
Date and Version # of Protocol Synopsis:
02 February 2018, Version 3.1
Sponsor:
Astellas Pharma Global Development, Inc. (APGD)
Protocol Number:
7163-CL-3201
Name of Study Drug:
Bleselumab (ASKP1240)
Phase of Development:
2a
Title of Study:
A Phase 2a, Randomized, Open-Label, Active Control, Multi-Center Study to Assess the Efficacy and 
Safety of Bleselumab in Preventing the Recurrence of Focal Segmental Glomerulosclerosis in de 
novo Kidney Transplant Recipients 
Planned Study Period:
From October 2016 to May 2020
Study Objective(s):
Primary Objective
To assess the efficacy of the bleselumab regimen (basiliximab induction, tacrolimus, steroids and 
bleselumab) compared with the Standard of Care (SOC) regimen (basiliximab induction, 
tacrolimus, steroids and mycophenolate mofetil [MMF]) in the prevention of the recurrence of 
focal segmental glomerulosclerosis (rFSGS) defined as nephrotic range proteinuria with
protein-creatinine ratio (≥3.0 g/g) through 3 months post-transplant. Death, graft loss or lost to 
follow-up will be imputed as rFSGS.
Secondary Objectives
To assess the incidence of nephrotic range proteinuria with protein-creatinine ratio (≥ 3.0 g/g)
through 6 and 12 months post-transplant. Death, graft loss or lost to follow-up will be imputed as 
rFSGS.
To assess the incidence of biopsy-proven acute rejection (BPAR, Banff Grade ≥ 1; local read) 
through 3, 6 and 12 months post-transplant.
To assess the incidence of efficacy failure defined as BPAR (Banff Grade ≥ 1; local read), death, 
graft loss or lost to follow-up through 12 months post-transplant.
To assess the incidence of biopsy-proven (blinded, central read) recurrence of FSGS (rFSGS)
through 3, 6 and 12 months post-transplant.

To assess the safety of the bleselumab regimen compared with the SOC regimen.
Exploratory Objectives
To assess graft and patient status through 12 months post-transplant.
To assess the Glomerular Filtration Rate (GFR, based on Modification of Diet in Renal Disease 
[MDRD] criteria) through 12 months post-transplant.
To assess rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio (≥3.0 g/g).
To assess the time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g).
To assess the time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g) or initiation of plasmapheresis.


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To assess the time to rFSGS defined as nephrotic-range proteinuria with protein-creatinine ratio 
(≥ 3 g/g), death, graft loss or lost to follow-up.
To assess the time to recurrence of biopsy-proven (blinded, central read) FSGS.
To assess the time to first BPAR (Banff Grade ≥ 1, local read).
To assess the urine protein-creatinine ratio through 6 and 12 months post-transplant.
To assess the urine albumin-creatinine ratio through 3, 6 and 12 months post-transplant.
To assess the change in auto-anti-cluster of differentiation (CD)40 antibody from baseline.
To assess the change in patient-reported outcomes from baseline (Short Form 36-Item Health 
Survey Score [SF-36s]), European Quality of Life-5 Dimensions-5 Levels [EQ-5D-5L], and 
Kidney Transplant Questionnaire [KTQ]).
Planned Total Number of Study Centers and Location(s):
Approximately 45 investigative centers in North America.
Study Population:
Male and female subjects 18 years of age or older who are de novo, living or deceased donor kidney 
recipients and have biopsy-proven primary focal segmental glomerulosclerosis (pFSGS)
Number of Subjects to be Enrolled/Randomized:
60 (30 subjects in each arm [Arm 1: SOC regimen (basiliximab induction, tacrolimus, steroids and 
MMF)] and [Arm 2: Bleselumab regimen (basiliximab induction, tacrolimus, steroids and
bleselumab)])
Study Design Overview:
This is a Phase 2a, randomized, open-label, active control, multi-center study to assess the efficacy 
and safety of bleselumab in preventing the rFSGS in de novo kidney transplant subjects.
The study will consist of the following periods:
Screening (days -21 to -1)
Transplant (day 0 [zero])
Post-transplant (day 0/post-skin closure through 12 months post-transplant)
Prior to any study-related assessments, the Informed Consent Form (ICF)/Authorization will be 
signed by the subject (visit 1). All subjects will enter into a screening period (days -21 to -1 prior to 
transplant), undergo a transplant (day 0), and are then to be followed for up to 12 months in the post-
transplant period (day 0/post-skin closure through 12 months post-transplant) for efficacy and safety.
Randomization can occur up to 4 days prior to or on day 0 (prior to transplant). Subjects will be 
assigned in a 1:1 ratio and stratified by previous kidney transplant status (no or yes) to open-label 
treatment of 1 of 2 arms as follows:
Arm 1 - SOC regimen (basiliximab induction, tacrolimus, steroids and MMF).
Arm 2 - Bleselumab regimen (basiliximab induction, tacrolimus, steroids and bleselumab).
All subjects will receive induction therapy with basiliximab (Simulect® [the first dose as a 20 mg 
bolus injection prior to transplantation or intra-operatively before revascularization, and the second a 
20 mg bolus injection on day 3 or 4 or 5 post-transplant]).
For subjects randomized to Arm 2, bleselumab 200 mg will be given intravenously over 30 minutes 
on day 0, to be initiated intra-operatively prior to revascularization of the allograft, and then at 
200 mg per infusion on days 7, 14, 28, 42, 56, 70 and 90/month 3, and once per month through 
month 12.




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Schedule of Assessments – Screening through 12 months Post-Transplant), for the collection of safety 
and clinical assessment information.
If a subject declines to be followed upon permanently discontinuing bleselumab, tacrolimus or MMF, 
the end of study (EOS, visit 21/month 12) procedures are to be completed within 30 days post-last 
dose.
Inclusion/Exclusion Criteria
Inclusion:
A subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written 
Informed Consent and privacy language as per national regulation (e.g., Health Insurance 
Portability and Accountability Authorization for US sites) must be obtained from the subject or 
legally authorized representative prior to any study-related procedures (including withdrawal of 
prohibited medication, if applicable).
2.
Male or female subject must be ≥ 18 years of age.
3.
Subject is a recipient of a de novo kidney from a living or deceased donor and has biopsy-proven, 
pFSGS as a cause of ESRD in their native kidneys (initial diagnosing biopsy report is required).
A subject who has biopsy-proven pFSGS as a cause of ESRD, and their most current graft 
failure(s) is due to biopsy-proven, recurrent FSGS, is eligible.
4.
Subject is anticipated to receive first oral dose of tacrolimus within 48 hours of transplant 
procedure.
5.
Female subject must either:
Be of non-child bearing potential:
Post-menopausal (defined as at least 1 year without any menses) prior to screening, or
Documented surgically sterile
Or, if of childbearing potential,
Agree not to try to become pregnant during the study and for 90 days post-last dose,
And have a negative serum pregnancy test at screening,
And, if heterosexually active, agree to consistently use two forms of highly-effective 
birth control* (at least one of which must be a barrier method) starting at screening, 
throughout the study and for 90 days post-last dose.
6.
Female subject must agree not to breastfeed starting at screening, throughout the study and for 
90 days post-last dose.
7.
Female subject must not donate ova starting at screening, throughout the study and for 90 days 
post-last dose.
8.
Male subject and their female spouse/partners who are of childbearing potential must be using 
highly effective form of contraception consisting of two forms of birth control* (at least one of 
which must be a barrier method) starting at screening, throughout the study and for 90 days post-
last dose.
9.
Male subject must not donate sperm starting at screening, throughout the study and for 90 days 
post-last dose.
10. Subject must be willing and able to comply with the study requirements including prohibited 
concomitant medication restrictions.
11. Subject agrees not to participate in another interventional study while on treatment.


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*Highly effective forms of birth control include:
Consistent and correct usage of established oral contraception
Injected or implant hormonal methods of contraception
Established intrauterine device (IUD) or intrauterine system (IUS)
Barrier methods of contraception: condom or occlusive cap (diaphragm ore cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository
Any male partner that has undergone effective surgical sterilization
Any female partner that has undergone effective surgical sterilization
Waivers to the inclusion criteria will NOT be allowed.
Exclusion:
A subject will be excluded from participation if any of the following apply:
1.
Subject has Induction therapy, other than study-assigned basiliximab, planned as part of initial 
immunosuppressive regimen.
2.
Subject has a diagnosis of secondary FSGS (familial, virus associated, medication, etc., protocol 
Appendix 12.5) or a defined genetic cause of FSGS.
3.
Subject has previously received any organ transplant including a kidney and the most current
graft failure(s) is not due to the recurrence of FSGS.
4.
Subject will receive a kidney as part of a multi-organ transplant. 
5.
Subject will receive a dual kidney transplant from a deceased donor. 
6.
Subject will receive a kidney with an anticipated cold ischemia time of > 30 hours.
7.
Subject will receive a kidney that meets BOTH Extended Criteria Donor (ECD) and Donation 
after Cardiac Death (DCD) criteria. (A kidney that meets either ECD OR DCD criteria may be 
eligible for inclusion.)
8.
Subject will receive a blood group system (A, AB, B, O, ABO) incompatible (including A2 into B 
or O) donor kidney.
9.
Recipient or donor is known to be seropositive for human immunodeficiency virus (HIV).
10. Subject has a current calculated panel reactive antibody (cPRA) level > 50%.
11. Subject has a current malignancy or a history of malignancy (within the past 5 years), except non-
metastatic basal or squamous cell carcinoma of the skin that has been treated successfully, or a 
renal cell carcinoma that has been treated successfully more than 2 years prior to transplantation.
12. Subject has significant liver disease, defined as having during the past 21 days consistently 
elevated aspartate aminotransferase (SGOT) (AST) and/or alanine aminotransferase (SGPT) 
(ALT) levels greater than 1.5 times the upper value of the normal range of the investigational site.
13. Subject is known to have a positive test for latent tuberculosis (TB) and has not previously 
received adequate anti-microbial therapy/or would require TB prophylaxis after transplant.
14. Subject has an uncontrolled concomitant infection or any other unstable medical condition that 
could interfere with the study objectives.
15. Subject is concurrently participating in another drug study or has received an investigational drug 
up to 30 days or 5 half-lives (depending on medication) prior to transplant.
16. Subject is currently receiving or has received up to 8 weeks prior to transplant an immunologic 


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biologic compound (i.e., tumor necrosis factor inhibitors, [e.g., etanercept, adalimumab], 
intravenous immunoglobulin). A subject who has previously received a kidney organ transplant
and is currently on an immunosuppression regimen that includes MMF, or any of its components, 
must discontinue MMF.
17. Subject has previously received bleselumab or participated in a clinical study with bleselumab.
18. Subject has a known hypersensitivity to tacrolimus, MMF, basiliximab, corticosteroids, or any of 
their components.
19. Subject has any form of substance abuse, psychiatric disorder, or a condition that in the opinion of 
the Investigator could invalidate communication with the Investigator.
20. Subject has a clinically significant abnormal electrocardiogram (ECG) at screening.
21. Subject is unlikely to comply with the visits scheduled in the protocol, in the opinion of the 
Investigator.
Waivers to the exclusion criteria will NOT be allowed.
Investigational Product(s):
Bleselumab (ASKP1240) – Immunosuppression
Bleselumab will be provided by the Sponsor for up to 12 months post-transplant and the subject is 
then to be placed on a SOC regimen of the Investigator’s choice.
Dose(s)
Up to a total of 17 doses, at 200 mg per dose
Mode of Administration
Intravenous infusion
Duration
Up through 12 months (day 0 [initiated intra-operatively, prior to revascularization of the allograft 
and may continue during reperfusion]; and, days 7, 14, 28, 42, 56, 70 and 90/month 3, and once per 
month through month 12 as a single, 30-minute infusion).
Comparative Drug(s):
Mycofenolate Mofetil (MMF) – Immunosuppression
The oral formulations (capsules and/or tablets) will be provided by the Sponsor through 12 months 
post-transplant and is then to be sourced by the site and provided via commercial supply.
MMF for intravenous administration is allowed but will not be supplied by the Sponsor.
A switch from MMF to mycophenolic acid (Myfortic®) will be allowed for medical reasons but will 
not be supplied by the Sponsor.
Dose(s)
Initial dose at 1 g bid may be given up to 12 hours preoperatively, or before revascularization.
Post-initial dose, adjustments in the post-transplant period are allowed.
Mode of Administration
Oral or intravenously
Duration
Post-initial dose, daily through 12 months post-transplant.




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Concomitant Medication Restrictions or Requirements:
Cytomegalovirus Prophylaxis
All subjects (with the exception of those in whom both the donor and recipient are serologically 
negative [D-/R-] for Cytomegalovirus (CMV) must receive prophylaxis with valganciclovir that will 
be dosed consistent with the package insert. Duration of therapy should be approximately 200 days in 
D+/R- combinations, and approximately 100 days in the remaining subjects.
For leukopenia, the recommended approach is to adjust doses of other drugs that may be associated 
with leukopenia prior to making changes in the valganciclovir dose.
Pneumocystis jiroveci Pneumonia Prophylaxis
Pneumocystis jiroveci pneumonia prophylaxis must be administered to all study participants 
according to the standard institutional protocol and applied uniformly to all enrolled subjects 
regardless of treatment group. If there is no institutional protocol, the investigator must decide on 
appropriate Pneumocystis jiroveci pneumonia prophylaxis.
Fungal Prophylaxis
A standard antifungal prophylactic regimen per institutional protocol must be given uniformly to all 
enrolled subjects regardless of treatment group. If there is no institutional protocol, the Investigator 
must decide on appropriate fungal prophylaxis.
Bacterial Prophylaxis
Peri-operative bacterial prophylaxis must be given per institutional protocol and should be given 
uniformly to all enrolled subjects regardless of treatment group. If there is no institutional protocol, 
the Investigator must decide on appropriate bacterial prophylaxis.
Duration of Treatment:
Up to 12 months.
Bleselumab will be provided for up to 12 months, after which subjects are to be placed on a SOC
regimen of the Investigator’s choice.
Formal Stopping Rules:
Subject Level
Subjects must discontinue bleselumab per below, but are allowed to continue on the protocol-defined
visit schedule for the collection of safety and clinical assessment information:
Subjects whose liver function tests meet one of the following criteria, verified by 2 consecutive 
measurements, and in the absence of other etiologies (e.g., biliary stenosis or obstruction, viral 
hepatitis other than CMV, etc.):
ALT or AST > 8 x upper limit of normal (ULN)
ALT or AST > 5 x ULN for more than 2 weeks
ALT or AST > 3 x ULN and (total bilirubin [TBL] > 2 x ULN or international normalized 
ratio [INR] > 1.5 x ULN)
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)

BK nephropathy confirmed by renal biopsy (Section 5.5.1.1.5)

CMV End Organ Disease (Appendix 12.6)

Subjects who develop severe bone marrow suppression as defined by the following in the absence 
of other etiologies (e.g., bleeding, other established causes of neutropenia) and have been verified 
by two (2) consecutive results within 14 days of the first detection that occur after Day 28 
post-transplant:


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Anemia: Hemoglobin < 6.5 g/dL graded National Cancer Institute Common Terminology 
Criteria for Adverse Events criteria (NCI-CTCAE) Grade 4 and/or
Agranulocytosis: Absolute Neutrophil Count (ANC) < 100 cells/mm3 graded NCI-CTCAE 
Grade 4
Subjects who require plasmapheresis for any reason post-initial bleselumab treatment
In the subjects’ best interest per Investigator discretion
Endpoints for Evaluation:
Primary:

Recurrence of FSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g) through 3 months post-transplant. Death, graft loss or lost to follow-up will be 
imputed as rFSGS.
Secondary:

Recurrence of FSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g) through 6 and 12 months post-transplant. Death, graft loss or lost to follow-up will be 
imputed as rFSGS.

Biopsy-proven acute rejection (BPAR, Banff Grade ≥ 1; local read) through 3, 6 and 12 months 
post-transplant.

Efficacy failure defined as BPAR (Banff Grade ≥ 1; local read), death, graft loss or lost to 
follow-up through 12 months post-transplant.

Biopsy-proven (blinded, central read) rFSGS through 3, 6 and 12 months post-transplant.
Exploratory:
Efficacy

Graft and patient status through 12 months post-transplant.

GFR, based on MDRD criteria through 12 months post-transplant.

Recurrence of FSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g).

Time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio (≥ 3.0 g/g).

Time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio (≥ 3.0 g/g) or 
initiation of plasmapheresis.

Time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio (≥ 3.0 g/g), 
death, graft loss or lost to follow-up.

Time to recurrence of biopsy-proven (blinded, central read) FSGS.

Time to first BPAR (Banff Grade ≥ 1, local read).

Urine protein-creatinine ratio through 6 and 12 months post-transplant.

Urine albumin-creatinine ratio through 3, 6 and 12 months post-transplant.

Change in auto-anti-CD40 antibodies from baseline.

Change in patient-reported outcomes from baseline (SF-36s, EQ-5D-5L, and KTQ).
Safety

Adverse events (AEs) graded by National Cancer Institute Common Terminology Criteria for 
Adverse Events criteria (NCI CTCAE).

Vital sign measurements.

Clinical laboratory tests.

Bleselumab pharmacokinetics (including anti-bleselumab and bleselumab bi-specific antibodies).

Viral serology (hepatitis B virus [HBV], hepatitis C virus [HCV], CMV, BK polyomavirus [BKV]
and EBV).

Viral load testing (CMV, BKV and EBV).


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Statistical Methods
Sample size justification
The primary variable is rFSGS defined by nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g) through 3 months post-transplant. Death, graft loss or lost to follow-up will be imputed as 
rFSGS.
This proof-of-concept study will provide an estimate of the effect size for the difference in the rFSGS 
between the standard of care and the experimental group and provide estimates of the recurrence rates 
for each treatment group. The estimate of the effect size will be needed to plan a future study.
The following table provides a subset of estimates and the 95% confidence interval for the FSGS 
recurrence rate with 30 subjects per treatment group. The width of these confidence intervals varies 
between 17 and 36% indicating the limit of the precision for the estimate.
Proportion (%)
95% Confidence Interval with 30 Subjects (%)
3.3 (1/30)
0.1 - 17.2*
16.7 (5/30)
3.4 - 30.0
33.3 (10/30)
16.4 - 50.2
50.0 (15/30)
32.1 - 67.9
66.7 (20/30)
49.8 - 83.6
83.3 (25/30)
70.0 - 96.6
96.7 (29/30)
82.8 - 99.9*
*Exact binomial confidence interval using Clopper-Pearson (exact method based on the Beta 
distribution); for all others the normal approximation was used to calculate the intervals.
It has been estimated from the literature that the expected FSGS recurrence rate for the SOC group is 
between 30 and 50% following a first kidney transplant and up to 80% for re-transplant with most 
occurring by three months post-transplant. In the previous study with these same treatments in kidney 
transplant patients, there were 3 of approximately 50 patients who experienced death, graft loss, or 
loss to follow-up in each of the two planned treatment arms. Thus, imputing death, graft loss or lost-
to-follow-up as rFSGS is not expected to have a sizeable and differential impact on the rFSGS 
estimates. Literature estimates of FSGS recurrence were used to examine the precision provided with 
30 subjects per treatment group.
Bleselumab was assumed to decrease the recurrence rate in the experimental arm by 20 to 60% 
relative to SOC. The following table provides the difference in the observed rates and the associated 
2-sided 95% confidence interval with 30 subjects per group. The width of the confidence interval for 
the difference between the two treatment groups ranges between 47 and 57%. The width of the 
confidence interval provides the precision of the estimate for the difference in recurrence between the 
two groups.


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Bleselumab Rate
SOC Rate
50%
(15/30)
40%
(12/30)
30%
(9/30)
60% Reduction from SOC
0.20
(6/30)
0.167
(5/30)
0.133
(4/30)
Difference and 95% CI
(2-sided)
0.30
0.038 to 0.562
0.233
-0.021 to 0.487
0.167
-0.07 to 0.404
50% Reduction from SOC
0.267
(8/30)
0.20
(6/30)
0.167
(5/30)
Difference and 95% CI
(2-sided)
0.233
-0.039 to 0.505
0.20
-0.06 to 0.46
0.133
-0.112 to 0.355
40% Reduction from SOC
0.30
(9/30)
0.267
(8/30)
0.20
(6/30)
Difference and 95% CI
(2-sided)
0.20
-0.068 to 0.434
0.133
-0.137 to 0.40
0.10
-0.151 to 0.351
30% Reduction from SOC
0.367
(11/30)
0.30
(9/30)
0.23
(7/30)
Difference and 95% CI
(2-sided)
0.133
-0.149 to 0.415
0.10
-0.173 to 0.373
0.07
-0.186 to 0.326
20% Reduction from SOC
0.40
(12/30)
0.333
(10/30)
0.267
(8/30)
Difference and 95% CI
(2-sided)
0.10
-0.184 to 0.384
0.067
-0.21 to 0.344
0.033
-0.228 to 0.294
General Considerations
For an analysis of variance (ANOVA) or analysis of covariance (ANCOVA), previous kidney 
transplantation (no, yes) will be included as a factor in the model if there is a sufficient number of 
patients with more than one kidney transplantation. Endpoints analyzed with Fisher’s Exact test may 
be analyzed with a CMH test stratifying by previous kidney transplant status (no or yes) if there is a 
sufficient number of patients with more than 1 kidney transplantation. For time-to-event endpoints, 
Cox regression will be used comparing the 2 treatment groups and will include previous kidney 
transplantation (no, yes) in the model provided there are sufficient multi-transplant patients.
Efficacy
The percentage of subjects who have a rFSGS, defined by nephrotic range proteinuria or death, graft 
loss or loss to follow-up, by 3, 6 and 12 months will be computed along with a 95% CI for each 
estimate and the treatment difference (Arm 2 – Arm 1). Similar summaries will be created for the 
biopsy-proven rFSGS by a blinded, central read at 3, 6 and 12 months. Treatment differences (Arm 2 
– Arm 1) in BPAR incidence (T- or B-cell) through 3, 6 and 12 months will be calculated. A 2-sided 
95% confidence interval will be constructed for the treatment differences
Efficacy failure, defined as BPAR, death, graft loss or lost to follow-up will be analyzed as described 
for rFSGS.
The mean estimated glomerular filtration rate (eGFR) value based on MDRD criterion at 12 months 
will be compared between the control and experimental groups using an analysis of covariance 
(ANCOVA) with treatment as a factor and the week 4 value as a covariate.


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Graft survival is defined as an absence of all of the following: subject death, re-transplant, 
nephrectomy, or return to permanent dialysis (> 30 days). Incidence of graft survival will be provided 
and compared between the treatment groups using Fisher’s exact test. A 95% CI will be constructed 
for the treatment difference (Arm 2 – Arm 1) in incidence of graft survival at one year. If there are 
subjects with an unknown outcome, they will be treated as having a graft loss in one analysis and 
excluded in the second analysis. Patient survival will be analyzed in a like manner.
Kaplan-Meier estimates of FSGS recurrence, biopsy-confirmed FSGS, BPAR, efficacy failure rate, 
graft survival, and patient survival at one year will be calculated. The treatment difference will be 
computed as Arm 2 - Arm 1. A positive difference indicates a higher failure rate in the test group and 
a negative difference indicates a higher failure rate in the standard of care arm. A 2-sided 95% 
confidence interval will be constructed for the treatment difference from the normal approximation 
using Greenwood’s formula. A Wilcoxon test will be used to compare survival curves. In kidney 
transplant studies efficacy failure tends to occur early and the Wilcoxon test is a more powerful test in 
detecting differences early in time. Recurrence of FSGS generally occurs early post-transplant.
Subjects with unknown outcome, if they exist, will be treated as having the event in one analysis and 
will be counted as censored in a second analysis.
There will be no adjustment for multiplicity in this proof-of-concept study.
The urine protein-creatinine ratio, albumin-creatinine ratio will be summarized over time. The 
urine-protein creatinine ratio and the urine albumin-creatinine ratio collected up to week 4 will be 
analyzed with an ANCOVA model with treatment group as a factor and the post-transplant value as 
the covariate. The urine-protein creatinine ratio and the urine albumin-creatinine ratio after week 4 
will be analyzed with an ANCOVA with treatment as a factor and the week 4 value as a covariate.
The eGFR at 3, 6 and 12 months, the change from week 4 will be analyzed using an ANCOVA with 
the week 4 value at the covariate.
Auto-anti-CD40 antibodies (present or absent), antibody level and change from baseline will be 
summarized by treatment group.
For the EuroQol-5 dimensions-5 levels (EQ-5D-5L), the percentage of patients in each treatment arm 
who report problems (dichotomized to no, yes) for each of the 5 dimensions (mobility, self-care, usual 
activities, pain/discomfort and anxiety/depression) will be tabulated and graphically displayed. For 
each dimension, the percentage of patients who respond with no issue, slight issue, moderate issue, 
severe issue, and unable to function will be provided. The percentage of patients who report ‘yes’ for 
each of the EQ-5D-5L dimensions will be compared between the treatment groups at each visit using 
Fisher’s Exact test. The change from baseline for the Visual Analogue Scale (VAS) Score, part of the 
EQ-5D-5L, will be analyzed by using an ANCOVA with treatment group as a fixed factor and the 
baseline VAS score as a covariate.
The change from baseline in the Kidney Transplant Questionnaire (KTQ) score for each of the 
5 domains (physical symptoms, fatigue, uncertainty/fear, appearance, and emotional) at 3 and 
12 months will be analyzed using an ANCOVA with treatment as a factor and baseline as a covariate.
QualityMetric will calculate SF-36v2 scale scores, and the Physical Component Summary (PCS) and 
Mental Component Summary (MCS). By-treatment group summaries of the 8t domains and the PCS 
and MCS will be provided at each visit using descriptive statistics (n, mean, median, sd, min and 
max). Between-group comparisons of the scores will be completed with an ANOVA with treatment 
group as the factor.
Pharmacokinetics


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Descriptive statistics will be used to summarize bleselumab concentrations for Arm 2 at the trough 
and peak concentrations over the course of the study (ng/mL) by scheduled collection visit. Bi-
specific bleselumab antibodies and anti-bleselumab antibodies (present or absent) will be listed and 
summarized using descriptive statistics.
Safety
For each treatment arm, the frequencies and percentages will be displayed for the following treatment 
emergent adverse events (coded using MedDRA) by system organ class and preferred term:

Overall

Serious

Related (considered by the Investigator to be possibly or probably related) to study drug

Leading to the permanent discontinuation of study drug
Descriptive statistics for each laboratory test (e.g., hematology, biochemistry, urinalysis) and its 
change from baseline (month 1 for renal tests) and vital signs will be tabulated by treatment group and 
scheduled time point.
Presence of CMV, EBV and BKV and the viral load data for each, if present, will be summarized by 
scheduled visit and treatment group.
Interim Analysis
An interim analysis is planned once all subjects have completed the 3 months post-transplant follow-
up to assess treatment differences for rFSGS. The purpose of this analysis is to support strategic 
decision making for future project development and study design. The result will aid in determining if 
this compound will continue development for rFSGS.




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Table 1
Schedule of Assessments  – Screening Through 12 Months Post-Transplant
Period
Screening
Transplant
Post-Transplant
Visit
11
21
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21/EOS2
Day
-21 to -1
03
1
4
7
14
28
42
56
70
90
Week
-3 to 1
1
12
16
20
24
28
32
36
40
44
48
52
Month
1
1
1
1
1
1
2
2
3
3
4
5
6
7
8
9
10
11
12
12
Visit Window (days)
none
none
0
-1
±1
±1
±2
±2
±2
±2
±2
±3
±3
±3
±7
±7
±7
±7
±7
±7
±7
ASSESSMENTS
Informed consent
X
Demographics
X
Physical examination 4
X
X
X
Height and weight 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (body temperature, BP and HR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical/surgical history 4, 6
X
Medication history and concomitant medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-ray
X
X
X
Electrocardiogram
X
X
X
Histocompatibility and crossmatch
X
Pregnancy test 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests (biochemistry and urinalysis) 8
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests – hematology panel and 
hepatic profile 8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Transplant information 9
X
Verify eligibility criteria
X
Randomization 10
X
Bleselumab dosing 11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sampling for pharmacokinetics 12
X
X
X
X
X
X
X
X
X
X
X
Table continued on next page


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Period
Screening
Transplant
Post-Transplant
Visit
11
21
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21/EOS2
Day
-21 to -1
03
1
4
7
14
28
42
56
70
90
Week
-3 to 1
1
12
16
20
24
28
32
36
40
44
48
52
Month
1
1
1
1
1
1
2
2
3
3
4
5
6
7
8
9
10
11
12
12
Visit Window (days)
none
none
0
-1
±1
±1
±2
±2
±2
±2
±2
±3
±3
±3
±7
±7
±7
±7
±7
±7
±7
ASSESSMENTS
Anti-bleselumab antibody sampling 12
X
X
X
X
X
X
X
Bleselumab bi-specific antibody sampling 12
X
X
X
X
X
Auto-Anti-CD40 antibody sampling 12
X
X
X
X
X
X
X
X
X
X
Urine protein-creatinine 13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine albumin-creatinine 13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tacrolimus level 14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sampling for pharmacogenomics 15
X
Clinical assessment 16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36s 17
X
X
X
X
X
EQ-5D-5L 18
X
X
X
KTQ 19
X
X
X
X
X
Adverse events 20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biopsy 21
X
EOT = End of Treatment - If bleselumab is permanently discontinued, subjects in Arm 2 can continue to receive study-supplied Prograf through 12 months post-transplant as 
previously assigned; however, any alternate therapy(ies) will not be provided by the Sponsor. Furthermore, subjects that permanently discontinue or replace bleselumab, tacrolimus, or 
MMF in the post-transplant period will be considered to have reached EOT and are to continue with the protocol-defined visit schedule for the collection of safety and clinical 
assessment information. If a subject declines to be followed upon permanently discontinuing bleselumab, tacrolimus or MMF, the end of study (EOS, visit 21/month 12) procedures are 
to be completed within 30 days post-last dose.
EOS = End of Study (visit 21/month 12). EOS for each subject has occurred when the final, protocol-defined assessment has been completed. The last protocol defined assessment is 
approximately 30 days after the last study drug dose. If a subject discontinues with the assigned treatment regimen AND discontinues participation (withdraws consent) in the study, 
he/she is considered to have reached EOS.
Footnotes continued on next page


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ABO: absent bed occupant blood group system (A, AB, B and O); AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; 
BKV: BK polyomavirus; BP: blood pressure; BUN: blood urea nitrogen; CD40: cluster of differentiation 40; CMV: cytomegalovirus; CPK: creatine phosphokinase; EBV: Epstein-
Barr virus; EQ-5D-5L: European Quality of Life-5 Dimensions–5 Levels; HBcAb IgM (or Anti-HBc IgM): hepatitis B core antibody IgM; HbsAg: hepatitis B surface antigen; HBV: 
hepatitis B virus; HCV: hepatitis C virus; HDL: high-density lipoprotein; INR: international normalized ratio; 
KTQ: Kidney Transplant Questionnaire; LDH: lactate dehydrogenase; LDL: low-density lipoprotein; HDL: high density lipoprotein; MMF: mycophenolate mofetil; PR: pulse rate; 
PRA: panel reactive antibodies; rFSGS: recurrence of focal segmental glomerulosclerosis; RBC: red blood cells; SAE: serious adverse event; SF-36s: Short Form 36-Item Health 
Survey Score; WBC: white blood cells.
1.
Visits 1 (screening [days -21 to -1]) and 2 (day 0/transplant) can be combined as one.
2.
Also unscheduled visit. Unscheduled visit assessments to be conducted are at the discretion of the Investigator. Urine protein-creatinine and urine albumin-creatinine must be 
collected at all unscheduled visits.
3.
The day of Transplant (day 0) is day/date of transplant completion (skin closure). For transplants that span midnight, assessments may be conducted on day -1.
4.
The screening physical examination includes significant, ongoing medical conditions. Any changes between screening and Randomization are to be captured in the 
Medical/Surgical History.
5.
Height will be measured one time at screening ONLY. Weight will be collected AT ALL VISITS.
6.
Medical/Surgical history includes: diagnosis for renal failure, duration and severity of renal disease at Randomization, and Screening medications (30 days prior to Transplant).
7.
Serum pregnancy test during the screening/transplant period is to be collected on admission to the hospital or within 7 days prior to transplant. All subsequent urine pregnancy tests 
are to be collected prior to continued treatment.
8.
Laboratory tests:

ABO blood-typing at screening ONLY.

Coagulation/thrombotic pathway (prothrombin time, activated partial thromboplastin time, INR).

Lipid profile (total cholesterol [including LDL, HDL and triglycerides]).

Hematology includes: hemoglobin, hematocrit, RBC, WBC with differential and bands (where available), and platelet count. Biochemistry includes: phosphorous, total 
protein, serum creatinine, BUN, albumin, CPK, LDH, amylase, electrolytes (sodium, potassium, calcium, magnesium, bicarbonate, chloride), and fasting glucose.

The Hematology panel and Hepatic profile (total bilirubin, direct bilirubin, AST, ALT and ALP) are to be collected at EVERY visit.

For subjects not making urine at screening, urinalysis for BKV will not be required.

Recipient viral serologies (i.e., antibodies [e.g., HBV, HCV, CMV and EBV]) performed > 1 year prior to transplant are to be repeated within the screening period (up to 
21 days prior to transplant). Results do not need to be available for randomization. Post-screening testing is to be conducted at day 90/month 3 and month 12/EOS.

If HBsAg is positive, HBcAb IgM and envelope (HBe) antigens are to be analyzed. If the subject has previously been tested for antibodies to HBsAg and the results are 
positive, then HBsAg testing does not need to be repeated at screening.

If HCV is positive, quantitative HCV ribonucleic acid is to be analyzed. If the screening results indicate the presence of antibodies, no further testing is required during 
the study. If the screening results are negative, testing needs to be repeated at day 90/month 3 and month 12/EOS.

Recipient viral load testing (CMV, BKV [serum and urine] and EBV) is to be conducted at screening, days 14, 28, 56 and 90/month 3, and months 4, 5, 6 and 12/EOS, 
ONLY if recipient viral serologies were positive at any time.
Footnotes continued on next page


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9.
Transplant information to be collected includes: donor demographics (age, sex, race), donor viral serology (HBV, HCV, CMVand EBV, if available), type of transplant (living 
related, living non-related, or deceased donor), total ischemia time, length of surgery, and most recent PRA results prior to transplant. A copy of the donor kidney biopsy report 
is to be collected where available.
10. Randomization will occur once subject has met ALL entry criteria and prior to initial dose of study drug. Randomization should occur on day 0, or the day prior to skin closure, 
but not more than 4 days prior to transplant start. Randomization will be stratified by previous kidney transplant status (no or yes).
11. Bleselumab dosing is to be initiated on day 0 (intravenous intra-operatively and prior to revascularization of the allograft) and may continue during reperfusion; days 7, 14, 28, 
42, 56, 70 and 90/month 3, and once per month through month 12/EOS as a single, 30-minute infusion.
12. SUBJECTS IN ARMS 1 AND 2

Auto-anti-CD40 antibody samples are to be collected at screening, and prior to each infusion at baseline (day 0), visit days 7, 14, 28, 56, 90/month 3, and months 6, 9 and 
12/EOS.
SUBJECTS IN ARM 2 ONLY

Pharmacokinetic (bleselumab blood concentration) samples are to be collected within 30 minutes or less pre-initial, and post-initial, intraoperative, bleselumab infusion at 
baseline (day 0). Two single, pharmacokinetic samples are to be collected at each subsequent 30 minute intravenous infusion: one within 30 minutes or less prior to the 
infusion (trough concentration), and the other at the end of the infusion (peak concentration) up through visit day 28. After that only trough concentrations (within 
30 minutes or less pre-infusion) are to be collected up through day 90/month 3, and months 6, 9 and 12/EOS visits.

Anti-bleselumab antibody samples are to be collected prior to each infusion at baseline (day 0), visit days 14, 28, 90/month 3, and months 6, 9, and 12/EOS.

Bleselumab bi-specific antibody samples are to be collected prior to each infusion at baseline (day 0), visit day 90/month 3, and months 6, 9, and 12/EOS.
13. Urine collection via a spot urine is to occur within 72 hours prior to transplant.
14. Whole blood trough samples are to be drawn 11 - 13 hours post-initial tacrolimus dose and immediately prior to all subsequent doses.
15. Sample to be collected one time, preferably prior to first dose on day 0; however, can be collected any time during the study.
16. Clinical assessment is to include: BPAR, clinically-treated acute rejection episodes, graft and patient survival, and rFSGS.
17. SF-36s, version 2.0. Subjects are to complete the questionnaire at screening, days 14 and 90/month 3, and months 6 and 12/EOS. If a subject is not able to provide an answer to 
the question(s), it is not a requirement to complete the rest of the ePRO assessment(s) at the respective visit.
18. EQ-5D-5L. The baseline EQ-5D-5L is to be completed by the subject at screening, day 90/month 3, and month 12/EOS. If a subject is not able to provide an answer to the 
question(s), it is not a requirement to complete the rest of the ePRO assessment(s) at the respective visit.
19. KTQ subjects are to complete the KTQ at screening, days 14 and 90/ month 3, and months 6 and 12/EOS. If a subject is not able to provide an answer to the question(s), it is not 
a requirement to complete the rest of the ePRO assessment(s) at the respective visit.
20. All AEs will be recorded from the time of consent through 30 days post-last dose. The transplantation that occurs on day 0 is not considered an AE or an SAE. Planned surgical 
procedures such as removal of venous catheter or peritoneal catheter, post-transplant are not considered an AE or an SAE.
21. All subjects who have not had a biopsy with a diagnosis of rFSGS by 3 months post- transplant will have a protocol-defined biopsy at the day 90/month 3 visit. There are no 
other protocol-required biopsies. Biopsies other than the protocol-indicated one at day 90/month 3 will be considered ‘for cause’ only. All images for electron microscopy (EM) 
and slides for light microscopy (LM) utilized for local pathological review for evaluation of possible BPAR and/or rFSGS are to be forwarded for a blinded, central review by an 
independent pathologist to assess (via EM and LM) rFSGS.


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1
INTRODUCTION
Focal segmental glomerulosclerosis (FSGS) is an important cause of glomerular disease in 
children and adults where approximately 40 to 60% of subjects will progress to ESRD in 10 to 
20 years [Cravedi et al, 2013]. In the US, primary focal segmental glomerulosclerosis (pFSGS)
is the leading glomerular disease in dialysis subjects. In pFSGS subjects who receive kidney 
transplants, the rate of developing recurrent focal segmental glomerulosclerosis (rFSGS) 
ranges from 6 to 55% [Trachtman et al, 2015] and patients with rFSGS who are re-transplanted
experience disease recurrence with a higher frequency [Delville, et al, 2014]. With no 
approved pharmacologic therapy and limited effectiveness with other treatment options such as 
plasmapheresis, many subjects with rFSGS suffer the consequences of the recurrence within 
3 months in the form of nephrotic syndrome and its sequelae [Canaud et al, 2010].
1.1
Background
Although the pathogenesis of FSGS is not fully understood, cluster of differentiation (CD)40 is 
reported to overexpress on podocytes from rFSGS subjects [Delville et al, 2014]. In addition,
anti-CD40 autoantibodies are present in the serum of rFSGS subjects; and pre-transplant
elevation of anti-CD40 antibody is reported to correlate with the risk of rFSGS post-transplant.
Bleselumab, a fully human immunoglobulin (IgG)4 anti-CD40 antagonistic monoclonal 
antibody, may block the interaction of the anti-CD40 autoantibodies with CD40 expressed on 
podocytes, thereby reducing antibody-mediated cytotoxicity. Alternatively, in an adriamycin-
induced FSGS animal model, an increase in CD40 expression was observed in the podocytes, 
and renal injury was reduced by the administration of the murine anti-CD40 ligand monoclonal 
antibody MR1; the authors suggest that MR1 might have inhibited the interaction of CD40
ligand (CD154, CD40L) expressing inflammatory cells with CD40 present on the podocytes
thereby reducing renal damage [Kairaitis et al, 2003]. Whichever mechanism is responsible for 
renal injury in FSGS, bleselumab could have a therapeutic effect by either preventing the
binding of CD40 autoantibodies to the podocytes or by blocking the interaction of CD40L
expressing inflammatory cells with the podocytes.
1.2
Non-clinical and Clinical Data
1.2.1
Mechanism of Action
Bleselumab is a fully human anti-CD40 monoclonal antibody (IgG4) antagonist that inhibits 
both humoral (immunoglobulin production) and cellular immune responses by blocking the 
CD40/CD154 interaction between T cells, B cells, and antigen-presenting cells.
Bleselumab inhibits peripheral blood mononuclear cell (PBMC) proliferation, up-regulation 
of B cell activation marker, and dendritic cell cytokine production (interleukin [IL]-12 and 
tumor necrosis factor [TNF]-alpha) induced by soluble CD154 (sCD154). Collectively, these 
results suggest that bleselumab will have an immunosuppressive effect.


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1.2.2
Summary of Nonclinical Pharmacology
An in vitro flow cytometry study confirmed that bleselumab binds to CD40 on human and
monkey B lymphocytes (Study 7163-PH-0001). Geometric mean half-maximal inhibitory
concentration (IC50) values for human and cynomolgus monkey B cells were 18.1 and
43.8 ng/mL, respectively.
Two pilot and one pivotal in vitro validation studies were performed to determine the effect of 
varying concentrations of bleselumab in human whole blood on CD40 surface antigen
occupancy (Studies 7163-PH-0002 [pilot], 7163-PH-0014 [pilot] and 7163-PH-0015 [pivotal]). 
All three studies showed that the level of cell surface CD40 antigen occupancy on human B 
cells (CD20+ cells) was concentration dependent. In the pivotal validation study, the mean 
IC50 was determined to be 22.2 ng/mL.
The results from in vitro studies with cynomolgus monkey B cells were very similar to those
seen with human B cells, suggesting that the cynomolgus monkey is the most appropriate
species for further investigation of bleselumab. The pharmacodynamics of bleselumab in the
monkey was related to the serum bleselumab concentration.
Bleselumbab monotherapy in a kidney transplantation model in cynomolgus monkeys showed
that the mean survival time (MST) for the minimum dose level (1 mg/kg twice weekly) during 
the induction phase of the study was 54.7 days compared to a MST of 6.0 days for the control 
group (Study 7163-PH-0005). These results together with the results from the delayed-type 


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hypersensitivity model (Study 7163-PH-0011) suggest that the minimum effective dose of 
bleselumab is 1 mg/kg. When bleselumab was used alone or in combination with other 
immunosuppressants in a cynomolgus monkey kidney transplantation study, bleselumab 
prolonged median survival time in a dose-dependent manner, and showed an additive effect 
when combined with tacrolimus (FK506; 1 mg/kg) or mycophenolate mofetil (MMF; 
15 mg/kg) plus steroid (Study 7163-PH-0004). In a kidney transplantation study in cynomolgus 
monkeys evaluating the relationship between pharmacokinetics and pharmacodynamics, 
bleselumab serum concentrations and antigen occupancy were correlated, with high antigen 
occupancy dependent on high serum bleselumab concentrations (Study 7163-PH-0017).
1.2.3
Summary of Toxicology
A single-dose intravenous toxicity study of bleselumab was conducted in cynomolgus monkeys 
(Study 7163-TX-0001). Seven animals per group were administered intravenous bleselumab at 
doses of 0 (saline or vehicle), 1, 10, and 100 mg/kg. There were no deaths or toxicologic 
findings related to bleselumab administration. Immunophenotypic and histopathologic changes 
related to the pharmacologic effect of bleselumab were noted. CD40+CD45+ cell counts 
decreased over time, most noticeably at 10 and 100 mg/kg. A decrease in CD3-CD20+ cells 
was noted in 1 male at 100 mg/kg. Atrophy of the germinal center in the spleen was noted with 
all doses. Atrophy of the germinal center in the mesenteric lymph node was observed at 10 and 
100 mg/kg, and occurred in the submandibular lymph node only at the 100 mg/kg dose level. 
No anti-bleselumab antibody was detected in any animal. 
A 4-week intermittent repeated dose toxicity study of bleselumab with a 4-week recovery 
period was conducted in the cynomolgus monkey (Study 7163-TX-0002). Bleselumab was 
evaluated in groups of 3 males and 3 female monkeys at dose levels of 0 (control), 1, 10 and 
100 mg/kg per week for 4 weeks. An additional 3 males and 3 females were added to each 
treatment group to assess the reversibility of findings during the recovery period. There were 
no deaths and no toxicological changes related to bleselumab administration with respect to 
clinical observations, body weight, food consumption, hematology, immunophenotyping, 
blood chemistry, urinalysis, organ weights, gross pathology, ophthalmology, electrocardiogram 
(ECG), blood gas analysis, respiration rate and body temperature [Investigator Brochure, 
2016]. No anti-bleselumab antibodies were detected in any animal at any time point.
Changes in histopathology and immunohistochemistry related to the pharmacological effect of 
bleselumab were noted at all dose levels of bleselumab. Histopathology findings included 
atrophy of the germinal center of the spleen, submandibular and mesenteric lymph nodes, and 
Peyer’s patches. Corresponding to these histopathologic findings, weak reaction to anti-CD20 
antibody was observed in the germinal center area of the spleen and lymph nodes in 
immunohistochemistry evaluations. These findings were almost completely reversed at the end 
of the 4-week recovery period in the 1 mg/kg treatment group and were partially reversed in 
the 10 mg/kg dose group. The 100 mg/kg dose group showed no attenuation in the findings at 
the end of the 4-week recovery period.


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A 13-week intermittent repeated dose toxicity study of bleselumab with a 13-week recovery 
period was conducted in the cynomolgus monkey (Study 7163-TX-0005). Bleselumab was 
administered intravenously once weekly for 4 weeks and once every 2 weeks, thereafter, from 
the 6th dosing, for a total of 9 dose administrations, at dose levels of 0 (control), 1, 10, and 
100 mg/kg to 3 male and 3 female cynomolgus monkeys per group in order to investigate its 
toxicity. Three males and three females were added to each group in order to assess the 
reversibility of any toxicity observed during the dosing period in a subsequent 13-week 
recovery period. The animals in the control group received bleselumab placebo. Systemic 
exposures to bleselumab and anti-bleselumab antibody production were also evaluated. Clinical 
signs, body weight, food consumption, body temperature, respiratory rate, blood pressure, 
electrocardiography, ophthalmology, urinalysis, hematology, immunophenotyping, blood 
chemistry, serum cytokine, gross pathology, organ weights, and histopathology were conducted. 
A progressive decline in erythrocyte count was noted in 1 female in the 100 mg/kg group from 
week 9 of dosing, and reticulocyte ratio also decreased. Erythrocyte count continued to decline 
and the animal was sacrificed in a moribund state on recovery day 47. Histopathology of the 
bone marrow showed only slight hematopoietic cell degeneration; however, electron 
microscopy showed presence of virus-like particles. It was hypothesized that the death of this 
female was due to an infectious process, possibly viral, secondary to the immunosuppressive 
activity of the test article.
The histopathology changes described below during or after the dosing period were considered 
to be results of a pharmacological effect. In the 1 mg/kg group, atrophy of the germinal center 
was observed in the spleen in 1 male and in the submandibular lymph nodes in 1 other male. In 
the 10 mg/kg group, atrophy of the germinal center was observed in the spleen, submandibular, 
and mesenteric lymph nodes in all males and females, and in the Peyer’s patches in 2 males 
and 2 females. In the 100 mg/kg group, atrophy of the germinal center was observed in the 
spleen, submandibular and/or mesenteric lymph nodes, and in the Peyer’s patches in all males 
and females. These histopathology changes were completely reversed by the end of the 
13 week recovery period.
Immunophenotypic changes were observed in both male and female monkeys administered 
bleselumab at the 10 or 100 mg/kg dose levels. At the 10 mg/kg dose level, CD3-CD20+ cell 
count decreased by more than 50% in 4 males and 1 female at weeks 9 and/or 13 of dosing. 
Two of the four male animals showed CD3-CD20+ cell counts that were below the lower limit 
of the predose level. At the 100 mg/kg dose level, CD3-CD20+ cell count decreased by more 
than 50% in 5 males and 2 females at Weeks 5, 9 and/or 13 of dosing. In addition, one male 
and three females had CD3-CD20+ cell counts that were below the lower limit of the predose 
level.
In toxicokinetic studies, Cmax showed a dose-proportional increase, but increases in AUC0-168h
and AUC0-336h tended to be greater than dose proportional at the higher dose levels. Cmax
increased gradually with weekly dosing until the fifth dosing, but then gradually decreased 
after changing the dose interval to bi-weekly administration and appeared to reach a steady 
state after the seventh dose. No sex difference was noted in the serum bleselumab profile. 


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At 1 mg/kg, anti-bleselumab antibody was detected in 1 male and 3 females, and these animals 
showed a decrease in bleselumab exposure.
The no-observed-adverse-effect level (NOAEL) was established (excluding the intended 
pharmacologic effect) for the 13-week repeated dose toxicity study was determined to be 
10 mg/kg.
A 52-week intermittent repeated dose toxicity study of bleselumab with a 13-week recovery 
period was conducted in the cynomolgus monkey (Study 7163-TX-0006). Bleselumab was 
administered intravenously once weekly for 4 weeks and once every 2 weeks, thereafter, from 
the 6th dosing, for a total of 29 dose administrations, at dose levels of 0 (control), 1, 10, 30, and 
100 mg/kg to 4 male and 4 female cynomolgus monkeys per group in order to investigate its 
toxicity. Two males and two females were added to each group in order to assess the 
reversibility of any toxicity observed during the dosing period in a subsequent 13-week 
recovery period. The animals in the control group received bleselumab placebo. Systemic 
exposures to bleselumab and anti-bleselumab antibody production were also evaluated. Clinical 
signs, body weight, food consumption, body temperature, respiratory rate, blood pressure, 
electrocardiography, ophthalmology, urinalysis, hematology, immunophenotyping, blood 
chemistry, serum cytokine, gross pathology, organ weights, and histopathology were conducted.
At the 100 mg/kg and the 30 mg/kg dose levels, 3 males (100 mg/kg) and 4 males (30 mg/kg)
were euthanized in a moribund state near the end of the dosing period or in the early stage of
the recovery period. Hematologic findings indicate that at least 4 of 6 male animals in the 
30 mg/kg group and 3 of 6 male animals in the 100 mg/kg group developed anemia as defined 
as a > 15% decrease in red blood cells (RBCs) compared to baseline. These findings became 
apparent on or after 39 weeks and eventually animals required termination for moribundity. 
Immunophenotypic changes were observed in both male and female monkeys administered 
bleselumab at the 10, 30, and 100 mg/kg dose levels. At the 10 mg/kg dose level, CD3-CD20+
cell count decreased by more than 50% in 4 of 6 males on both weeks 27 and 39 while 3 
females showed a 50% decrease in CD3-CD20+ cells on week 27 and 4 females at 39 weeks. At 
the 30 mg/kg dose level, 3 to 4 males and the same number of females showed 50% decreases 
in CD3-CD20+ cells on weeks 27, 39, and/or 53. Finally, at the 100 mg/kg dose level, CD3-
CD20+ cells declined by more than 50% in 3 to 4 males on weeks 9 through 53, while a similar 
decline was observed in 4 to 5 females on weeks 13 through 53.
The following changes were considered related to a pharmacological action of bleselumab:
decreased CD3-CD20+ cell count and CD40+CD45+ cell count in peripheral blood at 10 mg/kg 
and greater; homogeneous immunohistochemical reaction to anti-CD20 antibody in the follicles 
in the spleen and/or lymph nodes and disappearance of immunohistochemical reactivity to anti-
CD3 and anti-CD4 antibodies in the germinal center area of the spleen at 1 mg/kg and greater;
germinal center atrophy in the spleen and/or lymph node; basophilic change in the follicles in the 
spleen at 1 mg/kg and greater; and follicular hypertrophy in the spleen, lymph node and/or 
Peyer’s patches at 10 mg/kg and greater. After the 13-week recovery period, changes due to the 
pharmacological effects of bleselumab recovered. Some histopathological changes remained 
after the recovery period, but the extent of the changes was reduced.


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In toxicokinetic studies, Cmax and AUC0-168h increased dose-proportionally. After the fifth dosing,
Cmax tended to be greater and AUC0-168h was greater than after the first dosing. Except for some 
animals at 1 mg/kg, the Cmax, AUC0-168h, and AUC0-336h were constant from the fifth dose until 
the final (29th) dosing. No sex difference was noted in the serum bleselumab profile. bleselumab
non-binding cell ratio in B-cells and mean fluorescence intensity (MFI) of labeled-bleselumab-
binding B-cells decreased at 1 mg/kg group and greater. At 1 mg/kg, anti-bleselumab antibody 
was detected in 1 male and 3 females. These animals also showed decreases in bleselumab 
systemic exposure and in the bleselumab non-binding cell ratio and MFI.
The NOAEL was established (excluding the intended pharmacologic effect) for the 52-week 
repeated dose toxicity study was determined to be 1 mg/kg.
The range and type of genotoxicity studies routinely conducted for pharmaceuticals are not 
applicable to biotechnology-derived pharmaceuticals. There is no indication that bleselumab
would require a special approach to evaluate genotoxicity.
No carcinogenicity studies of bleselumab have been conducted.
A reproductive toxicity study of bleselumab (embryo-fetal development) in cynomolgus 
monkeys was performed (Study 7163-TX-0003). Bleselumab was administered intravenously 
once weekly over 6 weeks, to 12 pregnant cynomolgus monkeys per group at dose levels of 0, 1, 
10, and 100 mg/kg during the organogenesis period (on days 20, 27, 34, 41, 48, and 55 of 
gestation). No dam died in any group. No significant differences were noted in body weight or 
food consumption in any group. No significant differences were noted between groups in fetal 
sex, fetal or placental weight, external or placental measurement parameters, amniotic fluid 
volume, organ weights, number of vertebral centrum, length of ossified long bone, or external, 
placental, visceral or skeletal findings. Embryo-fetal loss was not seen in the 0 (control) or 
1 mg/kg bleselumab dose groups. In the 10 and 100 mg/kg bleselumab dose groups embryo-fetal 
loss was seen in 2 of 12 and 3 of 12 animals, respectively. Based on these data, the NOAEL for 
in the dams was 100 mg/kg while the NOAEL for embryo-fetal loss was 1 mg/kg. The historical 
average rate of embryo-fetal development at the facility that performed the embryo-fetal 
toxicology study is 8.6% with a range of 0 to 20%.
Anti-bleselumab antibody was detected in 3 dams in the 1 mg/kg group on treatment day 55 of 
gestation and/or at cesarean sectioning. Serum bleselumabconcentrations in these dams were 
decreased and/or disappeared by repeated dosing. No anti-bleselumab antibody was detected in 
the other dams or in any fetus in the 1 mg/kg group, or in any dam or fetus in the 100 or 
10 mg/kg group.
In toxicokinetic studies, Cmax and AUC of bleselumab in dams increased with ascending dose, 
and on treatment day 55 of gestation were higher than on treatment day 20 of gestation in all 
test article groups. On the day of cesarean sectioning, serum bleselumab concentrations were 
detected for all dams and fetuses in the 100 mg/kg group, and for 4 dams and 2 fetuses in the 
10 mg/kg group; however, bleselumab concentration was not detected for any dam or fetus in 
the 1 mg/kg group.


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Local tolerance of bleselumab was assessed as part of the 4-week and 13-week repeated dose 
toxicity study in cynomolgus monkeys (Studies 7163-TX-0002 and 7163-TX-0005). No 
noteworthy findings were noted in the animals dosed with bleselumab following macroscopic 
and histopathologic examination of the injection site. Based on these findings, the local 
tolerance NOAEL was determined to be 100 mg/kg.
1.2.4
Clinical Data
1.2.4.1 Study 7163-CL-0101
Study 7163-CL-0101 was a first-in-human (FIH) phase 1, randomized, double-blind, 
placebo-controlled study of single intravenous doses at escalating dose levels in 108 healthy 
subjects with 36 subjects receiving placebo and 72 subjects receiving bleselumab in 12 dose 
groups (0.00003, 0.0001, 0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, 0.3, 1, 3, or 10 mg/kg). 
Treatment-emergent adverse events (TEAEs) were reported by 47.2% (17/36) of subjects in
placebo and 52.8% (38/72) of subjects who received any dose of bleselumab. The most 
common TEAEs were headache, upper respiratory tract infection, cough, and dermatitis 
contact. There were no clinically significant drug-related ECG abnormalities or safety 
laboratory findings in any of the dose groups. No subjects experienced cytokine release 
syndrome.
For bleselumab dose levels between 0.1 to 10 mg/kg, AUCinf and cmax increased more than dose 
proportionality. The maximal concentration of bleselumab (tmax) was achieved at 
approximately 1.5 hours after administration while the t1/2 increased with increasing dose levels
of bleselumab, which was approximately 8 days at dose levels ranging from 1 to 10 mg/kg.
The primary pharmacodynamic variable was B cell CD40 occupancy over time (binding of 
bleselumab-biotin to B cells). At dose levels ranging from 0.03 to 10 mg/kg, the percent 
change from baseline (i.e., percent occupancy) ranged from approximately 67% to 85% 
starting at 0.5 hours after dosing. B cell CD40 occupancy was sustained above 50% for 1 day 
at 0.1 mg/kg bleselumab, for 4 days at 0.3 mg/kg bleselumab, for 7 days at 1 mg/kg 
bleselumab, for 29 days at 3 mg/kg bleselumab, and for 60 days at 10 mg/kg bleselumab. No 
meaningful percent change from baseline was noted for total lymphocyte counts or peripheral 
lymphocyte subsets (CD16, CD19, CD3, CD4, CD8).
Over the course of the study, a total of 5 subjects in the bleselumab 1 mg/kg group and 
1 subject in the bleselumab 10 mg/kg group seroconverted from anti-bleselumab antibody 
negative to anti-bleselumab antibody positive. No coagulation abnormalities were noted.
1.2.4.2 Study 7163-CL-0103
Study 7163-CL-0103 was a phase 1b, randomized, double-blind, parallel group, 
placebo-controlled, single-dose, pharmacokinetic, pharmacodynamic, safety and tolerability 
study of bleselumab in de novo kidney transplant recipients. A total of 46 subjects were 
randomized and received study drug in one of 5 treatment groups: placebo (n = 8), 
bleselumab 50 mg (n = 10), bleselumab 100 mg (n = 9), bleselumab 200 mg (n = 10) or 
bleselumab 500 mg (n = 9).


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Treatment emergent adverse events (TEAEs) occurred in 100% of subjects. Incidences of 
TEAEs were not bleselumab dose dependent. BK infection occurred in 12.5% of placebo, 
40.0% of bleselumab 50 mg, 0.0% of bleselumab 100 mg, 10.0% of bleselumab 200 mg and 
22.2% of bleselumab 500 mg treatment groups. Cytomegalovirus (CMV) infection occurred in 
a single subject in each of the placebo, bleselumab 100 mg and bleselumab 500 mg treatment 
groups. There were no thromboembolic events, myocardial infarctions or malignancies 
reported in the subjects receiving bleselumab. Serious adverse events (SAE) occurred in 37.5% 
of placebo, 60.0% of bleselumab 50 mg, 11.1% of bleselumab 100 mg, 0.0% of bleselumab 
200 mg and 33.3% of bleselumab 500 mg treatment groups. No subjects experienced cytokine 
release syndrome.
Both AUC and Cmax increased more than dose proportionally suggesting that bleselumab
showed nonlinear pharmacokinetics. Mean maximal B cell CD40 receptor occupancy (> 85%) 
was achieved initially in all dose groups, except the 500 mg dose group (> 70%). In general, 
there was a dose dependent duration of maximum B cell CD40 receptor occupancy.
Only one subject had treatment emergent anti-bleselumab antibodies formation. This subject 
was on bleselumab50 mg treatment group. No adverse events (AEs) attributable to anti-
bleselumab antibodies were reported.
1.2.4.3 Study 7163-CL-0107
This was a phase 2a, multi-center, randomized, double-blind, placebo-controlled, sequential 
dose group, multiple-dose escalation intravenous dose study to evaluate the safety, efficacy, 
pharmacokinetics and pharmacodynamics of bleselumab administered in subjects with 
moderate to severe plaque psoriasis. The subjects were randomized to receive multiple doses 
of either placebo or ASKP1240 at 0.1, 0.3, 1.0, or 3.0 mg/kg. The pharmacokinetics showed 
AUC336 and Cmax increased more than dose proportionally, suggesting bleselumab
demonstrated nonlinear pharmacokinetics after single and multiple doses in the dose range 
tested in subjects with psoriasis.
Although the study was not powered to demonstrate statistical differences in bleselumab
treatment from placebo, there was evidence of pharmacologic activity at the 3.0 mg/kg 
bleselumab dose relative to placebo as measured by classic and linear PASI score.
There were no clinically significant infusion reactions and no cytokine release syndrome or 
thromboembolic events. Reversible elevated liver function tests (LFTs) were observed but 
only in the high dose bleselumab cohorts (1.0 and 3.0 mg/kg). In general, a favorable safety 
profile with bleselumab was observed.
1.2.4.4 Study 7163-CL-0108
The 7163-CL-0108 Study is a phase 2a, randomized, open-label, active control, multi-center 
study to assess the efficacy and safety of bleselumab in de novo kidney transplant recipients. 
A total of 139 subjects were randomized and received study drug in one of 3 treatment groups: 
standard of care (SOC; Tacrolimus [Tac] + MMF + steroids), calcineurin inhibitor (CNI) 


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avoidance (bleselumab + MMF + steroids), and CNI minimization-MMF avoidance 
(bleselumab + reduced Tac (rTac) + steroids). 
The primary study duration of 7163-CL-0108 is 6 months after kidney transplantation, 
followed by a long term extension period of up to 3 years. The results showed bleselumab 
+ rTac regimen demonstrated similar efficacy for the prevention of acute rejection at the 
pre-specified 6-month end point and at the previously unplanned 12-month analysis (4/44, 
9.1%; 4/44, 9.1%) compared to SOC (3/48, 6.3%; 6/48, 12.5%), respectively. The difference 
(bleselumab + rTac – SOC) with the 95% CI at 6 and 12 months was 2.8% [-8.1%, 13.8%] and 
-3.4% [-16.0%, 9.2%]. The upper limit of the non-inferiority margin was less than 20%, the 
pre-specified limit, indicating similar efficacy.
The bleselumab + MMF group did not achieve non-inferiority compared to SOC at both the 
6- and 12-month analyses with the incidence of biopsy-proven acute rejection (BPAR) in 
bleselumab + MMF group statistically higher than SOC. Subjects and graft survival were 
similar in all three treatment groups.
The higher rate of AEs in the bleselumab + MMF group in the various categories is 
predominantly driven by the higher rate of acute rejection in that group. Other AEs were 
generally consistent with those seen in renal transplant subjects. The elevated LFTs were 
observed in all three groups but the subjects in the ASKP1240 + rTac group had higher 
incidences of elevated transaminases or total bilirubin than the SOC and ASKP1240 + MMF 
groups; however, the elevated LFTs seemed transient and reversible regardless of whether the 
subjects discontinued or continued ASKP1240 treatment.
BK virus (BKV) infection occurred more commonly in the bleselumab + rTac group (27.3%) 
compared to SOC (10.2%) and bleselumab + MMF (15.2%) groups. Also BK virus 
associated nephropathy (BKVAN) occurred at 6.8% in the bleselumab + rTac group 
compared to SOC (4.1%) and bleselumab + MMF (4.3%) groups. No subject had graft loss 
due to BK infection/nephropathy by 12 months. Cytomegalovirus (CMV) infection was 
reported in all three treatment arms as follows, SOC (4.1%), bleselumab +MMF (6.5%) and 
bleselumab + rTac (6.8%). By month 12, the accumulated occurrence of CMV infection was 
reported for SOC (6.1%), bleselumab +MMF (10.9%) and ASKPK1240 + rTac (13.6%) 
treatment arms.
During the six month study period, three malignancies were reported; one renal cell 
carcinoma and one squamous cell carcinoma in bleselumab + MMF. A single subject in 
bleselumab + rTac had a squamous cell carcinoma of skin. Between the 6 to 12 month period, 
there were two more malignancies reported, both in bleselumab + rTac, one basal cell 
carcinoma and one polycythemia vera. There was no case of post-transplant 
lymphoproliferative (PTLD) reported during the study to-date.
Two subjects died during the six month study period. A death was reported in the bleselumab 
+ rTac group on day 45 primarily due to sepsis following an inadvertent injury to the 
appendix during the transplant procedure. Another death reported in the bleselumab + MMF 
group on day 4 was due to cardiac arrest and was considered not related to any of the study 


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drugs. During the 6 to 12 months study period, one additional subject in the bleselumab + 
rTac group was reported dead at home on day 420 due to unknown reason.
Two subjects experienced graft loss during the six month study period. One subject in SOC 
group underwent allograft nephrectomy on day 18 due to thrombosis. The second subject in 
the bleselumab + rTac treatment arm underwent placement of a donor kidney that was 
immediately removed due to poor perfusion. During the same procedure the mate donor 
kidney was then implanted and continues to function well. The first donor kidney has been 
counted as a graft loss. There was no graft loss during the 6 to 12 months follow-up period.
Overall, the study showed bleselumab + rTac regimen demonstrated similar efficacy in the 
prevention of acute rejection at both six months end point and 12 months analysis. A
favorable safety profile with ASKP1240 was consistently observed in the subjects with 
kidney transplantation.
1.3
Summary of Key Safety Information for Study Drugs
Cross-reactivity studies of human tissues demonstrated specific binding of bleselumab to 
lymphocytes in lymphoid tissues as well as binding to infiltrating lymphocytes in 
non-lymphoid human tissues. Non-lymphoid staining of bleselumab was seen in membranes of 
sinusoidal lining cells in the liver and in glandular epithelium in the prostate, thyroid, kidney 
and parathyroid. Bleselumab also specifically stained human lymphocytes, monocytes, and 
platelets in peripheral blood.
Bleselumab inhibited sCD154-induced IL-12 and TNF-alpha release from dendritic cells. 
bleselumab inhibited human and cynomolgus monkey PBMC proliferation induced by sCD154 
in a concentration-related manner. A correlation was observed between serum concentration of 
bleselumab and % binding to CD40 on B cells. Bleselumab did not inhibit collagen-induced 
platelet aggregation.
In non-human primates (NHP), bleselumab inhibited delayed type hyper-sensitivity reaction 
and antigen-specific antibody production at a dose of ≥1 mg/kg. Bleselumab exhibited a 
potent immunosuppressive effect and prolonged renal allograft survival when administered as 
induction and/or maintenance therapy in the cynomolgus monkey.
Further examinations of the effects of bleselumab on major physiologic systems were 
examined in a 4-week, 13-week and 52-week toxicity studies in the monkey. No treatment-
related effects were noted on the cardiovascular, respiratory, renal, or central nervous systems. 
Anemia has been noted in 1 animal in the 13-week repeat dose toxicology study and in 4 of 5 
animals beginning at the 39-week time point of the 52-week toxicology study. In the 52-week 
study some animals were euthanized due to moribundity in the 30 mg/kg and 100 mg/kg dose 
groups. Histologic change in lymphoid organs has been observed following repeated dose 
administration of bleselumab to cynomolgus monkeys. Specifically in the nonhuman primate 
studies of bleselumab, germinal centers (GC) were shown to be either small or they could not 
be observed. Signs of toxicity (degeneration, necrosis, and apoptosis) were not observed in the 
follicular tissue with small or absent GC. No toxicological changes were observed in the cells 
or tissue in the regions other than the GC atrophy of follicle. These findings indicate an 


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impairment of B cell maturation to be the primary cause of the GC atrophy. This would be 
consistent with the mechanism of action of bleselumab. The findings were reversible following 
cessation of drug administration. Decreases in peripheral blood CD3-CD20+ B cells also 
occurred and are considered to reflect the pharmacological action of bleselumab on B cell 
maturation in lymphoid tissues. The decreased peripheral circulatory B cell counts were also 
reversible on cessation of drug administration. Given the coincidence of the reformation of 
GC, the peripheral blood B cell counts may be a correlate of alterations in the germinal center 
morphology.
Reproductive toxicity studies are completed. Effects of bleselumab may result embryo-fetal 
loss at doses higher than 1 mg/kg.
The FIH healthy volunteer study (Study 7163-CL-0101) described above showed that a single 
dose of bleselumab was well tolerated. No evidence of cytokine release syndrome was seen. 
Activation of the coagulation cascade was not seen. Drug infusions were relatively well 
tolerated with a single occurrence of a drug related skin rash suggesting that cutaneous 
reactions may be seen following administration of bleselumab. Over the course of the study, a 
total of 6 subjects in bleselumab dose groups seroconverted from anti-bleselumab antibody 
negative to anti-bleselumab antibody positive.
Study 7163-CL-0103 described above showed that a single dose of bleselumab was well 
tolerated by de novo renal transplant subjects. No evidence of cytokine release was seen and 
there were no thromboembolic events observed. One subject in the bleselumab 50 mg 
treatment group developed treatment emergent anti-bleselumab antibodies.
Study 7163-CL-0107 in subjects with psoriasis and study 7163-CL-0108 in de novo renal 
transplant subjects also showed multiple doses of bleselumab was well tolerated with no 
evidence of cytokine release and no thromboembolic events observed.
The CD40-CD40L interaction has been targeted in humans previously [Pree and Wekerle, 
2006; Kirk et al, 2001]. Two humanized anti-CD40L antibodies have been investigated in the 
setting of various autoimmune disorders and renal transplantation. Anti-CD40L antibody 
(hu5C8, monoclonal antibody against CD154 [ligand for CD40]), was effective in NHPs in 
preventing renal allograft rejection and prolonging survival [Kirk et al, 1999] but was 
associated with thrombotic events in humans [Kirk et al, 2001]. The other agent, IDEC-131, 
was evaluated in a variety of autoimmune disorders, and treatment was complicated by a 
thromboembolic event in a patient with Crohn’s Disease [Pree and Wekerle, 2006]. The 
thromboembolic events involved both venous and arterial vasculature. The exact mechanisms 
for these events are not clear at present and may represent effects on platelets and/or vascular 
endothelium [Sidiropoulos and Boumpas, 2004; Kirk et al, 2001]. The absence of CD40L has 
been shown to affect the stability of ex vivo-generated thrombi in high shear flow conditions 
and arterial thrombi in in vivo nonclinical models. Animals and platelets deficient for CD40 
had a phenotype similar to wild type in these studies [Andre et al, 2002].
Antagonistic and agonistic anti-CD40 antibodies have been administered clinically [Hussein et 
al, 2010; Advani et al, 2009; Vonderheide et al, 2007; Kasran et al, 2005]. For example, an 


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antagonistic anti-CD40 IgG1 was administered to subjects with non-Hodgkin’s lymphoma 
[Hussein et al, 2010; Advani et al, 2009]. Although well tolerated clinically in the 16 subjects, 
depletion of B cells was noted. An antagonistic anti-CD40 IgG4 was also administered to 
subjects with moderate-to-severe Crohn’s disease and single-dose administration was clinically 
well tolerated [Kasran et al, 2005]. Transient decreases of B cells were also noted.
Although bleselumab is not a CD40 agonist, it is important to note that the administration of 
agonistic CD40 monoclonal antibodies has also been performed. Vonderheide et al [2007] 
reported that following the administration of an agonistic anti-CD40 IgG2 to subjects with 
various advanced solid organ tumors, cytokine release syndrome occurred in 16 of 29 subjects;
however, the cytokine release syndrome was generally mild and resolved within 24 hours 
following dosing. Lymphocytopenia, thrombocytopenia, and dose-related transient elevations
in serum liver transaminases were also noted. Hypersensitivity or antibody-dependent cellular 
cytotoxicity was not considered to be involved. To date, no subjects have experienced cytokine 
release syndrome in any previous clinical studies.
1.4
Risk-Benefit Assessment
Results from nonclinical studies with bleselumab have not identified significant safety issues 
that would preclude clinical development of bleselumab. As noted above anemia has been 
observed in NHPs dose with bleselumab 30 mg/kg and 100 mg/kg for more than 4 weeks. 
Histologic change in lymphoid organs and reductions of CD3-CD20+ cell counts have also 
been observed in NHPs dosed at 10 mg/kg, 30 mg/kg and 100 mg/kg. Whether these findings 
constitute an unacceptable risk to subjects in the study is unclear. GC atrophy, including severe 
lymphoid depletion, has also been observed pre-clinically with a number of commercial 
products (e.g., rituximab, belimumab, atacicept, methotrexate and abatacept) in association 
with varying degrees of reduction in peripheral CD3-CD20+ cells.
In populations of subjects with rheumatoid arthritis and/or SLE where comparative data is 
available, abnormalities of germinal center histology alone do not result in an incremental risk 
of infectious complications. Moreover, neither isolated profound peripheral blood total B cell 
depletion nor depletion of specific subsets of B cells are associated with clinically meaningful 
differences in incidence of infection.
The results of the FIH study (7163-CL-0101) indicated that a single dose of bleselumab was 
well tolerated. Anemia and reductions in CD3-CD20+ cell counts were not observed following 
a single dose of bleselumab at any dose. In addition, bleselumab has been evaluated following 
a single dose in kidney transplant recipients (Study 7163-CL-0103). Although the study was 
not designed to assess efficacy bleselumab showed mean maximal B cell CD40 receptor 
occupancy (> 85%) achieved in all dose groups and was found to be well tolerated. In the 
ongoing 3-year long multiple-dose study in kidney transplant recipients (Study 7163-CL-
0108), the 6-month and 12-month preliminary results showed that bleselumab was found to be
well tolerated and bleselumab + Tac group also showed non-inferiority to the SOC in the 
prevention of rejection.


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There is a known risk of cytokine release syndrome, characterized by rapid induction of 
pro-inflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, 
erythema, vasodilatation, and hypotension, with subsequent life-threatening lung injury, renal 
failure, and disseminated blood clots [Suntharalingam et al, 2006] following administration of 
monoclonal antibodies in man. Immunoreactivity appears to be related in part to Fc receptor 
(FcR) binding and antibody dependent cellular cytotoxicity and/or complement dependent 
cytotoxicity. Bleselumab is an IgG4 isotype that has been genetically modified with the intent 
to decrease binding to FcR, thereby reducing antibody dependent cellular cytotoxicity 
potential. In addition, IgG4 has lower complement activating potential than other IgG isotypes. 
Additionally in the nonclinical studies, bleselumab related cytokine release was not observed in 
vivo in cynomolgus monkeys at doses up to 100 mg/kg or in vitro in human blood at 
concentrations up to 200 mcg/mL. Finally cytokine release syndrome was not observed in the 
FIH (Study 7163-CL-0101) single dose study or the single dose study in kidney transplant 
recipients (Study 7163-CL-0103), as well as the multiple dose study in kidney transplant 
recipients (Study 7163-CL-0108).
Most biologic therapies elicit some level of antibody response which may contribute to AEs or 
loss of efficacy of the therapeutic agent. As bleselumab is a fully human antibody, the potential 
for human anti-human antibodies is relatively low. Treatment emergent antibodies to bleselumab 
following single doses have been seen in 6.9 to 11.1% of subjects receiving bleselumab; however 
less events were reported in the 7163-CL-0108 study where other immunosuppressants were 
concomitantly used. There have been no AEs attributed to anti-bleselumab antibodies reported.
Bleselumab is intended to be an immunosuppressive agent and, therefore, the potential to 
increase the risk of infection and reactivate latent, chronic infections is expected.
Animal reproduction studies are not always predictive of human response. There are no 
adequate and well-controlled studies in pregnant women; therefore, the risk to the development 
of the fetus in humans is unknown. Women who are able to become pregnant must use 
contraception during treatment with bleselumab and during any protocol-defined treatment 
period. If a woman becomes pregnant, while taking bleselumab, she should be informed of the 
potential hazards to the fetus and bleselumab treatment must be discontinued immediately. If a 
man impregnates his partner while taking bleselumab, both parties should be informed of the 
potential hazards to the fetus. Additionally, sperm donation is prohibited during and for 
90 days post-last study drug dosing.
Subjects will be closely monitored by the Principal Investigator for signs and symptoms of 
anemia, infection, cytokine release, and thromboembolic events. In addition to being closely 
monitored by the Investigator, the Sponsor Medical Monitor and the Sponsor Medical Safety 
Pharmacovigilance physician/designee will periodically review the safety data. A full range of 
safety data will be assessed, including but not limited to, hematology, biochemistry, vital signs, 
and AEs. 
Multiple doses of bleselumab monotherapy showed evidence of efficacy in a psoriasis study and 
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rejection compared to SOC in renal transplant subjects. Two important identified risks are 
hepatic toxicity and viral infections. The blood chemical findings in preclinical studies showed 
isolated elevations of alanine phosphatase (SGPT) (ALP), aspartate aminotransferase (SGOT) 
(AST), alkaline aminotransferase (ALT) and lactate dehytdrogenase (LDH) that were not dose-
related and in some cases returned to lower values with continued dosing; in phase I completed 
studies TEAEs related to abnormal LFTs (e.g., ALT) were not clinically significant. In both 
phase II studies (one complete and one ongoing) elevated liver chemistries are transient and 
reversible regardless of bleselumab continuation or discontinuation and have not been associated 
with significant clinical findings. The occurrences of BK infection are of concern but have not 
resulted in significant impairment of renal survival and no graft loss.
The Sponsor is continuously monitoring safety in the ongoing clinical study and has instituted 
mitigating measures for this study. The Sponsor believes that the risks recognized with 
bleselumab are acceptable and do not preclude further clinical investigations. A DMC that will 
be responsible for the evaluation of data is to be organized and meet periodically.
There is no approved pharmacologic therapy and limited effectiveness with other treatment 
options such as plasmapheresis. Many subjects with rFSGS suffer the consequences of the 
recurrence in the form of nephrotic syndrome and its sequelae. Based on this unmet medical 
need and the safety and efficacy results from previous and ongoing clinical studies with 
bleselumab, the Sponsor believes bleselumab may have potential benefit in the prevention of 
rFSGS.
2
STUDY OBJECTIVE(S), DESIGN, AND ENDPOINTS
2.1
Study Objectives
2.1.1
Primary Objective
●
To assess the efficacy of the bleselumab regimen (basiliximab induction, tacrolimus, 
steroids and bleselumab) compared with the SOC regimen (basiliximab induction, 
tacrolimus, steroids and MMF) in the prevention of the recurrence of focal segmental 
glomerulosclerosis (rFSGS) defined as nephrotic range proteinuria with protein-
creatinine ratio (≥ 3.0 g/g) through 3 months post-transplant. Death, graft loss or lost to 
follow-up will be imputed as rFSGS.
2.1.2
Secondary Objectives
●
To assess the incidence of nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g) through 6 and 12 months post-transplant. Death, graft loss or lost to follow-up 
will be imputed as rFSGS.
●
To assess the incidence of biopsy-proven acute rejection (BPAR, Banff Grade ≥ 1; local 
read) through 3, 6 and 12 months post-transplant.
●
To assess the incidence of efficacy failure defined as BPAR (Banff Grade ≥ 1; local 
read), death, graft loss or lost to follow-up through 12 months post-transplant.


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●
To assess the incidence of biopsy-proven (blinded, central read) rFSGS through 3, 6 and 
12 months post-transplant.
●
To assess the safety of the bleselumab regimen compared with the SOC regimen.
2.1.3
Exploratory Objectives
●
To assess graft and patient status through 12 months post-transplant.
●
To assess the Glomerular Filtration Rate (GFR, based on Modification of Diet in Renal 
Disease [MDRD] criteria) through 12 months post-transplant.
●
To assess the incidence of FSGS defined as nephrotic range proteinuria with 
protein-creatinine ratio (≥ 3.0 g/g).
●
To assess the time to rFSGS defined as nephrotic range proteinuria with protein-
creatinine ratio (≥ 3.0 g/g).
●
To assess the time to rFSGS defined as nephrotic range proteinuria with protein-
creatinine ratio (≥ 3.0 g/g) or initiation of plasmapheresis.
●
To assess the time to rFSGS defined as recurrence of nephrotic range proteinuria with 
protein-creatinine ratio (≥ 3.0 g/g), death, graft loss or lost to follow-up.
●
To assess the time to recurrence of biopsy-proven (blinded, central read) FSGS.
●
To assess the time to first BPAR (Banff Grade ≥ 1, local read).
●
To assess the urine protein-creatinine ratio through 6 and 12 months post-transplant.
●
To assess the urine albumin-creatinine ratio through 3, 6 and 12 months post-transplant.
●
To assess the change in auto-anti-CD40 antibodies from baseline.
●
To assess the change in patient-reported outcomes from baseline (Short Form 36-Item 
Health Survey Score [SF-36s]), European Quality of Life-5 Dimensions-5 Levels 
[EQ-5D-5L], and Kidney Transplant Questionnaire [KTQ]).
2.2
Study Design and Dose Rationale
2.2.1
Study Design
This is a Phase 2a, randomized, open-label, active control, multi-center study to assess the 
efficacy and safety of bleselumab in preventing the rFSGS in de novo kidney transplant subjects.
The study will consist of the following periods:
●
Screening (days -21 to -1)
●
Transplant (day 0 [zero])
●
Post-transplant (day 0/post-skin closure through 12 months post-transplant)
Prior to any study-related assessments, the informed consent form (ICF)/authorization will be 
signed by the subject (visit 1). All subjects will enter into a screening period (days -21 to -1
prior to transplant), undergo a transplant (day 0), and are then to be followed for up to 
12 months in the post-transplant period (day 0/post-skin closure through 12 months 
post-transplant) for efficacy and safety.




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Only subjects in Arm 2 are to provide pharmacokinetic samples. On day 0, pharmacokinetic 
samples are to be collected within 30 minutes or less pre-initial, and post-initial, intraoperative,
bleselumab administration. Two single, pharmacokinetic samples are to be collected at each 
subsequent 30 minute, intravenous infusion: one within 30 minutes or less prior to the infusion 
(trough concentration), and the other at the end of the infusion (peak concentration) up through 
the day 28 visit. After that only trough concentrations (within 30 minutes or less pre-infusion) 
are to be collected up through day 90/month 3, and months 6, 9 and 12/EOS visits.
All subjects who have not had a biopsy with a diagnosis of recurrent FSGS (rFSGS) by 3 months 
post- transplant will have a protocol-defined biopsy at the day 90/month 3 visit. There are no 
other protocol-defined biopsies. Biopsies other than the protocol-indicated one at day 90/month 
3 will be considered ‘for cause’ only.
All episodes of kidney dysfunction based on clinical signs and symptoms will be evaluated for 
possible BPAR and/or rFSGS. All subjects should have a biopsy confirmation of a rejection 
episode prior to the initiation of treatment for rejection, or within 48 hours of initiation of 
treatment for acute rejection. BPAR (T- or B-cell) will be determined via local review at the 
study center using the 2007 Banff criteria.
All images for electron microscopy (EM) and slides for light microscopy (LM) utilized for local 
pathological review for evaluation of possible BPAR and/or rFSGS are to be forwarded for a 
blinded, central review by an independent pathologist to assess (via EM and LM) rFSGS.
A Data Monitoring Committee (DMC) will be responsible for data evaluation and will meet 
as defined in the DMC charter.
If bleselumab is permanently discontinued, subjects in Arm 2 can continue to receive 
study-supplied Prograf through 12 months post-transplant as previously assigned; however, 
any alternate therapy(ies) will not be provided by the Sponsor. Furthermore, subjects that 
permanently discontinue or replace bleselumab, tacrolimus or MMF in the post-transplant 
period will be considered to have reached end of treatment (EOT) and are to continue with 
the protocol-defined visit schedule (Table 1, Schedule of Assessments) for the collection of 
safety and clinical assessment information.
If a subject declines to be followed upon permanently discontinuing bleselumab, tacrolimus 
or MMF, the end of study (EOS, visit 21/month 12) procedures are to be completed within 
30 days post-last treatment.
2.2.2
Dose Rationale
Although the pathogenesis of FSGS is still not fully understood, literature suggests that 
auto-anti-CD40 antibody is potentially associated with rFSGS. In cultured human podocytes, 
a monoclonal CD40-blocking antibody partially reversed the podocyte depolarization and 
shrinking seen after treatment with purified anti-CD40 antibody from the sera of subjects
who developed rFSGS, indicating that blocking the interaction of the CD40 auto-antibody 
with the CD40 on podocytes may be a potential therapeutic target in the treatment of rFSGS.


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Bleselumab, a fully human IgG4 anti-CD40 antagonistic monoclonal antibody, could have a 
therapeutic effect for the prevention of FSGS following renal transplantation by either 
preventing the binding of CD40 autoantibodies to the podocytes or by blocking the 
interaction of CD40L expressing inflammatory cells with the podocytes. None of the 
6 subjects from the 7163-CL-0108 study with a medical history of FSGS treated with 
bleselumab (6 subjects, 5 treated with bleselumab + MMF and 1 treated with bleselumab + 
rTac) had a rFSGS while the SOC arm had recurrence in 2 of 2 subjects.
The dosing regimen proposed in this study is as same as the 7163-CL-0108 study, which 
demonstrated efficacy in preventing acute rejection with manageable safety profiles. The 
dosing rationale for this study is to ensure the sufficient immunosuppression to prevent acute 
rejection and to assess the efficacy in the prevention of rFSGS.
2.3
Endpoints
2.3.1
Primary Endpoint
●Recurrence of FSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g) through 3 months post-transplant. Death, graft loss or lost to follow-up will 
be imputed as rFSGS.
2.3.2
Secondary Endpoints
●Recurrence of FSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥ 3.0 g/g) through 6 and 12 months post-transplant. Death, graft loss or lost to follow-up
will be imputed as rFSGS.
●BPAR (Banff Grade ≥1, local read) through 3, 6 and 12 months post-transplant.
●Efficacy failure defined as BPAR (Banff Grade ≥ 1; local read), death, graft loss or lost to 
follow-up through 12 months post-transplant.
●Biopsy-proven (blinded, central read) rFSGS through 3, 6 and 12 months post-transplant.
2.3.3
Exploratory Endpoints
Efficacy
●Graft and patient status through 12 months post-transplant.
●GFR based on MDRD criteria through 12 months post-transplant.
●Recurrence of FSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥ 3.0 g/g).
●Time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g).
●Time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g) or initiation of plasmapheresis.
●Time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g), death, graft loss, or lost to follow-up.
●Time to recurrence of biopsy-proven (blinded, central read) FSGS.
●Time to first BPAR (Banff Grade ≥ 1, local read).
●Urine protein-creatinine ratio through 6 and 12 months post-transplant.


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●Urine albumin-creatinine ratio through 3, 6 and 12 months post-transplant.
●Change in auto-anti-CD40 antibodies from baseline.
●Change in patient-reported outcomes from baseline (SF-36s, EQ-5D-5L and KTQ).
Safety
●Adverse events (AEs) graded by National Cancer Institute Common Terminology Criteria 
for Adverse Events criteria (NCI CTCAE).
●Vital sign measurements.
●Clinical laboratory tests.
●Bleselumab pharmacokinetics (including anti-bleselumab and bleselumab bi-specific 
antibodies).
●Viral serology (hepatitis B virus [HBV], hepatitis C virus [HCV], CMV, BK 
polyomavirus [BKV] and EBV).
●Viral load testing (CMV, BKV and EBV).
3
STUDY POPULATION
3.1
Selection of Study Population 
Male and female subjects 18 years of age or older who are de novo, living or deceased donor 
kidney recipients and have biopsy-proven pFSGS.
3.2
Inclusion Criteria
A subject is eligible for the study if all of the following apply:
1.
Institutional Review Board (IRB)/Independent Ethics Committee (IEC)-approved written 
Informed Consent and privacy language as per national regulation (e.g., Health Insurance 
Portability and Accountability Act [HIPAA] Authorization for US sites) must be 
obtained from the subject or legally authorized representative prior to any study-related 
procedures (including withdrawal of prohibited medication, if applicable).
2.
Male or female subject must be ≥ 18 years of age.
3.
Subject is a recipient of a de novo kidney from a living or deceased donor and has biopsy-
proven, pFSGS as a cause of ESRD in their native kidneys (initial diagnosing biopsy 
report is required). A subject who has biopsy-proven pFSGS as a cause of ESRD, and 
their most current graft failure(s) is due to biopsy-proven, recurrent FSGS, is eligible.
4.
Subject is anticipated to receive first oral dose of tacrolimus within 48 hours of 
transplant procedure. 
5.
Female subject must either:
Be of non-child bearing potential:
Post-menopausal (defined as at least 1 year without any menses) prior to 
screening, or
Documented surgically sterile


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Or, if of childbearing potential,
Agree not to try to become pregnant during the study and for 90 days post-last 
dose,
And have a negative serum pregnancy test at screening,
And, if heterosexually active, agree to consistently use two forms of 
highly-effective birth control* (at least one of which must be a barrier method) 
starting at screening, throughout the study and for 90 days post-last dose.
6.
Female subject must agree not to breastfeed starting at screening, throughout the study 
and for 90 days post-last dose.
7.
Female subject must not donate ova starting at screening, throughout the study and for 90 
days post-last dose.
8.
Male subject and their female spouse/partners who are of childbearing potential must be 
using highly effective form of contraception consisting of two forms of birth control* (at
least one of which must be a barrier method) starting at screening, throughout the study 
and for 90 days post-last dose.
9.
Male subject must not donate sperm starting at screening, throughout the study and for 
90 days post-last dose.
10. Subject must be willing and able to comply with the study requirements including 
prohibited concomitant medication restrictions.
11. Subject agrees not to participate in another interventional study while on treatment.
*Highly effective forms of birth control include:
Consistent and correct usage of established oral contraception
Injected or implant hormonal methods of contraception
Established intrauterine device (IUD) or intrauterine system (IUS)
Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
Any male partner that has undergone effective surgical sterilization
Any female partner that has undergone effective surgical sterilization
Waivers to the inclusion criteria will NOT be allowed.
3.3
Exclusion Criteria
A subject will be excluded from participation if any of the following apply:
1.
Subject has Induction therapy, other than study-assigned basiliximab, planned as part of 
initial immunosuppressive regimen.
2.
Subjects with a diagnosis of secondary FSGS (familial, virus associated, medication, 
etc., Appendix 12.5) or a defined genetic cause of FSGS.
3.
Subject has previously received any organ transplant including a kidney and the most 
current graft failure(s) is not due to the recurrence of FSGS.


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4.
Subject will receive a kidney as part of a multi-organ transplant.
5.
Subject will receive a dual kidney transplant from a deceased donor.
6.
Subject will receive a kidney with an anticipated cold ischemia time of > 30 hours.
7.
Subject will receive a kidney that meets BOTH Extended Criteria Donor (ECD) and 
Donation after Cardiac Death (DCD) criteria. (A kidney that meets either ECD OR DCD 
criteria may be eligible for inclusion.)
8.
Subject will receive a blood group system (A, AB, B, O, ABO) incompatible (including 
A2 into B or O) donor kidney.
9.
Recipient or donor is known to be seropositive for human immuno-deficiency virus (HIV).
10. Subject has a current calculated panel reactive antibody (cPRA) level > 50%.
11. Subject has a current malignancy or a history of malignancy (within the past 5 years), 
except non-metastatic basal or squamous cell carcinoma of the skin that has been treated 
successfully, or a renal cell carcinoma that has been treated successfully more than 
2 years prior to transplantation.
12. Subject has significant liver disease, defined as having during the past 21 days 
consistently elevated AST (SGOT) and/or ALT (SGPT) levels greater than 1.5 times 
the upper value of the normal range of the investigational site.
13. Subject is known to have a positive test for latent tuberculosis (TB) and has not 
previously received adequate anti-microbial therapy/or would require TB prophylaxis 
after transplant.
14. Subject has an uncontrolled concomitant infection or any other unstable medical 
condition that could interfere with the study objectives.
15. Subject is concurrently participating in another drug study or has received an 
investigational drug up to 30 days or 5 half-lives (depending on medication) prior to 
transplant.
16. Subject is currently receiving or has received up to 8 weeks prior to transplant an 
immunologic biologic compound (i.e., TNF inhibitors, [e.g., etanercept, adalimumab], 
intravenous immunoglobulin [IVIG]). A subject who has previously received a kidney 
organ transplant and is currently on an immunosuppression regimen that includes MMF, 
or any of its components, must discontinue MMF.
17. Subject has previously received bleselumab or participated in a clinical study with 
bleselumab.
18. Subject has a known hypersensitivity to tacrolimus, basiliximab, MMF, corticosteroids, 
or any of their components.
19. Subject has any form of substance abuse, psychiatric disorder, or a condition that in the 
opinion of the Investigator could invalidate communication with the Investigator.


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20. Subject has a clinically significant abnormal ECG at screening.
21. Subject is unlikely to comply with the visits scheduled in the protocol, in the opinion of 
the Investigator.
Waivers to the exclusion criteria will NOT be allowed.
4
TREATMENT(S)
4.1
Identification of Investigational Product(s)
4.1.1
Test Drug(s)
Bleselumab (ASKP1240) is manufactured by Kyowa Hakko Kirin Co., Ltd. in partnership with 
Astellas.
Bleselumab is formulated at 100 mg/mL insterile Water for Injection (WFI). Bleselumab drug 
product for intravenous injection will be supplied as 1 mL solution (1.350 mL: ~ 30% overfill).
The clinical material is a clear or slightly opalescent, colorless to light brownish-yellow liquid
product provided in 3 mL glass, single-use vials.
Product should be stored refrigerated between 2 and 8°C (36 and 46°F); do not freeze and 
protect from light.
Instructions for handling and preparation/dilution of the study drug can be found in the 
Pharmacy Manual.
4.1.2
Comparative Drug(s)
4.1.2.1 Basiliximab
Basiliximab (Simulect®) will be provided via commercial supply.
For manufacturing, formulation, storage, handling and preparation details please refer to the 
package insert, summary of product characteristics (SPC), or local product information 
supplied by the manufacturer.
4.1.2.2 Tacrolimus
Prograf® (Tacrolimus) is manufactured by Astellas Pharma Inc., Toyama, Japan.
Prograf is available for oral administration as capsules (tacrolimus capsules) containing the 
equivalent of 0.5, 1.0 or 5.0 mg of anhydrous tacrolimus. Inactive ingredients include lactose, 
hydroxypropyl methylcellulose, croscarmellose sodium, and magnesium stearate. The 0.5 mg 
capsule shell contains gelatin, titanium dioxide and ferric oxide, the 1 mg capsule shell 
contains gelatin and titanium dioxide, and the 5 mg capsule shell contains gelatin, titanium 
dioxide and ferric oxide.
Tacrolimus appears as white crystals or crystalline powder. It is practically insoluble in water, 
freely soluble in ethanol, and very soluble in methanol and chloroform.


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Only the oral formulations of 0.5, 1.0 and 5.0 mg capsules will be supplied by the Sponsor 
through 12 months post-transplant, and is then to be sourced by the site and provided via 
commercial supply.
Product should be stored at 25°C (77°F), controlled room temperature;excursions permitted 15 
to 30°C (59 to 86°F).
For further manufacturing and formulation details please refer to the package insert, SPC, or 
local product information supplied by the manufacturer.
Tacrolimus for intravenous administration will not be provided by the Sponsor.
4.1.2.3 Mycophenolate Mofetil
Mycophenolate mofetil (MMF) is a white to off-white crystalline powder. It is slightly soluble 
in water (43 μg/mL at pH 7.4); the solubility increases in acidic medium (4.27 mg/mL at 
pH 3.6). It is freely soluble in acetone, soluble in methanol, and sparingly soluble in ethanol. 
The apparent partition coefficient in 1-octanol/water (pH 7.4) buffer solution is 238. The pKa 
values for MMF are 5.6 for the morpholino group and 8.5 for the phenolic group.
Mycophenolate mofetil hydrochloride has a solubility of 65.8 mg/mL in 5% Dextrose Injection 
USP (D5W). The pH of the reconstituted solution is 2.4 to 4.1.
Only the oral formulations of 250 and 500 mg capsules and tablets, respectively, will be 
provided by the Sponsor through 12 months post-transplant, and is then to be sourced by the 
site and provided via commercial supply.
Inactive ingredients in MMF 250 mg capsules include croscarmellose sodium, magnesium 
stearate, povidone (K-90), microcrystalline cellulose, hydroxyl propyl cellulose and talc. The 
capsule shells contain black iron oxide, FD&C blue #2, gelatin, red iron oxide, sodium lauryl 
sulfate, titanium dioxide, and yellow iron oxide. The imprinting ink contains shellac, iron 
oxide and potassium hydroxide.
Inactive ingredients in MMF 500 mg tablets include iron oxide black, croscarmellose sodium, 
FD&C blue #2 aluminum lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, 
hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol 400, 
povidone (K-90), iron oxide red, talc and titanium dioxide.
Product should be stored at 25°C (77°F), controlled room temperature; excursions permitted 
15 to 30°C (59 to 86°F).
For further manufacturing and formulation details please refer to the package insert, SPC, or 
local product information supplied by the manufacturer.
MMF for intravenous administration will not be provided by the Sponsor.
A switch from MMF to mycophenolic acid (Myfortic®) will be allowed for medical reasons 
but will not be supplied by the Sponsor.


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4.1.2.4 Corticosteroids
Corticosteroids will be sourced by the site and provided via commercial supply.
For manufacturing, formulation, storage, handling and preparation details please refer to the 
package insert, SPC, or local product information supplies by the manufacturer.
4.2
Packaging and Labeling
Bleselumab, tacrolimus and MMF will be prepared, packaged, and labeled under the 
responsibility of a qualified person at Astellas Pharma Global Development, Inc. (APGD) and
Astellas US Technologies, Inc. (AUST) in accordance with APGD - AUST Standard 
Operating Procedures (SOPs), Good Manufacturing Practice (GMP) guidelines, International 
Conference on Harmonization (ICH) Good Clinical Practices (GCP) guidelines, and applicable 
local laws/regulations.
Bleselumab will be packaged as a carton of 8 vials. Each vial will be assigned an identification 
number.
Tacrolimus and MMF will be packaged as 100 capsules and/or tablets per bottle. Each bottle 
will be assigned an identification number.
Each carton and bottle will bear a label conforming to regulatory guidelines, GMP, and local 
laws and regulations, which identifies the contents as investigational drug. Each carton label 
must remain affixed to the carton and must not be concealed by any over-labeling.
4.3
Study Drug Handling
Current ICH GCP Guidelines require the investigator to ensure that study drug deliveries from 
the Sponsor are received by the Investigator/designee and
●that such deliveries are recorded
●that study drug is handled and stored according to labeled storage conditions
●that study drug with appropriate expiry/retest and is only dispensed to study subjects in 
accordance with the protocol
●that any unused study drug is returned to the Sponsor
Drug inventory and accountability records for the study drugs will be kept by the Investigator. 
Study drug accountability throughout the study must be documented and reconciled. The 
following guidelines are therefore pertinent:
●The Investigator agrees not to supply study drugs to any persons except the eligible 
subjects in this study in accordance with the protocol.
●The Investigator will keep the study drugs in a pharmacy or other locked and secure 
storage facility under controlled storage conditions, accessible only to those authorized 
by the investigator to dispense these test drugs.
●A study drug inventory will be maintained by the Investigator. The inventory will 
include details of material received and a clear record of when they were dispensed and 
to which subject.


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●At the conclusion or termination of this study, the Investigator agrees to conduct a final 
drug supply inventory and to record the results of this inventory on the Drug 
Accountability Record. It must be possible to reconcile delivery records with those of 
used and/or returned medication. Any discrepancies must be accounted for and 
documented. Appropriate forms of deliveries and returns must be signed by the person 
responsible.
●The site must return study drug to the Sponsor at the end of the study or upon expiration.
Detailed instructions for the handling of study drug can be found in the Pharmacy Manual.
4.4
Blinding
This section is not applicable as this is an open label study.
4.5
Assignment and Allocation
All subject numbers will be assigned using the Interactive Response Technology (IRT) 
starting at screening. All subjects will have a unique, ten-digit subject id. The first 5 digits of 
this number will be the site’s protocol-specific number. The second 5 digits assigned will 
represent the subject’s accession number. This will be the number that identifies a subject 
during the course of the study.
All baseline procedures will be performed prior to Randomization. Only subjects who meet 
all inclusion criteria and exhibit none of the exclusion criteria (Section 3, Study Population) 
will be randomly assigned to one of the two treatment arms in a 1:1 ratio and stratified by 
previous kidney transplant status (no or yes). There will be a central randomization with 
treatment assignments balanced between the 2 study arms and previous kidney transplant.
Randomization is to be performed via IRT. If a patient is assigned a subject number and 
transplanted, but does not receive the assigned treatment regimen, the subject number will not 
be used again. If a patient is assigned a subject number but not transplanted nor receives the 
assigned treatment regimen within the screening period, the subject may be rescreened and is 
to receive a new subject number.
Patients that are randomized (assigned a subject number), but are not transplanted and not
dosed per assigned regimen will be replaced to ensure that 60 evaluable subjects are dosed.
The randomization schedules that determine subject treatment will be computer-generated by 
Astellas Pharma US Research Data Science department (or designee) before the beginning of 
the study.
Specific procedures for randomization through the IRT are contained in the study-specific 
IRT manual.
The Randomization list will be maintained in the IRT.




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5.1.2
Increase or Reduction in Dose of the Study/Drug(s)
5.1.2.1 Bleselumab
Increases or reductions of bleselumab ARE NOT allowed.
5.1.2.2 Basiliximab
Increases or reductions of basiliximab ARE NOT allowed.
5.1.2.3 Tacrolimus
Increases and reductions of tacrolimus ARE allowed, where medically indicated.
5.1.2.4 Mycophenolate Mofetil
Increases and reductions of MMF ARE allowed, where medically indicated.
5.1.3
Previous and Concomitant Treatment (Medication and Non-medication 
Therapy)
Previous, recent or concomitant use of hepatotoxic medications such as: drugs, toxins, and 
herbs, will be collected at screening, each visit and in case of liver related AE. All 
medications (type and route) will be recorded in the electronic Case Report Forms (eCRFs),
included in case narratives and used for analysis of hepatotoxicity related cases as necessary.
Refer to Appendix 12.1.1, List of Known Drug-Induced Hepatotoxicity, for the list of 
possible hepatotoxic medications.
All concomitant medications, immunosuppressive agents and therapies administered during 
treatment period through month 12/EOS will be recorded at each study visit on the eCRF. 
Subjects should be instructed not to take any new medications or change the dose and 
frequency of their ongoing medications throughout the study period without consulting the 
investigator.
Medications used for anesthesia purposes, with the exception of immunosuppressive agents 
and blood products, will not be recorded.
Any medication and therapies taken to treat an AE during the 12-month treatment period are to
be captured on the Concomitant Medication, Other Immunosuppressant, or Non-medication 
eCRFs.
All investigational medication administered as part of another clinical study are prohibited and 
must be discontinued up to 30 days or 5 half-lives (depending on medication) prior to initiating 
study drug.
Any immunologic biologic compound will be prohibited and must be discontinued at least 
8 weeks prior to transplant.


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5.1.3.1 Other Immunosuppressant Medications
A subject who has previously received a kidney organ transplant and is currently on an 
immunosuppression regimen that includes MMF, or any of its components, must discontinue
MMF.
A switch from MMF to mycophenolic acid (Myfortic®) will be allowed for medical reasons 
but will not be supplied by the Sponsor.
All other immunosuppressant medication substitutions must be discussed with the medical 
monitor to determine continuation of bleselumab infusions as applicable.
Any additional immunosuppressive medications used throughout the study are to be recorded 
on the appropriate eCRF.
5.1.3.2 Cytomegalovirus Prophylaxis
All subjects (with the exception of those in whom both the donor and recipient are 
serologically negative [D-/R-] for CMV) must receive prophylaxis with valganciclovir that 
will be dosed consistent with the package insert. Duration of therapy should be approximately 
200 days in D+/R- combinations, and approximately 100 days in the remaining subjects.
For leukopenia, the recommended approach is to adjust doses of other drugs that may be 
associated with leukopenia prior to making changes in the valganciclovir dose.
5.1.3.3 Pneumocystis jiroveci Pneumonia Prophylaxis
Pneumocystis jiroveci pneumonia prophylaxis must be administered to all study participants 
according to the standard institutional protocol and applied uniformly to all enrolled subjects 
regardless of treatment group. If there is no institutional protocol, the investigator must decide 
on appropriate Pneumocystis jiroveci pneumonia prophylaxis.
5.1.3.4 Fungal Prophylaxis
A standard antifungal prophylactic regimen per institutional protocol must be given uniformly 
to all enrolled subjects regardless of treatment group. If there is no institutional protocol, the 
investigator must decide on appropriate fungal prophylaxis.
5.1.3.5 Bacterial Prophylaxis
Peri-operative bacterial prophylaxis must be given per institutional protocol and should be 
given uniformly to all enrolled subjects regardless of treatment group. If there is no 
institutional protocol, the investigator must decide on appropriate bacterial prophylaxis.
5.1.4
Treatment Compliance
Study subjects should be counseled on the need to be compliant with their study drug 
regimen.


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5.1.5
Restrictions During the Study
Subjects must discontinue bleselumab per below, but are allowed to continue on the 
protocol-defined visit schedule for the collection of safety and clinical assessment information:
●
Subjects whose liver function tests meet one of the following criteria, verified by two (2) 
consecutive measurements, and in the absence of other etiologies (e.g., biliary stenosis or 
obstruction, viral hepatitis other than CMV, etc.):
●
ALT or AST > 8 x upper limit of normal (ULN)
●
ALT or AST > 5 x ULN for more than 2 weeks
●
ALT or AST > 3 x ULN and (total bilirubin [TBL] > 2 x ULN or international 
normalized ratio [INR] > 1.5 x ULN)
●
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
●
BK nephropathy confirmed by renal biopsy (Section 5.5.1.1.5)
●
CMV End Organ Disease (Appendix 12.6)
●
Subjects who develop severe bone marrow suppression as defined by the following in the 
absence of other etiologies (e.g., bleeding, other established causes of neutropenia) and 
have been verified by two (2) consecutive results within 14 days of the first detection 
that occur after Day 28 post-transplant:
●
Anemia: Hemoglobin < 6.5 g/dL graded National Cancer Institute Common 
Terminology Criteria for Adverse Events criteria (NCI-CTCAE) Grade 4 and/or
●
Agranulocytosis: Absolute Neutrophil Count (ANC) < 100 cells/mm3 graded 
NCI-CTCAE Grade 4
●
Subjects who require plasmapheresis for any reason post-initial bleselumab treatment
●
In the subjects’ best interest per Investigator discretion
5.2
Demographics and Baseline Characteristics
5.2.1
Demographics
The following demographic information will be collected during screening: date of birth, sex, 
race and ethnicity.
5.2.2
Medical History
Site personnel will collect and record information regarding the subject’s medical history 
during the screening period and any changes between screening and randomization are to be 
captured. Medical history includes: diagnosis for renal failure, duration and severity of renal 
disease at randomization, previous kidney transplant (no or yes), date of previous kidney 
transplant, graft failure due to rFSGS (no or yes), date of transplant failure, and screening 
medications (30 days prior to transplant). Additionally, the following information will be 
obtained: type of transplant (living related, living non-related, or deceased donor), total 
ischemia time in hours and minutes; length of transplant surgery, and panel reactive antibody 
testing (most recent cPRA level). A copy of the donor kidney biopsy report is to be collected 
where available.


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Donor viral serology information (HBV, HCV, CMV, and EBV), if available, will be 
collected and recorded.
5.2.3
Diagnosis of the Target Disease, Severity, and Duration of Disease
Medical/surgical history including de novo kidney recipient and has biopsy-proven, pFSGS 
as a cause of ESRD in their native kidneys at randomization will be collected at screening.
5.3
Efficacy | Pharmacokinetics | Immunogenicity Assessment
The last value prior to the first study drug dose will be used as the baseline to which post-
study drug dosing values will be compared.
5.3.1
Efficacy
5.3.1.1 Recurrence of Focal Segmental Glomerulosclerosis
The primary efficacy variable rFSGS is defined as nephrotic range proteinuria with a protein-
creatinine ratio (≥ 3.0 g/g) through 3 months post-transplant. Death, graft loss or lost to 
follow-up will be imputed as rFSGS.
This definition and imputation rule will be used to define the secondary variables and the 
rFSGS through 6 and 12 months post-transplant.
5.3.1.2 Blinded, Central Read for Recurrence of Focal Segmental Glomerulosclerosis
All episodes of kidney dysfunction based on clinical signs and symptoms will be evaluated 
by a biopsy at the local pathological laboratory for recurrence of FSGS and for possible 
rejection. The same slides and images of the biopsy will also be sent to a central pathology 
lab and read by an independent pathologist to determine recurrence of FSGS. The central 
pathology lab will not be provided the subject’s treatment regimen. 
Subjects who have not had a biopsy with a diagnosis of recurrent FSGS by 3 months post-
transplant will have a protocol-defined biopsy at the day 90/month 3 visit. There are no other 
protocol-required biopsies. All other biopsies conducted will be ‘for cause’ only.
5.3.1.3 Biopsy-proven Acute Rejection
All episodes of kidney dysfunction based on clinical signs and symptoms will be evaluated for 
possible rejection. All subjects should have biopsy confirmation of rejection before treatment 
is begun or within 48 hours of initiation of treatment for acute rejection. The pathologist at the 
clinical site will grade all biopsies using the 2007 Banff criteria (Appendix 12.8, Grading of 
Acute Kidney Allograft Rejection). Biopsy-proven acute rejection (BPAR, T- or B-cell) will 
be determined by local review. All biopsies should be evaluated for presence of C4d.
Subjects who receive immunosuppressive medications for the treatment of suspected or 
biopsy-confirmed acute rejection are considered to have a clinically-treated acute rejection. 
The rejection treatment start date will be used to denote the start for the clinically treated 
acute rejection. If the subject has an acute rejection, allowable rejection therapy may include, 
but is not limited to, steroid pulse, thymoglobulin, basiliximab, OKT3, or alemtuzumab.


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Subjects may remain on their assigned treatment regimen following treatment of acute 
rejection. If subjects permanently discontinue bleselumab, tacrolimus or MMF treatment, 
they are to continue with the protocol-defined visit schedule (Table 1, Schedule of 
Assessments) for the collection of safety and clinical assessment information.
5.3.2
Exploratory Efficacy Variables
The following exploratory efficacy variables will be assessed:
●
Graft and patient status through 12 months post-transplant
●
GFR based on MDRD criteria through 12 months post-transplant
●
Recurrence of FSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥ 3.0 g/g)
●
Time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g)
●
Time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g) or initiation of plasmapheresis
●
Time to rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥3.0 g/g), death, graft loss or lost to follow-up
●
Time to recurrence of biopsy-proven (blinded, central read) FSGS
●
Time to first BPAR (Banff Grade ≥ 1, local read)
●
Urine protein-creatinine ratio through 6 and 12 months post-transplant
●
Urine albumin-creatinine ratio through 3, 6 and 12 months post-transplant
●
Change in auto-anti-CD40 antibodies from baseline
●
Change in patient-reported outcomes from baseline (SF-36s, EQ-5D-5L and KTQ)
5.3.3
Pharmacokinetics
Further details on sample collection, processing, labeling, storage, and shipment procedures 
will be provided in the laboratory manual.
5.3.3.1 Bleselumab
Sample collection for bleselumab pharmacokinetics for subjects in Arm 2 ONLY is to occur 
at the times shown in Table 1, Schedule of Assessments. The timing of blood collections will 
take priority over all other scheduled study assessments except for study drug dosing.
Pharmacokinetic samples are to be collected within 30 minutes or less pre-initial, and post-
initial, intraoperative bleselumab infusion at baseline (day 0). Two single, pharmacokinetic
samples are to be collected at each subsequent 30-minute intravenous infusion: one within 
30 minutes or less prior to the infusion (trough concentration), and the other at the end of the 
infusion (peak concentration) up through visit day 28. After that only trough concentrations 
(within 30 minutes or less pre-infusion) are to be collected up through day 90/month 3, and 
months 6, 9 and 12/EOS visits.


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5.3.3.2 Anti-Bleselumab and Bleselumab Bi-Specific Antibodies
Sample collection for anti-bleselumab and bleselumab bi-specific antibodies for subjects in 
Arm 2 ONLY is to occur at the times shown in Table 1, Schedule of Assessments. The timing 
of blood collections will take priority over all other scheduled study assessments except for 
study drug dosing.
Anti-bleselumab antibody samples are to be collected prior to each infusion at baseline (day 0), 
visit days 14, 28, 90/month 3, and months 6, 9, and 12/EOS.
Bleselumab bi-specific antibody samples are to be collected prior to each infusion at baseline 
(day 0), visit day 90/month 3, and months 6, 9, and 12/EOS.
5.3.3.3 Auto-Anti-CD40 Antibody
Sample collection for auto-anti-CD40 antibodies for subjects in BOTH Arms 1 and 2 is to 
occur at the times shown in Table 1, Schedule of Assessments. The timing of blood collections 
will take priority over all other scheduled study assessments except for study drug dosing.
Samples are to be collected at screening, and prior to infusion at baseline (day 0), visit days 7, 
14, 28, 56, 90/month 3, and months 6, 9 and 12/EOS.
5.4
Safety Assessment
The safety assessments include the following:
●
AEs graded by NCI CTCAE criteria
●
Vital sign measurements
●
Clinical laboratory tests
●
Bleselumab pharmacokinetics (including anti-bleselumab and bleselumab bi-specific 
antibodies)
●
Viral serology (HBV, HCV CMV and EBV)
●
Viral load testing (CMV, BKV and EBV)
Unscheduled assessments will be performed if clinically warranted. Refer to Table 1,
Schedule of Assessments, for the visit assessment collection schedule.
5.4.1
Vital Sign Measurements
Vital sign measurements are to be collected as shown in Table 1, Schedule of Assessments.
Vital signs, including body temperature, systolic and diastolic blood pressure and pulse rate will 
be collected at all study visits. When vital signs are to be collected at the same time as a blood 
sample, vital signs are to be taken prior to the blood draw.
5.4.2
Adverse Events
See Section 5.5, Adverse Events and Other Safety Aspects, for information regarding AE 
collection and data handling.


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5.4.2.1 Adverse Events of Possible Hepatic Origin
See Appendix 12.2, Liver Safety Monitoring and Assessment, for detailed information on 
liver abnormalities, monitoring and assessment, if the AE for a subject enrolled in a study and 
receiving study drug is accompanied by increases in LFTs, bilirubin, hepatic enzyme 
increased (e.g., AST, ALT) or is suspected to be due to hepatic dysfunction.
Subjects with AE’s of hepatic origin accompanied by LFT abnormalities should be evaluated 
and carefully monitored.
Please review the requirements related to the evaluation, reporting and analysis of Drug-Induced 
Liver Injury (DILI) information found in Appendix 12.2, Liver Safety Monitoring and 
Assessment. In the event of a confirmed, marked hepatic abnormality as defined in Section 12.2, 
it is the Investigator’s responsibility to ensure contact with the Sponsor/delegated contract 
research organization (CRO) by telephone or fax immediately (i.e., within 24 hours of 
awareness).
5.4.3
Laboratory Assessments
Below are the local and central laboratory assessments that will be performed during the 
conduct of the study. Refer to Table 1, Schedule of Assessments, for study visit collection days.
Clinical significance of out-of-range laboratory findings is to be determined and documented 
by the Investigator/sub-Investigator who is a qualified physician.
Screening safety laboratory tests may be repeated in order to confirm eligibility.
5.4.3.1 Local Laboratory Testing
Blood and urine will be collected for the following local laboratory assessments:
●
Histocompatibility and crossmatch
o
Record prior results at screening
●
ABO compatibility
o
Record prior results at screening
●
Hematology (hemoglobin, hematocrit, RBCs, white blood cells [WBCs] with differential 
[including bands, if available] and platelet count)
●
Biochemistry (phosphorus, total protein, serum creatinine, blood urea nitrogen [BUN], 
albumin, creatine phosphokinase [CPK], LDH, amylase, electrolytes [sodium, potassium, 
calcium, magnesium, bicarbonate, chloride], and fasting glucose)
●
Coagulation/thrombotic pathway (prothrombin time, activated partial thromboplastin 
time and INR)
●
Hepatic profile (total and direct bilirubin, AST, ALT and ALP)
●
Lipid profile (total cholesterol [including low-density lipoprotein (LDL), high density 
lipoprotein [HDL] and triglycerides])
o
Blood specimen for the lipid profile should be drawn after the subject has fasted 
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Urinalysis (pH, specific gravity, protein, glucose, ketones, bilirubin, blood and
microscopic evaluation)
●
Urine protein-creatinine ratio and urine albumin-creatinine ratio via a spot collection
●
Serum pregnancy testing for females of child bearing potential
o
Post-initial serum pregnancy test (collected on admission to the hospital or 
within 7 days prior to transplant), all subsequent pregnancy tests are via urine 
and are to be collected prior to continued treatment
o
If a urine pregnancy test is positive at any time, a serum pregnancy test is to be 
performed and MUST be negative for the subject to continue participation in the 
study
●
Recipient viral serologies (i.e., antibodies [e.g., HBV, HCV, CMV and EBV])
o
Those performed > 1 year prior to transplant are to be repeated within the 
screening period (up to 21 days prior to transplant)
o
Results do not need to be available for randomization
o
Post-screening testing is to be conducted at visit day 90/month 3, and month 12/EOS
●
Viral load testing (CMV, BKV [serum and urine] and EBV)
o
Conducted at screening, days 14, 28, 56 and 90/month 3, and months 4, 5, 6 and 
12/EOS, ONLY if recipient viral serologies were positive at any time
●
Tacrolimus whole blood trough level specimens
o
11 - 13 hours post-initial dose, and immediately prior to all subsequent infusions
5.4.3.2 Central Laboratory Testing
Blood will be collected for the following central laboratory assessments:
●
Bleselumab pharmacokinetic levels
●
Anti-bleselumab antibodies
●
Bleselumab bi-specific antibodies
●
Auto-anti-CD40 antibodies
Refer to the laboratory manual for detailed instructions on sample collection, processing, 
labeling, storage and shipment procedures.
Refer to Appendix 12.2 for additional DILI laboratory testing requirements and timing.
5.4.4
Physical Examination
The subject will be examined by a medically qualified person, at the times specified in 
Table 1, Schedule of Assessments.
A complete physical examination consisting of an examination of general appearance, eyes, 
nose throat, neck (including thyroid), lymph nodes, chest, lungs, cardiovascular, abdomen, 
skin, extremities, musculoskeletal, and neurological system including mental status is to be 
conducted at screening, day 90/month 3 and month 12/EOS. A symptom-directed physical 
exam may be performed at any of the other visits, if necessary.


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Height will be measured one time at screening only. Weight will be collected at all visits.
The screening physical examination also includes significant, ongoing medical conditions. 
Any changes between screening and randomization are to be captured in the medical/surgical 
history.
Any abnormal finding(s) at screening must not be exclusionary per the eligibility criteria and 
must be assessed and documented as not clinically significant if a subject is to be enrolled in 
the study. Post-initial study drug dosing, new abnormal findings or a worsening of an 
ongoing abnormal condition must be recorded as an AE.
5.4.5
Electrocardiogram
Standard 12-lead electrocardiogram (ECG) recordings will be used for the purposes of safety 
assessment and subject management by the Investigator.
A 12-lead, resting ECG is to be recorded at each timepoint as indicated in Table 1, Schedule of 
Assessments. Subjects should remain supine for at least 5 minutes prior to all ECGs being 
performed. Dates and times may be generated by the machine’s internal clock and are 
considered source data. The results are to be interpreted by qualified personnel in real time for 
the management of the subjects’ clinical condition. The principal investigator (PI)/designee 
will initial and date, and provide his/her clinical interpretation on each report. The results 
(normal, abnormal not clinically significant, abnormal clinically significant) are to be recorded 
in the eCRFs.
The ECG recorded during screening will be used to determine eligibility for study 
participation. Subjects who have a clinically significant abnormal ECG will not be eligible for 
the study. The interpretation of the ECG from screening will be the baseline to which post-
study drug dosing ECGs will be compared.
Unscheduled ECGs will be performed if clinically indicated.
ECGs should be performed before the scheduled pharmacokinetic blood draws.
If a machine-read QTc exceeds 500 msec, this should be reported as an AE.
The original print-out and an electronic copy of all scheduled and unscheduled ECG tracings 
should be maintained on site as source data.
5.4.6
Imaging
A chest radiograph (x-ray) is to be performed in two views – lateral and anterior-posterior 
will be used for the purposes safety assessment and subject management by the Investigator.
Chest x-rays are to be performed as indicated in Table 1, Schedule of Assessments. The results 
are to be interpreted by qualified personnel in real time for the management of the subjects’
clinical condition. The PI/designee will initial and date, and provide his/her clinical 
interpretation on each report. The results (normal, abnormal not clinically significant, abnormal 
clinically significant) are to be recorded in the eCRF.


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Subjects who have x-ray findings suggestive of acute or chronic lung disease may be eligible 
for the study and must be discussed with the Sponsor Medical Monitor before the subject is 
enrolled in the study.
Subjects who have had a normal chest x-ray within 3 months of screening are not required to 
have x-rays performed at screening, per Investigator discretion.
The interpretation of the chest x-ray from screening will be the baseline to which post-study 
drug dosing x-rays will be compared.
Unscheduled chest x-rays will be performed if clinically indicated.
5.5
Adverse Events and Other Safety Aspects
5.5.1
Definition of Adverse Events (AEs)
An AE is defined as any untoward medical occurrence in a subject administered a study drug 
or has undergone study procedures and which does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product.
All AEs will be recorded in the eCRF from the time of consent through 30 days post-last 
dose. For ALL subjects this is to conclude at the month 12/EOS visit. (The transplant that 
occurs on day 0 is not considered an AE or an SAE).
Some countries may have additional local requirements for events that are required to be 
reported as AEs or in an expedited manner similar to an SAE. In these cases, it is the 
investigator’s responsibility to ensure these AEs or other reporting requirements are followed 
and the information is appropriately recorded in the eCRF accordingly.
An abnormality identified during a medical test (e.g., laboratory parameter, vital sign, ECG 
data, physical exam) should be defined as an AE only if the abnormality meets one of the 
following criteria:
●
Induces clinical signs or symptoms
●
Requires active intervention
●
Requires interruption or discontinuation of study medication
●
The abnormality or investigational value is clinically significant in the opinion of the 
investigator.


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5.5.1.1 Definitions of Specific Adverse Events
5.5.1.1.1
Infection
Bacterial, fungal and viral infections are to be reported as an AE or an SAE.
Except for CMV, EBV and BK, infection is defined as any of the following:
●
Treatment with a antimicrobial agent for a specific clinical syndrome (not prophylaxis)
●
Positive cultures, pathologic identification of microbial agents or significant serological 
changes related to clinical symptoms
●
Typical clinical presentation documented by investigator or appropriate consultant
●
Other infectious hepatitis to be considered as differential diagnosis in case of LFT 
abnormalities
5.5.1.1.2
Definition of Cytomegalovirus
Cytomegalovirus (CMV) active infection:
●
Replicative infection can be diagnosed by growing the virus in vitro, finding evidence of 
viral infection by intra-cytoplasmic or intra-nuclear inclusions or by antibody-based 
staining techniques for CMV in histopathologic sections or finding evidence of replication 
using nucleic acid based assays or antigenemia studies.
CMV disease:
●
CMV disease is defined by evidence of CMV infection with attributable symptoms. CMV 
disease can be subclassified into CMV viral syndrome or tissue invasive disease. 
Definitions are listed in Appendix 12.6, Definition of CMV Disease in Solid Organ 
Transplant Recipients.
5.5.1.1.3
Definition of Epstein-Barr Virus
Epstein-Barr Virus (EBV) infection:
●
Active, asymptomatic EBV infection is defined by the presence of a detectable EBV 
viral load as measured by a nucleic acid amplification assay. Asymptomatic infection 
may also be identified in lymphoid rich histopathologic specimens.
EBV disease:
●
EBV disease is defined by the presence of active EBV infection with symptoms or signs 
attributable to the virus. 
5.5.1.1.4
BK Virus Infection
BK virus (BKV) infection (replicative infection) defined as quantitative BK viral DNA load, in 
blood or urine above the detection threshold for the given laboratory's assay. BK infection 
should be classified as either BK viruria or BK viremia or both. While the presence of decoy 
cells in urine on cytology is suggestive of BK infection, confirmation with a specific test (e.g., 
polymerase chain reaction [PCR]) is required.


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5.5.1.1.5
BK Virus Associate Nephropathy
Proven BKVAN is defined by evidence of BKV infection and the presence of:
●
Renal biopsy associated with:
o
an acute tubular necrosis-like picture or
o
interstitial nephritis mimicking acute rejection or
o
chronic allograft nephropathy with confirmation of the presence of BKV by 
electron microscopy, immunohistochemistry or in-situ hybridization for BKV. 
Although intra-nuclear viral inclusions are usually seen, their presence is not 
mandatory for a diagnosis of BKVAN. 
For purposes of this study, subjects with presumptive BKVAN diagnosed in the presence of 
renal allograft dysfunction and a positive BKV DNA PCR result from blood in a subject with 
no viral inclusions at light microscopy and negative immunohistochemistry/in-situ
hybridization should be classified as BKV infection (i.e., BK viremia rather than BKVAN).
5.5.1.1.6
Malignancy
All malignancies are to be captured as AEs.
5.5.1.1.7
Post-transplant Lymphoproliferative Disorder
Diagnosis of PTLD should be made following review of tissue specimens. The anatomic staging 
of PTLD will be captured, specifically if the allograft or if the central nervous system (CNS) is 
involved. PTLD will be classified according to the criteria in Appendix 12.7  Additionally, if 
available, ancillary pathologic information related to cell phenotype, clonality, presence of EBV 
in the tissue specimen, and donor vs. recipient origin will be collected.
Tissue samples should be interpreted by a hematopathologist or pathologist who is familiar with 
the histopathologic features of PTLD. If as a matter of the subject’s routine medical evaluation 
tissues are examined for the presence of EBV by in situ hybridization, the cell of origin (B, T, 
null, mixed) is determined or radiographic evaluation is performed to document the extent of 
disease (e.g., computed tomography scans) this information will be captured on the eCRF.
5.5.2
Definition of Serious Adverse Events)
An AE is considered “serious” if, in the view of either the Investigator or Sponsor, it results 
in any of the following outcomes:
●
Results in death
●
Is life threatening (an AE is considered “life-threatening” if, in the view of either the 
Investigator or Sponsor, its occurrence places the subject at immediate risk of death. It 
does not include an AE that, had it occurred in a more severe form, might have caused 
death)
●
Results in persistent or significant disability/incapacity or substantial disruption of the 
ability to conduct normal life functions
●
Results in congenital anomaly, or birth defect


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●
Requires inpatient hospitalization or leads to prolongation of hospitalization 
(hospitalization for treatment/observation/examination caused by AE is to be considered 
as serious) 
●
Other medically important events
Medical and scientific judgment should be exercised in deciding whether expedited reporting 
is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the 
definition above. These events, including those that may result in disability/incapacity, 
should also usually be considered serious. Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions 
that do not result in hospitalization; or development of drug dependency or drug abuse.
Special situation events on the medicinal products administered to the subject as part of the 
study (e.g., study drug, comparator, background therapy) that may require expedited 
reporting and/or safety evaluation include, but are not limited to:
●
Overdose of the medicinal product(s)
●
Suspected abuse/misuse of the medicinal product(s)
●
Inadvertent or accidental exposure to the medicinal product(s)
●
Medication error involving the medicinal product(s) (with or without subject/patient 
exposure to the Sponsor medicinal product, e.g., name confusion)
All of the special situation events noted above should be recorded on the eCRF. Any situation 
involving these special situation events that also meets the criteria for an SAE should be
reported as an SAE, recorded on the AE page of the eCRF and marked ‘serious’ on the SAE 
worksheet.
All the special situation events will be recorded from the time of consent through 30 days 
post-last dose.
The Sponsor has a list of events that they classify as “always serious” events. If an AE is 
reported that is considered to be an event per this classification as “always serious,” additional 
information on the event may be requested, those events should be reported as an SAE.
If a subject or a subject’s partner becomes pregnant during the study, this should be reported as 
if it were an SAE (Section 5.5.8, Procedure in Case of Pregnancy).
5.5.3
Criteria for Causal Relationship to the Study Drug
Adverse events that fall under either "Possible" or "Probable" should be defined as "AEs 
whose relationship to the study drugs could not be ruled out." Relationship to study drug will 
be assessed using the following criteria:


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Causal relationship to 
the study drug
Criteria for causal relationship
Not Related
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and/or in which other drugs, chemicals or underlying disease 
provide plausible explanations.
Possible
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, but which could also be 
explained by concurrent disease or other drugs or chemicals. Information 
on drug withdrawal may be lacking or unclear.
Probable
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to administration of the drug, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on re-administration (rechallenge) or 
withdrawal (dechallenge).
5.5.4
Criteria for Defining the Severity of an Adverse Event
Adverse events, including abnormal clinical laboratory values, will be graded using the NCI
CTCAE guidelines (Version 4.03). The items that are not stipulated in the NCI CTCAE 
Version 4.03 will be assessed according to the criteria below and entered into the eCRF:
Grade
Assessment Standard
1 - Mild
Asymptomatic or mild symptoms, clinical or diagnostic observations noted; 
intervention not indicated.
2 - Moderate
Local or noninvasive intervention indicated.
3 - Severe
Medically significant but not immediately life threatening, hospitalization or 
prolonged hospitalization.
4 - Life Threatening
Life threatening consequences, urgent intervention indicated.
5 - Death
Death related to AE.
5.5.5
Reporting of Serious Adverse Events (SAEs)
SAEs will be captured for all subjects from the time the subject signs the informed consent. If 
a subject signs the informed consent but never receives study drug or is deemed a screen 
failure, any SAEs reported from the time of consent until determination of screen failure 
should be reported to the Sponsor via an SAE worksheet and followed until resolution. For 
subjects who are randomized, SAEs will be captured from the time of consent 30 days post-
last dose. For ALL subjects this is to conclude at the month 12/EOS visit.
In the case of a SAE, the Investigator must contact the Sponsor by telephone, fax or email
immediately (within 24 hours of awareness).
The Investigator should complete and submit an SAE Worksheet containing all information 
that is required by the Regulatory Authorities to the Sponsor by fax or email immediately 
(within 24 hours of awareness). If the faxing of an SAE Worksheet is not possible or is not 
possible within 24 hours, the local drug safety contact should be informed by phone.


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For contact details, see Section II Contact Details of Key Sponsor's Personnel. Please fax or 
email the SAE Worksheet to: 
Astellas Pharma Global Development, Inc.
Medical Safety Pharmacovigilance
Fax number: 1-888-396-3750
Email: safety-us@astellas.com
If there are any questions, or if clarification is needed regarding the SAE, please contact the 
Sponsor's Medical Director (Section II, Contact Details of Key Sponsor’s Personnel).
Follow-up information for the event should be sent promptly (within 7 days if the initial 
notification) as necessary.
Full details of the SAE should also be recorded on the medical records and on the eCRF.
The following minimum information is required:
●
ISN/Study number 
●
Subject number (for randomized subjects only), sex and age
●
The date of report
●
A description of the SAE (event, seriousness of the event)
●
Causal relationship to the study drug
●
Batch number of study medication
The Sponsor or Sponsor's designee will submit expedited safety reports (i.e., IND Safety 
Reports) to the regulatory agencies (i.e., FDA) as necessary, and will inform the investigators 
of such regulatory reports. Investigators must submit safety reports as required by their 
IRB/IEC within timelines set by regional regulations (i.e., EU, (e)CTD, FDA). Documentation 
of the submission to and receipt by the IRB/IEC of expedited safety reports should be retained 
by the site.
The Sponsor will notify all Investigators responsible for ongoing clinical studies with the study 
drug of all SAEs which require submission per local requirements to their IRB/IEC.
The Investigators should provide written documentation of IRB/IEC notification for each 
report to the Sponsor.
You may contact the Sponsor's Medical Monitor/Expert for any other problem related to the 
safety, welfare, or rights of the subject.
5.5.6
Follow-up of Adverse Events
All AEs occurring during or after the subject has discontinued the study are to be followed up 
until resolved or judged to be no longer clinically significant, or until they become chronic to 
the extent that they can be fully characterized.
If during AE follow-up, the AE progresses to an "SAE," or if a subject experiences a new 
SAE, the investigator must immediately report the information to the Sponsor.


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Please refer to Appendix 12.2, Liver Safety Monitoring and Assessment, for detailed 
instructions on DILI.
5.5.7
Monitoring of Common Serious Adverse Events
Common SAEs are anticipated to occur in the study population independent of drug 
exposure. SAEs classified as “common” are provided in Appendix 12.3, Common Serious 
Adverse Events. The list does NOT change your reporting obligations or prevent the need to 
report an AE meeting the definition of an SAE as detailed above. The purpose of this list is to 
alert you that some events reported as SAEs may not require expedited reporting to the 
regulatory authorities based on the classification of “common SAEs” as specified in 
Appendix 12.3  The Sponsor will monitor these events throughout the course of the study for 
any change in frequency. Any changes to this list will be communicated to the participating 
investigational sites. Investigators must report individual occurrences of these events as stated 
in Section 5.5.5, Reporting of Serious Adverse Events.
5.5.8
Procedure in Case of Pregnancy
If a female subject or partner of a male subject becomes pregnant during the study dosing 
period or within 30 days from the discontinuation of dosing, the Investigator should report the 
information to the Sponsor as if it is an SAE. The expected date of delivery or expected date of 
the end of the pregnancy, last menstruation, estimated contraception date, pregnancy result and
neonatal data etc., should be included in this information.
The Investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor.
When the outcome of the pregnancy falls under the criteria for SAEs [spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly (including anomaly in a 
miscarried fetus)], the Investigator should respond in accordance with the report procedure for 
SAEs. 
Additional information regarding the outcome of a pregnancy (which is categorized as an 
SAE) is mentioned below:
●
"Spontaneous abortion" includes miscarriage, abortion and missed abortion
●
Death of an infant within 1 month after birth should be reported as an SAE regardless of 
its relationship with the study drug
●
If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by 
the Investigator
●
In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
the birth
●
Unless a congenital anomaly is identified prior to spontaneous abortion or miscarriage, 
the embryo or fetus should be assessed for congenital defects by visual examination.


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If during the conduct of a clinical trial, a male subject makes his partner pregnant, the subject 
should report the pregnancy to the Investigator. The Investigator will report the pregnancy to 
the Sponsor as an SAE.
5.5.9
Emergency Procedures and Management of Overdose
In the event of suspected bleselumab overdose, the subject should receive supportive care and 
monitoring. The Astellas Medical Monitor/Expert should be contacted as applicable.
5.5.10
Supply of New Information Affecting the Conduct of the Study
When new information becomes available necessary for conducting the clinical study properly, 
the Sponsor will inform all Investigators involved in the clinical study as well as the regulatory 
authorities. Investigators should inform the IRB/IEC of such information when needed.
5.6
Test Drug Concentration
5.6.1
Blood Sampling and Processing for Bleselumab
Whole blood samples (4 mL/sample) for pharmacokinetics will be collected via venipuncture 
or cannulation of a forearm vein(s) into a serum separating tube (SST).
Blood collection for analysis will be performed according to Table 1, Schedule of 
Assessments.
Refer to the laboratory manual for detailed instructions on sample collection, processing, 
labeling, storage and shipment procedures.
Measurement of the pharmacokinetics, anti-bleselumab antibodies, bleselumab bi-specific 
antibodies, auto-anti-CD40 antibodies, and potentially for podocyte injury, in serum, will be 
performed using a validated method at a bioanalytical laboratory specified by the Sponsor.
5.7
Other Measurements, Assessments or Methods
5.7.1
Patient-reported Outcomes
All patient-reported outcome (PRO) measures will be completed by the subject via 
computerized administration on a sponsor-sourced, vendor-provided electronic device.
If a subject is not able to provide an answer to the question(s), it is not a requirement to 
complete the rest of the ePRO assessment(s) at the respective visit.
5.7.1.1 Short Form 36-Item Health Survey Score
The Short Form 36-Item Health Survey Score (SF-36s, version 2.0, Appendix 12.9) is a 
measure of health status. The SF-36 provides scores for each of the 8 health domains and 
psychometrically-based physical component summary (PCS) and mental component 
summary (MCS) scores.
The 8 domains are the weighted sums of the questions in their section. Each domain is 
directly transformed into a 0 - 100 scale on the assumption that each question carries equal 
weight. Lower scores indicate greater disability. The higher the score the less disability (i.e., 


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a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no 
disability).
The SF-36s is a multipurpose health survey that measures overall health status, functional 
status, and health-related quality of life. It is a generic measure and its use is not restricted to 
a single disease state. Using an 8-scale profile of physical and mental health summary 
measures, the SF-36s is a valid and reliable tool that allows comparisons between and within 
clinical and general populations.
Subjects will complete this self-assessment at screening, days 14 and 90/month 3, and 
months 6 and 12/EOS visits.
5.7.1.2 European Quality of Life – 5 - Dimensions - 5 Levels
The European Quality of Life – 5-Dimensions – 5 Levels (EQ-5D-5L, Appendix 12.10) is an 
international standardized non-disease specific (i.e., generic) instrument for describing and 
valuing health status. It is a measure of health-related QoL, capable of being expressed as a 
single index value and specifically designed to complement other health status measures. The 
questionnaire will be provided in the local language of the subject. The EQ-5D-5L has 
5 dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression. 
In the newest version, each dimension has 5 response levels (e.g., no problems, slight 
problems, moderate problems, severe problems and unable to perform the activity). In addition, 
it has a visual analogue scale (VAS) that elicits a self-rating by the respondent of his/her health 
status.
The EQ-5D-5L is to be completed by the subject at screening, and at the day 90/month 3 and 
month 12/EOS visits.
5.7.1.3 Kidney Transplant Questionnaire
The Kidney Transplant Questionnaire (KTQ, Appendix 12.11) is a 25-item questionnaire that 
includes 5 domains or subscales (i.e., physical symptoms [based on 6 items], fatigue [based on 
5 items], uncertainty/fear [based on four items], appearance [based on four items], and 
emotional [based on six items].
A mean score ranging from 1 to 7 is reported for each of the 5 subscales, with higher scores 
representing better functioning, well-being, or fewer problems [Laupacis et al, 1993].
Subjects are to complete this self-assessment at screening, days 14 and 90/month 3, and 
months 6 and 12/EOS visits.
5.7.2
Blood Sample for Future Pharmacogenetic Analysis (Retrospective PGx Analysis)
Pharmacogenetic (PGx) research may be conducted in the future to analyze or determine genes 
of relevance to clinical response, pharmacokinetics, and toxicity/safety issues. After 
randomization (see schedule of assessments), a 4 mL sample of whole blood for possible 
retrospective PGx analysis will be collected using a vacutainer tube containing EDTA. After 
collection, gently invert the blood sample 8 to 10 times. The blood collection tube may either 


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be stored upright at 4°C for up to 5 days prior to shipment or stored frozen at -20°C or below at 
the site for extended storage. Samples will be shipped to a Sponsor designated banking CRO.
Labels should uniquely identify each sample and contain at least:
●
Protocol number (7163-CL-3201)
●
Subject number
●
Purpose and biological matrix (i.e., “biobanking,” “whole blood”)
Details on sample collection, labeling, storage and shipment procedures will be provided in 
the laboratory manual.
See Appendix 12.4, Retrospective Pharmacogenetic Sub-study for further details on the 
banking procedures.
5.8
Total Amount of Blood
The total volume of whole blood (including for clinical laboratory, pharmacokinetic and 
pharmacogenetic sampling) that is to be collected during the entire study is approximately 415 
mL per subject for subjects in Arm 2 and approximately 
360 mL for subjects in Arm 1.
A volume of approximately 300 mL will be collected from screening through month 12/EOS 
for scheduled clinical “safety” laboratory evaluations including serum pregnancy (for 
females).
A total of approximately 118 and 64 mL will be collected during the study for 
pharmacogenetic and pharmacokinetic sampling over the course of the study for subjects in 
Arms 2 and 1, respectively.
6
DISCONTINUATION
6.1
Discontinuation of Individual Subject(s) 
A discontinuation is a subject who enrolled in the study and for whom study drug is 
permanently discontinued for any reason.
The subject is free to withdraw from the study treatment and/or study for any reason and at any 
time without giving reason for doing so and without penalty or prejudice. The investigator is 
also free to terminate a subject's involvement in the study at any time if the subject's clinical 
condition warrants it.
If a subject is discontinued from the study with an ongoing AE or an unresolved laboratory 
result that is significantly outside of the reference range, the investigator will attempt to 
provide follow-up until the condition stabilizes or no longer is clinically significant.
Subjects that permanently discontinue or replace bleselumab, tacrolimus or MMF in the post-
transplant period will be considered to have reached EOT and are to continue with the 
protocol-defined visit schedule (Table 1  Schedule of Assessments – Screening through 
12 months Post-Transplant), for the collection of safety and clinical assessment information.


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If a subject declines to be followed upon permanently discontinuing bleselumab, tacrolimus 
or MMF, the EOS visit (visit 21/month 12) procedures are to be completed within 30 days 
post-last dose.
Subjects must discontinue bleselumab per below, but are allowed to continue on the 
protocol-defined visit schedule for the collection of safety and clinical assessment 
information:
●
Subjects whose liver function tests meet one of the following criteria, verified by two (2) 
consecutive measurements, and in the absence of other etiologies (e.g., biliary stenosis or 
obstruction, viral hepatitis other than CMV, etc.):
●
ALT or AST > 8 x upper limit of normal (ULN)
●
ALT or AST > 5 x ULN for more than 2 weeks
●
ALT or AST > 3 x ULN and (total bilirubin [TBL] > 2 x ULN or international 
normalized ratio [INR] > 1.5 x ULN)
●
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
●
BK nephropathy confirmed by renal biopsy (Section 5.5.1.1.5)
●
CMV End Organ Disease (Appendix 12.6)
●
Subjects who develop severe bone marrow suppression as defined by the following in the 
absence of other etiologies (e.g., bleeding, other established causes of neutropenia) and 
have been verified by two (2) consecutive results within 14 days of the first detection 
that occur after Day 28 post-transplant:
●
Anemia: Hemoglobin < 6.5 g/dL graded National Cancer Institute Common 
Terminology Criteria for Adverse Events criteria (NCI-CTCAE) Grade 4 and/or
●
Agranulocytosis: Absolute Neutrophil Count (ANC) < 100 cells/mm3 graded 
NCI-CTCAE Grade 4
●
Subjects who require plasmapheresis for any reason post-initial bleselumab treatment
●
In the subjects’ best interest per Investigator discretion
6.2
Discontinuation of the Site
If an Investigator intends to discontinue participation in the study, the Investigator must 
immediately inform the Sponsor.
6.3
Discontinuation of the Study
The Sponsor may terminate this study prematurely, either in its entirety or at any study site, 
for reasonable cause provided that written notice is submitted in advance of the intended 
termination. Advance notice is not required if the study is stopped due to safety concerns. If 
the Sponsor terminates the study for safety reasons, the Sponsor will immediately notify the 
investigator and subsequently provide written instructions for study termination.


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7
STATISTICAL METHODOLOGY
The statistical analysis will be coordinated by the responsible biostatistician of APGD. A 
Statistical Analysis Plan (SAP) will be written to provide details of the analysis, along with 
specifications for tables, listings and figures (TLFs) to be produced. The SAP will be 
finalized prior to the interim data analysis of the 3-month primary endpoint, rFSGS. Any 
changes from the analyses planned in the SAP will be justified in the clinical study report 
(CSR).
Prior to database lock, a final meeting will be held to review data and tables, listings and 
figures (TLFs) to verify the data that will be used for analysis set classification. If required, 
consequences for the statistical analysis will be discussed and documented. A meeting to 
determine analysis set classifications may also be held prior to database lock.
In general, all data will be summarized with descriptive statistics (number of subjects, mean, 
standard deviation, minimum, median and maximum) for continuous endpoints, and 
frequency and percentage for categorical endpoints. There will be no adjustment for 
multiplicity in this proof-of-concept study.
7.1
Sample Size
The primary aim of this study is to assess the rFSGS defined as nephrotic range proteinuria 
with protein-creatinine ratio (≥ 3.0 g/g) through 3 months post-transplant. Death, graft loss or 
lost to follow-up will be imputed as rFSGS.
This proof of concept study will provide an estimate of the effect size for the difference in the 
rFSGS between the standard of care and the experimental group and provide estimates of the 
recurrence rates for each treatment group. The estimate of the effect size will be needed to 
plan a future study.
The following table provides a subset of estimates and the 95% confidence interval for the 
FSGS recurrence rate with 30 subjects per treatment group. The width of these confidence 
intervals varies between 17 and 36% indicating the limit of the precision for the estimate.
Proportion (%)
95% Confidence Interval with 30 subjects (%)
3.3 (1/30)
0.1 - 17.2*
16.7 (5/30)
3.4 - 30.0
33.3 (10/30)
16.4 - 50.2
50.0 (15/30)
32.1 - 67.9
66.7 (20/30)
49.8 - 83.6
83.3 (25/30)
70.0 - 96.6
96.7 (29/30)
82.8 - 99.9*
*Exact binomial confidence interval using Clopper-Pearson (Exact method based on the Beta distribution); for 
all others the normal approximation was used to calculate the intervals.


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It has been estimated from the literature that the expected FSGS recurrence rate for the SOC 
group is between 30 and 50% with most occurring by 3 months post-transplant. In the 
previous study with these same treatments in kidney transplant patients, there were 3 of
approximately 50 patients, who experienced death, graft loss or lost to follow-up, in each of 
the two planned treatment arms. Thus, imputing death, graft loss or lost to follow-up as 
rFSGS is not expected to have a sizeable and differential impact on the rFSGS estimates. 
Literature estimates of rFSGS were used to examine the precision of the treatment difference 
provided with 30 subjects per treatment group.
Bleselumab was assumed to decrease the recurrence rate in the experimental arm by 20% to 
60% relative to SOC. The following table provides the difference in the observed rates and 
the associated 2-sided 95% confidence interval with 30 subjects per group. The width of the 
confidence interval for the difference between the two treatment groups ranges between 47%
and 57%. The width of the confidence interval provides the precision of the estimate for the 
difference in recurrence between the two groups.
Bleselumab Rate
SOC Rate
50%
(15/30)
40%
(12/30)
30%
(9/30)
60% Reduction from SOC
0.20
(6/30)
0.167
(5/30)
0.133
(4/30)
Difference and 95% CI
(2-sided)
0.30
0.038 to 0.562
0.233
-0.021 to 0.487
0.167
-0.07 to 0.404
50% Reduction from SOC
0.267
(8/30)
0.20
(6/30)
0.167
(5/30)
Difference and 95% CI
(2-sided)
0.233
-0.039 to 0.505
0.20
-0.06 to 0.46
0.133
-0.112 to .355
40 % Reduction from SOC
0.30
(9/30)
0.267
(8/30)
0.20
(6/30)
Difference and 95% CI
(2-sided)
0.20
-0.068 to .434
0.133
-0.137 to 0.40
0.10
-0.151 to 0.351
30% Reduction from SOC
0.367
(11/30) 
0.30
(9/30)
0.23
(7/30)
Difference and 95% CI
(2-sided)
0.133
-0.149 to 0.415
0.10
-0.173 to 0.373
0.07
-0.186 to 0.326
20 % Reduction from SOC
0.40
(12/30)
0.333
(10/30)
0.267
(8/30)
Difference and 95% CI
(2-sided)
0.10
-0.184 to 0.384
0.067
-0.21 to 0.344
0.033
-0.228 to 0.294
SOC = standard of care


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7.2
Analysis Set
Detailed criteria for analysis sets will be specified in Classification Specifications and 
allocation of subjects to analysis sets will be determined prior to database hard-lock.
7.2.1
Full Analysis Set
The full analysis set (FAS) will consist of all subjects who are randomized, receive at least 
one dose of study drug and receive a transplanted kidney. This will be the primary analysis 
set for efficacy analyses.
7.2.2
Per Protocol Set
No per protocol set (PPS) is planned for this study; however, exploratory analyses including 
certain subjects may be performed if clinically meaningful.
7.2.3
Safety Analysis Set
The Safety Analysis Set (SAF) consists of all subjects who took at least one dose of study
medication, and will be used for safety analyses.
7.2.4
Pharmacokinetic Analysis Set
The Pharmacokinetic Analysis Set (PKAS) will consist of subjects from the SAF who have at 
least one measureable pharmacokinetic concentration. The PKAS will be used for summaries 
and exploratory analysis of the pharmacokinetic data.
7.3
Demographics and Other Baseline Characteristics
Demographics and baseline characteristics will be summarized overall and by treatment group 
for age, sex, race, ethnicity, height, weight, donor type (living [related/nonrelated] or deceased 
donor), donor and recipient serology, donor demographics, panel reactive antibody and total 
ischemia time.
Continuous variables will be summarized by descriptive statistics (n, mean, standard deviation, 
and minimum, median, maximum). The means will be compared among treatment groups 
using an analysis of variance (ANOVA) or analysis of covariance (ANCOVA) with treatment 
group as a factor.
Discrete variables will be summarized by number/percentage of subjects in each category. A 
2-sided 95% confidence interval will be constructed for the treatment differences.
7.4
Analysis of Efficacy
General Considerations
For an analysis of variance (ANOVA) or analysis of covariance (ANCOVA), previous 
kidney transplantation (no, yes) will be included as a factor in the model if there is a 
sufficient number of patients with more than one kidney transplant. Endpoints analyzed with 
Fisher’s Exact test may be analyzed with a CMH test stratifying by previous kidney 
transplant status (no or yes) if there is a sufficient number of patients with multiple kidney 
transplants. For time-to-event endpoints, Cox regression will be used comparing the 


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2 treatment groups and will include previous kidney transplantation (no or yes) in the model 
provided there are sufficient multi-transplant patients.
There are two treatment arms for comparison in this study:
●
Bleselumab with Tacrolimus (Arm 2) vs. SOC (Arm 1)
Fisher’s Exact test will be used to analyze all count data, unless otherwise specified. An 
ANOVA or ANCOVA will be used to analyze continuous data.
7.4.1
Analysis of Primary Endpoint
7.4.1.1 Primary Analysis
The primary efficacy endpoint is the percentage of subjects who have rFSGS defined as 
nephrotic range proteinuria with protein-creatinine ratio (≥ 3.0 g/g) through 3 months 
post-transplant. Death, graft loss or lost to follow-up will be imputed as rFSGS.
The percentage of subjects who have rFSGS will be computed, along with a 2-sided 95% 
confidence interval (CI) for each of the treatment groups. The difference between the two 
groups will be given and a 2-sided 95% CI will be constructed for the treatment differences 
using the normal approximation. As a secondary analysis, Fishers’ exact will be used to test 
for treatment differences.
7.4.1.2 Subgroup Analysis
For each treatment group, incidence of rFSGS at three months will be calculated for the 
following subgroups: age (<65, ≥ 65), gender, race (African-American vs Others), donor 
types (deceased donors vs others), and donor relationship (related vs non-related).
7.4.2
Analysis of Secondary Endpoints
7.4.2.1 Recurrence of Focal Segmental Glomerulosclerosis through 6 and 12 Months
The percentage of subjects with rFSGS through 6 and 12 months post-transplant will be 
computed along with a 2-sided 95% CI for each of the treatment groups and for the treatment 
difference (Arm 2 - Arm 1). As a secondary analysis, Fishers’ exact will be used to test for 
treatment difference. Death, graft loss or lost to follow-up will be imputed as rFSGS.
7.4.2.2 Biopsy-Proven Acute Rejection determined by Local Review
By-treatment group summaries will be provided for the incidence of BPAR (Banff Grade ≥ 1, 
local read) through 3, 6 and 12 months post-transplant. A 2-sided 95% CI will be constructed 
for each of the treatment groups and for the treatment difference. Subjects with an unknown 
outcome prior to each of the defined time points (3, 6 or 12 months post transplant), if any, 
will be counted as a BPAR in a secondary analysis. A 2-sided 95% CI will be constructed for 
the treatment differences using the normal approximation.


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7.4.2.3 Efficacy Failure
The incidence of efficacy failure defined as death, graft loss, BPAR (Banff Grade >1; local 
read) and lost to follow-up through 12 months post-transplant will be summarized by 
treatment group. A 2-sided 95% CI for each of the treatment groups and for the difference 
using the normal approximation will be constructed. As a secondary analysis, Fisher’s exact 
will be used to test for treatment differences.
For each treatment group, Kaplan-Meier estimates will be provided for efficacy failure at one 
year. The treatment difference will be computed as Arm 2 - Arm 1. A 2-sided 95% CI will be 
constructed for the treatment difference using Greenwood’s formula for standard error. A 
Wilcoxon test will be used to compare survival curves.
7.4.2.4 Biopsy-Proven Recurrence of Focal Segmental Glomerulosclerosis through 3, 
6 and 12 Months determined by Central Blinded Review of the Biopsy Slides
Biopsy-proven rFSGS will include only those for whom slides are reviewed by the 
independent pathologist who will be the blinded, central reader. All subjects are required to 
provide a biopsy either after the appearance of symptoms for rejection or rFSGS, or at the 
day 90/month 3 visit, if there has not been a previous biopsy indicating rFSGS in the 
transplanted kidney. The blinded, central reader will objectively assess podocyte changes to 
identify those with rFSGS. Subjects who drop out of the study and do not provide a biopsy 
for slide review will not be included in the analysis of biopsy-proven rFSGS.
Any “for-cause” biopsies after 3 months post-transplant will be reviewed by the blinded, 
central reader for rFSGS.
Summaries of biopsy-proven rFSGS will be provided by treatment group and the results for 
the comparison of the two treatment groups using all provided biopsies will be provided for 3, 
6 and 12 months post-transplant.
The percentage of subjects who have rFSGS will be computed along with a 2-sided 95% CI 
for each of the treatment groups and for the treatment difference (Arm 2 - Arm 1).
7.4.3
Analysis of Exploratory Endpoints
7.4.3.1 Graft and Patient Status (Graft and Patient Survival)
Summaries by treatment group (and a 2-sided 95% CI for each) for graft and patient status 
through 12 months’ post-transplant will be given. Subject status is defined as alive or 
deceased. Graft status is defined as graft loss determined by subject death, re-transplant, 
nephrectomy, or return to permanent dialysis (> 30 days) or graft survival determined as the 
absence of any of the above. The treatment difference and a 2-sided 95% CI for the 
difference will be provided.
For each treatment group, Kaplan-Meier estimates will be used to estimate graft and subject 
survival at one year. Any drop-outs prior to one-year will be censored at the time of drop-out. 
The treatment difference will be computed as Arm 2 - Arm 1. A 2-sided 95% CI will be 
constructed for the treatment difference using Greenwood’s formula for standard error. 


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A Wilcoxon test will be used to compare survival curves. In kidney transplant studies 
efficacy failure tends to occur early and the Wilcoxon test is more powerful test in detecting 
differences early in time.
7.4.3.2 Estimated Glomerular Filtration Rate
Summaries for the mean eGFR value based on MDRD criterion will be given for 3, 6 and 
12 months and analyzed at each time point using an ANCOVA with treatment as a factor and 
the week 4 value as a covariate. A summary and comparison of the results for the two 
treatment groups at three months will provide kidney function information at the time of the 
three-month interim analysis. 
Between-group comparisons at each visit of the mean eGFR based on the MDRD criterion 
will be made with an ANCOVA with treatment as the factor and the week 4 eGFR as the
covariate.
7.4.3.3 Time to rFSGS; Time to rFSGS or Initiation of Plasmapheresis; Time to Death, 
Graft Loss or Lost to Follow-up Imputed as rFSGS; Time to Biopsy-Proven 
rFSGS 
For each of the listed variables, Kaplan-Meier will be used to provide estimates for each 
treatment group at one year. The treatment difference will be computed as Arm 2 - Arm 1. 
A 2-sided 95% CI will be constructed for the treatment difference using Greenwood’s 
formula for standard error. A Wilcoxon test will be used to compare survival curves. Those 
who drop out of the study prematurely without sufficient information to determine recurrence 
will be censored at the time of withdrawal.
7.4.3.4 Time to First BPAR
Kaplan-Meier will be used to provide estimates for each treatment group and their difference 
at one year. The treatment difference will be computed as Arm 2 - Arm 1. A 2-sided 95% CI 
will be constructed for the treatment difference using Greenwood’s formula for standard error. 
A Wilcoxon test will be used to compare survival curves. Those who drop out of the study 
prematurely without sufficient information to determine recurrence will be censored at the 
time of withdrawal.
7.4.3.5 Urine Protein-Creatinine Ratio
The urine protein-creatinine ratio, the change from week 1 for collections up to week 4, and 
the change from week 4 for collections after week 4 will be summarized for each scheduled 
collection time. The urine protein-creatinine ratio collected up to week 4 will be analyzed 
with an ANCOVA with treatment group as a factor and the first available post-transplant 
value as the covariate. The urine protein-creatinine ratio after week 4 will be analyzed with 
an ANCOVA with treatment as a factor and the week 4 value as a covariate.


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7.4.3.6 Urine Albumin-Creatinine Ratio
The urine albumin-creatinine ratio, the change from week 1 for collections up to week 4, and 
the change from week 4 for collections after week 4 will be summarized for each scheduled 
collection time. The urine albumin-creatinine ratio collected up to week 4 will be analyzed 
with an ANCOVA with treatment group as a factor and the post-transplant value as the 
covariate. The urine albumin-creatinine ratio after week 4 will be analyzed with an 
ANCOVA with treatment as a factor and the week 4 value as a covariate.
7.4.3.7 Auto-anti-CD40 antibodies
Auto-anti-CD40 antibodies (present or absent), antibody level and change from baseline will 
be summarized by treatment group.
7.4.3.8 Patient-Reported Outcomes
7.4.3.8.1
Short Form 36-Item Health Survey Score
The SF-36 (SF-36, v2) provides scores for each of 8 health domains (physical functioning, 
bodily pain, role limitations due to physical health problems, role limitations due to personal 
or emotional problems, emotional well-being, social functioning, energy/fatigue, and general 
health perceptions). The 8t subscales are summarized into two scores, the PCS and MCS 
scores. SF-36 scale scores, and the PCS and MCS will be calculated by QualityMetric.
Descriptive statistics (n, mean, median, sd, min and max) will be provided for each of the 8
domains and the PCS and MCS at each visit by treatment group. Between-group comparisons 
of the scores will be provided.
7.4.3.8.2
European Quality of Life – 5 – Dimensions - 5 Levels
The EQ-5D-5L is an international and standardized non-disease specific instrument for 
describing and valuing health status. The percentage of patients in each treatment arm who 
report problems (dichotomized to no, yes) for each of the each of the 5 dimensions will be 
tabulated and graphically displayed. The distribution of responses ranging from none, slight, 
moderate, severe, and unable to function will be given for each treatment group. The 
percentage of patients who report ‘Yes’ for each of the EQ-5D-5L dimensions will be 
compared between the treatment groups at each visit using Fisher’s Exact test. For the 
EQ-5D-5L VAS records, summaries by treatment group and visit will be given for the 
EQ-5D-5L VAS score and the change from baseline. The change from baseline for the VAS 
score will be analyzed by using an ANCOVA model with treatment group as a fixed factor 
and the baseline VAS score as a covariate.
7.4.3.8.3
Kidney Transplant Questionnaire
The change from baseline at 3 and 12 months in the score for each of the 5domains of the 
KTQ (i.e., physical symptoms, fatigue, uncertainty/fear, appearance, and emotional) will be 
analyzed using ANCOVA with treatment as a factor and baseline as a covariate.


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7.5
Analysis of Safety
For each treatment arm, the frequencies and percentages will be displayed for the following 
TEAEs (coded using MedDRA by system organ class and preferred term:
●
Overall
●
Serious
●
Related (considered by the Investigator to be possible or probable related) to study drug
●
Leading to the permanent discontinuation of study drug
Descriptive statistics for each laboratory test (e.g., hematology, biochemistry, urinalysis) and 
its change from baseline (month 1 for renal tests) and vital signs will be tabulated by treatment 
group and scheduled time point.
The viral load data (CMV, BKV and EBV) will be summarized by scheduled visit and 
treatment group.
The number and percent of subjects with positive anti-bleselumab antibodies will be displayed 
by visit. The maximum titer, time to first positive titer and time to last positive titer will also be 
provided. Efficacy and safety data may be examined for those with and without anti-
bleselumab antibodies.
Bi-specific bleselumab antibody concentrations will be listed and summarized (n, mean, sd, 
%CV, min, median, max and GM) by treatment group for each collection time point.
7.6
Analysis of Pharmacokinetics
The serum concentration data of bleselumab will be listed and summarized using descriptive 
statistics for the concentrations obtained for peak and trough concentrations at each visit for 
Arm 2.
7.7
Protocol Deviations and Other Analyses
Protocol deviations as defined in Section 8.1.6, Protocol Deviations, will be summarized for 
all randomized subjects by treatment group and total as well as by site. A data listing will be 
provided by site and subject.
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:
PD1 – Entered into the study even though they did not satisfy entry criteria
PD2 – Developed withdrawal criteria during the study and was not withdrawn
PD3 – Received wrong treatment or incorrect dose
PD4 – Received excluded concomitant treatment
Study drug exposure will be summarized by treatment group and visit using descriptive 
statistics. Tacrolimus trough levels will also be summarized.


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7.8
Interim Analysis (and Early Discontinuation of the Clinical Study)
An interim analysis is planned once all subjects have completed the 3 months post-transplant 
follow-up to assess treatment differences for rFSGS. The purpose of this analysis is to 
support strategic decision making for future project development and study design. The result 
will aid in determining if this compound will continue development for rFSGS.
7.9
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
As a general principle, no imputation of missing data will be done. Exceptions are the start 
and stop dates of AEs and concomitant medication. The imputed dates will be used to 
allocate the concomitant medication and AEs to a treatment group, in addition to determining 
whether an AE is/is not treatment emergent. Listings of the AEs and concomitant 
medications will present the actual partial dates; imputed dates will not be shown.
See the SAP for details of the definitions for windows to be used for analyses by visit.
8
OPERATIONAL AND ADMINISTRATIVE CONSIDERATIONS
8.1
Procedure for Clinical Study Quality Control
8.1.1
Data Collection
The Investigator (or site designee) will enter data collected using an electronic data capture 
system. In the interest of collecting data in the most efficient manner, the Investigator should 
record data (including laboratory values, if applicable) in the eCRF within 
5 days after the subject visit.
The Investigator is responsible to ensure that all data in the eCRFs and queries are accurate 
and complete and that all entries are verifiable with source documents. These documents 
should be appropriately maintained by the site.
The monitor should verify the data in the eCRFs with source documents and confirm that 
there are no inconsistencies between them.
When laboratory tests are performed at a central laboratory, data will be transferred 
electronically to the Sponsor or designee at predefined intervals during the study. The 
laboratory will provide the Sponsor or designee with a complete and clean copy of the data.
ECGs are to be performed locally. A 12-lead ECG will be performed as part of screening, 
day 90/month 3 and month 12/EOS visits. The results (normal, abnormal not clinically 
significant, abnormal clinically significant) will be recorded in the eCRF. Subjects who have 
a clinically significant abnormal ECG during Screening will not be eligible for the study.
Chest x-rays are to be performed locally. An x-ray will be performed as part of screening, 
day 90/month 3 and month 12/EOS visits. The results (normal, abnormal not clinically 
significant, abnormal clinically significant) will be recorded in the eCRF


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For screen failures the demographic data, reason for failing, informed consent, inclusion and 
exclusion criteria and AEs will be collected in the eCRF.
8.1.2
Specification of Source Documents
Source data must be available at the site to document the existence of the study subjects and 
to substantiate the integrity of study data collected. Source data must include the original 
documents relating to the study, as well as the medical treatment and medical history of the 
subject.
The following information should be included in the source medical records:
●
Demographic data (age, sex, race, ethnicity, height and body weight)
●
Inclusion and exclusion criteria details
●
Participation in study and original signed and dated ICFs
●
Visit dates
●
Medical history and physical examination details including the pathology report to 
confirm the subject’s pFSGS
●
Key efficacy and safety data, if applicable (as specified in the protocol)
●
AEs and concomitant medication 
●
Results of relevant examinations (e.g., ECG charts, X-ray films etc.)
●
Laboratory printouts (if applicable)
●
Dispensing and return of study drug details
●
Reason for premature discontinuation (if applicable)
●
Randomization number (if applicable)
All patient-reported outcome measures will be completed by the subject via computerized 
administration on a sponsor-sourced, vendor-provided device. The SF-36, EQ-5D-5L and the 
KTQ surveys will be completed directly on a device and may then be considered as source.
Electronic case report form (eCRF) data of biopsy image(s) and slide assessment(s) via EM 
and LM, respectively, for the rFSGS will be directly entered by the blinded, central reader.
8.1.3
Clinical Study Monitoring
The Sponsor or delegated CRO is responsible for monitoring the clinical study to ensure that 
subject's human rights, safety, and well-being are protected, that the study is properly 
conducted in adherence to the current protocol and GCP, and study data reported by the 
investigator/sub-investigator are accurate and complete and that they are verifiable with study-
related records such as source documents. The Sponsor is responsible for assigning study 
monitor(s) to this study for proper monitoring. They will monitor the study in accordance with 
planned monitoring procedures.
8.1.4
Direct Access to Source Data/Documents
The investigator and the study site must accept monitoring and auditing by the Sponsor or 
delegated CRO as well as inspections from the IRB/IEC and relevant regulatory authorities. In 
these instances, they must provide all study-related records, such as source documents 


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(Section 8.1.2, Specification of Source Documents) when they are requested by the Sponsor
monitors and auditors, the IRB/IEC, or regulatory authorities. The confidentiality of the 
subject's identities shall be well protected consistent with local and national regulations when 
the source documents are subject to direct access.
8.1.5
Data Management
Data Management will be coordinated by the Data Science department of the Sponsor in 
accordance with the SOPs for data management. All study specific processes and definitions 
will be documented by Data Management. eCRF completion will be described in the eCRF 
instructions. Coding of medical terms and medications will be performed using MedDRA and 
WHO Drug Dictionary respectively.
8.1.6
Protocol Deviations
A protocol deviation is generally an unplanned excursion from the protocol that is not 
implemented or intended as a systematic change. The Investigator is responsible for ensuring 
the study is conducted in accordance with the procedures and evaluations described in this 
protocol and must protect the rights, safety, and welfare of subjects. The Investigator should 
not implement any deviation from, or changes of, the protocol, unless it is necessary to 
eliminate an immediate hazard to trial subjects.
A protocol waiver is a documented prospective approval of a request from an Investigator to 
deviate from the protocol. Protocol waivers are strictly prohibited.
For the purposes of this protocol, deviations requiring notification to Sponsor are defined as 
any subject who:
●
Entered into the study even though they did not satisfy entry criteria
●
Developed withdrawal criteria during the study and not withdrawn
●
Received wrong treatment or incorrect dose
●
Received excluded concomitant treatment
When a deviation from the protocol is identified for an individual subject, the Investigator or 
designee must ensure the Sponsor is notified. The Sponsor will follow-up with the Investigator, 
as applicable, to assess the deviation and the possible impact to the safety and/or efficacy of the 
subject to determine subject continuation in the study.
If a deviation impacts the safety of a subject, the Investigator must contact the Sponsor 
immediately.
The Investigator will also assure that deviations meeting IRB/IEC and applicable regulatory 
authorities’ criteria are documented and communicated appropriately. All documentation and 
communications to the IRB/IEC and applicable regulatory authorities will be provided to the 
Sponsor and maintained within the Trial Master File (TMF).
NOTE: Other deviations outside of the categories defined above that are required to be 
reported by the IRB/IEC in accordance with local requirements will be reported, as 
applicable.


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8.1.7
End of Trial in All Participating Countries
The end of trial in all participating countries is defined as the last subject’s last visit.
8.2
Ethics and Protection of Subject Confidentiality
8.2.1
Institutional Review Board (IRB) / Independent Ethics Committee (IEC) / 
Competent Authorities (CA)
Good Clinical Practice (GCP) requires that the clinical protocol, any protocol amendments, 
the Investigator’s Brochure, the informed consent and all other forms of subject information 
related to the study (e.g., advertisements used to recruit subjects) and any other necessary 
documents be reviewed by an IEC/IRB. The IEC/IRB will review the ethical, scientific and 
medical appropriateness of the study before it is conducted. IEC/IRB approval of the 
protocol, informed consent and subject information and/or advertising, as relevant, will be 
obtained prior to the authorization of drug shipment to a study site.
Any substantial amendments to the protocol will require IEC/IRB approval prior to 
implementation of the changes made to the study design at the site. The investigator will be 
required to submit, maintain and archive study essential documents according to ICH GCP.
Any SAEs that meet reporting criteria, as dictated by local regulations, will be reported to 
both responsible Ethics Committees and Regulatory Agencies, as required. During the 
conduct of the study, the investigator should promptly provide written reports (e.g., ICH 
Expedited Reports, and any additional reports required by local regulations) to the IEC/IRB 
of any changes that affect the conduct of the study and/or increase the risk to subjects. 
Written documentation of the submission to the IEC/IRB should also be provided to Sponsor.
If required by local regulations, the investigator shall make accurate and adequate written 
progress reports to the IEC/IRB at appropriate intervals, not exceeding one year. The 
investigator shall make an accurate and adequate final report to the IRB/IEC within 90 days 
after the close-out visit for APGD-sponsored studies, or for APEB/APEL-sponsored studies 
within one year after last subject out (LSO) or termination of the study.
8.2.2
Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, ICH guidelines, applicable 
regulations and guidelines governing clinical study conduct and the ethical principles that have 
their origin in the Declaration of Helsinki.
8.2.3
Informed Consent of Subjects
8.2.3.1 Subject Information and Consent
The Investigator or his/her representative will explain the nature of the study to the subject or 
his/her guardian or legal representative, and answer all questions regarding this study. Prior 
to any study-related screening procedures being performed on the subject, the informed 
consent statement will be reviewed and signed and dated by the subject or his/her guardian or 
legal representative, the person who administered the ICF and any other signatories according 
to local requirements. A copy of the signed ICF will be given to the subject and the original 


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will be placed in the subject’s medical record. An entry must also be made in the subject’s 
dated source documents to confirm that informed consent was obtained prior to any study-
related procedures and that the subject received a signed copy.
The signed consent forms will be retained by the investigator and made available (for review 
only) to the study monitor and auditor regulatory authorities and other applicable individuals 
upon request.
8.2.3.2 Supply of New and Important Information Influencing the Subject’s Consent 
and Revision of the Written Information
The Investigator or his/her representative will immediately inform the subject orally 
whenever new information becomes available that may be relevant to the subject’s consent or 
may influence the subject’s willingness to continue to participate in the study (e.g., report of 
serious drug adverse drug reaction). The communication must be documented in the subject’s 
medical records and must document whether the subject is willing to remain in the study or 
not.
The Investigator must update their ICF and submit it for approval to the IRB/IEC. The 
investigator or his/her representative must obtain written informed consent from the subject 
on all updated ICFs throughout their participation in the study. The Investigator or his/her 
designee must re-consent subjects with the updated ICF even if relevant information was 
provided orally. The Investigator or his/her representative who obtained the written informed 
consent and the subject should sign and date the informed consent form. A copy of the signed 
ICF will be given to the subject and the original will be placed in the subject’s medical 
record. An entry must be made in the subject’s records documenting the re-consent process.
8.2.4
Subject Confidentiality
Individual subject medical information obtained as a result of this study is considered 
confidential and disclosure to third parties is prohibited. Such medical information may be 
given only after approval of the subject to the subject's physician or to other appropriate 
medical personnel responsible for the subject's well-being.
The Sponsor shall not disclose any confidential information on subjects obtained during the 
performance of their duties in the clinical study without justifiable reasons.
The Sponsor affirms the subject's right to protection against invasion of privacy. Only a 
subject identification number and/or initials will identify subject data retrieved by the 
Sponsor. However, the Sponsor requires the Investigator to permit the Sponsor, Sponsor's 
representative(s), the IRB/IEC and when necessary, representatives of the regulatory health 
authorities to review and/or to copy any medical records relevant to the study.
The Sponsor will ensure that the use and disclosure of protected health information obtained 
during a research study complies with the federal and/or regional legislation related to the 
privacy and protection of personal information (i.e., HIPAA).


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8.3
Administrative Matters
8.3.1
Arrangement for Use of Information and Publication of the Clinical Study
Information concerning the study drug, patent applications, processes, unpublished scientific 
data, the Investigator's Brochure and other pertinent information is confidential and remains 
the property of the Sponsor. Details should be disclosed only to the persons involved in the 
approval or conduct of the study. The Investigator may use this information for the purpose 
of the study only. It is understood by the Investigator that the Sponsor will use the 
information obtained during the clinical study in connection with the development of the drug 
and therefore may disclose it as required to other clinical Investigators or to regulatory 
agencies. In order to allow for the use of the information derived from this clinical study, the 
investigator understands that he/she has an obligation to provide the Sponsor with all data 
obtained during the study.
Publication of the study results is discussed in the Clinical Study Agreement.
8.3.2
Documents and Records Related to the Clinical Study
The Investigator will archive all study data (e.g., Subject Identification Code List, source 
data, eCRFs, and Investigator's File) and relevant correspondence. These documents are to be 
kept on file for the appropriate term determined by local regulation (for US sites, two years 
after approval of the NDA or discontinuation of the IND). The Investigator agrees to obtain 
the Sponsor's agreement prior to disposal, moving, or transferring of any study-related 
records. The Sponsor will archive and retain all documents pertaining to the study according 
to local regulations.
Data generated by the methods described in the protocol will be recorded in the subjects' 
medical records and/or study progress notes. All data will be entered on the eCRFs supplied 
for each subject.
8.3.3
Protocol Amendment and/or Revision
Any changes to the study that arise after approval of the protocol must be documented as 
protocol amendments: substantial amendments and/or non-substantial amendments. 
Amendments to this protocol must be signed by the Sponsor and the Investigator. Depending 
on the nature of the amendment, either IRB/IEC, Competent Authority approval or 
notification may be required. The changes will become effective only after the approval of 
the Sponsor, the Investigator, the regulatory authority and the IRB/IEC (if applicable).
Written verification of IRB/IEC approval will be obtained before any amendment is 
implemented which affects subject safety or the evaluation of safety, and/or efficacy. 
Modifications to the protocol that are administrative in nature do not require IRB/IEC 
approval, but will be submitted to the IRB/IEC for their information, if required by local 
regulations.


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If there are changes to the Informed Consent, written verification of IRB/IEC approval must 
be forwarded to the Sponsor. An approved copy of the new Informed Consent must also be 
forwarded to the Sponsor.
8.3.4
Signatory Investigator for Clinical Study Report
ICH E3 guidelines recommend and EU Directive 2001/83/EC requires that a final study 
report which forms part of a marketing authorization application be signed by the 
representative for the Coordinating Investigator(s) or the Principal Investigator(s). The 
representative for the Coordinating Investigator (s) or the Principal Investigator(s) will have 
the responsibility to review the final study results to confirm to the best of his/her knowledge 
it accurately describes the conduct and results of the study. The representative for 
Coordinating Investigator(s) or the Principal Investigator(s) will be selected from the 
participating investigators by the Sponsor prior to database lock.
9
QUALITY ASSURANCE
The Sponsor is implementing and maintaining quality assurance and quality control systems 
with written SOPs to ensure that trials are conducted and data are generated, documented, 
recorded, and reported in compliance with the protocol, GCP, and applicable regulatory 
requirement(s).
The Sponsor or Sponsor's designee may arrange to audit the clinical study at any or all 
investigational sites and facilities. The audit may include on-site review of regulatory 
documents, case report forms, and source documents. Direct access to these documents will 
be required by the auditors.
10
STUDY ORGANIZATION
10.1
Data Monitoring Committee
A Data Monitoring Committee (DMC) will be organized to assess the progress of the study, 
the safety data and the critical efficacy endpoints, and to recommend to the Sponsor whether 
to continue, modify or stop the study. A separate DMC Charter will be maintained detailing 
the complete roles and responsibilities of the DMC and will be provided to sites upon 
request. Stopping rules for safety events will be described in the DMC Charter.
10.2
Other Study Organization
Not applicable.


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11
REFERENCES
Advani R, Forero-Torres A, Furman RR, Rosenblatt JD, Younes A, Ren H, et al. Phase I Study of the 
Humanized Anti-CD40 Monoclonal Antibody Dacetuzumab in Refractory or Recurrent Non-
Hodgkin’s Lymphoma J Clin Oncol. 2009;27:4371-7.
Andre P, Prasad KS, Denis CV, He M, Papalia JM, Hynes RO, et al. CD40L stabilizes arterial 
thrombi by a β3 integrin-dependent mechanism. Nat Med. 2002;8(3):247-52.
Canaud G, Martinez F, Noël LH, Mamzer MF, Niaudet P, Legendre C. Therapeutic approach to focal
and segmental glomerulosclerosis recurrence in kidney transplant recipients. Transplant Rev
(Orlando). 2010;24:121-8.
Cravedi P, Kopp JB, Remuzzi G. Recent progress in the pathophysiology and treatment of FSGS
recurrence. Am J Transplant. 2013;13:266-74.
Delville M, Sigdel TK, Wei C, Li J, Hsieh SC, Fornoni A, et al. A circulating antibody panel for 
pretransplant prediction of FSGS recurrence after kidney transplantation. Sci Transl Med.
2014;6:256ra136.
Faggion I., Quirino T. Risk factors for hepatotoxicity in subjects treated with highly active 
antiretroviral therapy. J Acquir Immune Defic Syndr. 2001;27: 316–18.
Grimbert S., Pessayre D., Degott C., Benhamou J.P. Acute hepatitis induced by HMG-CoA reductase 
inhibitor, lovastatin. Digest Dis Sci. 1994;39:2032–33.
Helliwell P.S., Taylor W.J. Treatment of psoriatic arthritis and rheumatoid arthritis with disease 
modifying drugs- comparison of drugs and adverse reactions. J Rheumatol. 2008;35:472–76.
Hussein MA, Berenson JR, Niesvizky R, Munshi NC, Matous J, Sobecks R, et al. A phase I multidose 
study of dacetuzumab (SGN-40; humanized anti-CD40 monoclonal antibody) in subjects with 
multiple myeloma. Haematologica. 2010;95:845-48.
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO 
clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012;2:182.
Kairaitis L, Wang Y, Zheng L, Tay YC, Wang Y, Harris DC. Blockade of CD40-CD40 ligand 
protects against renal injury in chronic proteinuric renal disease. Kidney Int. 2003;64:1265-72.
Kasran A, Boon L, Wortel CH, Van Hogezand RA, Schreiber S, Goldin E, et al. Safety and 
tolerability of antagonist anti-human CD40 mab ch5D12 in subjects with moderate to severe 
Crohn’s disease. Aliment Pharmacol Ther. 2005;22:111-22.
Kirk AD, Burkly LC, Batty DS, Baumgartner RE, Berning JD, Buchanan K, et al. Treatment with 
humanized monoclonal antibody against CD154 prevents acute renal allograft rejection in 
nonhuman primates. Nat Med 1999;5(6):686-93.
Kirk AD, Knechtle SJ, Sollinger HW, Vincenti FG, Stecher S, and Nadeau KC. Preliminary results of 
the use of humanized anti-CD154 in human renal allotransplantation [Abstract]. Am J 
Transplant. 2001;1(suppl 1):191.
Laupacis A, Pus N, Muirhead N, Wong C, Ferguson B, Keown P. Disease-specific questionnaires for 
patients with a renal transplant. Nephron. 1993;64(2):226-31.
Pree I and Wekerle T. New approaches to prevent transplant rejection: co-stimulation blockers anti-
CD40L and CTLA41g. Drug Discov Today. 2006;3(1):41-7.
Sidiropoulos PI and Boumpas DT. Lessons learned from anti-CD40L treatment is systemic lupus 
erythematosus subjects. Lupus. 2004;13:391-7.


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Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD. Cytokine storm in a 
phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med. 2006;355:1018-28.
Trachtman R, Sran SS, Trachtman H. Recurrent focal segmental glomerulosclerosis after kidney
transplantation. Pediatr Nephrol. 2015;30:1793-802.
Temple R. Hy's law: predicting serious hepatotoxicity. Pharmacoepidemiol Drug Saf. 2006 
Apr;15(4):241-3.
Vonderheide RH, Flaherty KT, Khalil M, Stumacher MS, Bajor DL, Hutnick NA, et al. Clinical 
activity and immune modulation in cancer patients treated with CP-870, 893, a novel CD40 
agonist monoclonal antibody. J Clin Oncol. 2007;25(7):876-83.
Company Reports:
Bleselumab (ASKP1240) Investigator Brochure


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12
APPENDICES
12.1
List of Excluded Concomitant Medications
The following medications are prohibited:
●
Another investigational drug intervention treatment up to 30 days or 5 half-lives 
(depending on medication) prior to transplant and throughout participation in the study.
●
Prior treatment with bleselumab (ASKP1240).
●
Currently receiving or have received up to 8 weeks prior to transplant any immunologic 
biologic compound.
●
Induction agent other than study-assigned basiliximab (Simulect®).
Subjects who require plasmapheresis for any reason post-initial bleselumab dosing cannot 
continue receiving bleselumab.
If bleselumab is discontinued subjects in Arm 2 can continue to receive study-supplied 
Prograf through 12 months post-transplant as previously assigned.
12.1.1
List of known Drug-Induced Hepatotoxicity
Causality assessment of suspected drug-induced liver injury (DILI) related to antibiotics can be 
difficult, particularly because some cases occur long after the drug has been stopped. Antibiotic-
induced DILI appears, in most instances, to be idiosyncratic. Genetic-association studies have 
recently identified genotypes (flucloxacillin, amoxicillin-clavulanate)
●
Antibiotics: Penicillins, amoxicillin-clavulanate Amoxicillin, oxacillin, (di-) cloxacillin, 
flucloxacillin. Cephalosporins, ceftriaxone Ciprofloxacin, 
Sulfamethoxazole/trimethoprim,nitrofurantoin. Macrolides, Erythromycin,
telithromycin.Tetracyclines, Minocycline and Quinolones (rare)
●
Antifungals: Fluconazole and itraconazole
●
Anti-Hyperlipidemic Drugs: Lovastatin, Simvastatin, Atorvastatin, Pravastatin, Niacin, 
Ezetimibe, Clofibrate and Gemfibrozil
●
TNF inhibitors: adalimumab, etanercept and infliximab
●
Anti-Hypertensive Drugs: Methyl dopa
●
Anti-Retroviral Drugs: Protease inhibitors: Ritonavir, Indinavir, Saquinavir, Nelfinavir.
●
Nucleoside analogues reverse transcriptase inhibitors (NRTI): Lamivudine, Tenofovir, 
Zidovudine, Didanosine, Stavudine, Abacavir and Tenofovir
●
Non-nucleoside analogues reverse transcriptase inhibitors (NNRTI): Nevirapine, 
Emtricitabine and Efavirenz
●
Oral contraceptives
●
Anti-Rheumatic Drugs: Sulfasalazine, Gold-salt-induced cholestasis, Azathioprine and
Methotrexate
●
Anti-TB: Rifampicin, Isoniazid and Pyrazinamide
●
Non-Steroidal Anti-Inflammatory Drugs: Acetaminophen, Nimesulide, Diclofenac, 
Ibuprofen and Sulindac


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●
Selective COX-2 inhibitors: celecoxib, rofecoxib, nimesulide
●
Anthranilic acid derivatives: Cinchophen and Glafanine
●
Acetic acid derivatives: Amphenac, Fenclozic acid, Isoxepac and Bromofenac
●
Propionic acid derivatives: Benoxaprofen, Ibufenac, Pirprofenac, Suprofenac and 
Fenbufen
●
Pyrazolone derivatives: Phenylbutazone and Oxyphenbutazone
●
Oxicams: Isoxicam and Sudoxicam
●
Quinazonlone derivatives: Fluproquazone
●
Anaesthetic Agents: Halothane, Chloroform, Isoflurane, Enflurane, Desflurane and 
Nitrous oxide
●
Anti-Epileptic Drugs (AED): Carbamazepine (CBZ), Chlorpromazine (CPZ), 
Haloperidol,(rare), Risperidone and Quetiapine (cholestasis), Olanzapine and Clozapine
(neuroleptic)
●
Anti-Depressants: Most tricyclic antidepressants(less extent amitriptyline, desipramine), 
Amineptine and Amineptine
●
MAO inhibitors: Hydrazines and phenelzine
●
Acetylcholinesterase Inhibitors: Tacrine
●
Drugs of Abuse: Cocaine


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12.2
Liver Safety Monitoring and Assessment
Any subject enrolled in a clinical study with active drug therapy and reveals an increase of 
serum aminotransferases to > 3 × ULN, or bilirubin > 2 × ULN, should undergo detailed 
testing for liver function analyses (including at least ALT, AST, ALP, and TBL). Testing
should be repeated within 48 - 72 hours of notification of the test results. 
Subjects should be asked if they have any symptoms suggestive of hepatobiliary dysfunction.
Complete physical examination searching for sign or symptoms of hepatitis such as:
●
fever, scleral icterus (Jaundice), darkening of the urine, pale or clay-colored stools
●
fainting, weakness, fatigue
●
altered mental status
●
hepatomegaly
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and severe where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 × ULN 
Or
> 2 × ULN
Severe*
> 3 × ULN
and
> 2 × ULN
In addition, the subject should be considered to have severe hepatic abnormalities for any of 
the following:
●
ALT or AST > 8 x ULN
●
ALT or AST > 5 x ULN for more than 2 weeks
●
ALT or AST > 3 x ULN and (TBL > 2 x ULN or INR > 1.5 x ULN)
●
ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
The Investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or severe abnormalities and require additional monitoring 
and follow-up.
*Hy’s Law or rule is based on the combined evidence of hepatic injury, decreased hepatic 
function and the absence of disease related damage. 
Subjects with all 4 of the below criteria are considered Hy’s Law cases:
1.
Increased rate (compared to control) of aminotransferase elevation to ≥ 3 x ULN 
indicating hepatocellular injury, greater elevation cause greater concern, but alone do not 
predict severe toxicity
2.
Total BIL > 2 x ULN (or INR > 1.5 × ULN), if the change is clinically significant in the 
absence of obstruction
3.
Alkaline phosphatase (ALP) close to normal
4.
No other good explanation for the liver injury (viral excluded, alcohol ingestion, 
congestive heart failure)


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Exclusion of alcoholic hepatitis:
Heavy alcohol use is a prerequisite for the development of alcoholic hepatitis. The history is 
usually apparent; however, in some subjects, alcohol use may be covert.
Follow-up Procedures
Confirmed moderate and severe abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, 
physical examination and laboratory tests. The site should complete the Liver Abnormality 
Case Report Form (LA-CRF) or an appropriate document. Subjects with confirmed abnormal 
liver function testing should be followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2 - 3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.
Severe hepatic liver function abnormalities as defined above, in the absence of another 
etiology, may be considered an important medical event and may be reported as a SAE. The 
Sponsor should be contacted immediately and informed of all Investigators and subjects for 
whom severe hepatic liver function abnormalities possibly attributable to study drug are 
observed.
In order to distinguish if bleselumab is likely to cause DILI or have a low potential for 
causing severe liver injury, subjects will be evaluated and closely monitored.
For further detection, assessment, mitigation and reporting of abnormal hepatic laboratory 
findings, the Investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new onset-diseases should be recorded as ‘adverse events’ on the AE page of the
eCRF. Illnesses and conditions such as hypotensive events, and decompensated cardiac 
disease that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis (NASH) is seen in obese hyper-lipoproteinemic, and/or diabetic subjects
and may be associated with fluctuating aminotransferase levels. Gilbert’s syndrome 
which characterized by fluctuating elevation of serum bilirubin. The Investigator should 
ensure that the medical history form captures any illness that pre-dates study enrollment 
that may be relevant in assessing hepatic function.
●
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, specific 
toxic insults such as Amanita sp. (mushroom), and special diets. Medications should be 
entered on the concomitant medication page of the eCRF. Information on alcohol, other 
substance use, and diet should be entered on the LA-CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents.


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●
Based on the subject’s history, other testing may be appropriate including:
○
acute viral hepatitis (A, B, C, D, E or other infectious agents)
○
ultrasound or other imaging to assess biliary tract disease
○
other laboratory tests including INR, total and direct bilirubin
●
Consider gastroenterology or hepatology consultations.
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
Subjects must discontinue bleselumab per below, but are allowed to continue on the protocol-
defined visit schedule for the collection of safety and clinical assessment information:
●
Subjects whose liver function tests meet one of the following criteria, verified by two (2) 
consecutive measurements, and in the absence of other etiologies (e.g., biliary stenosis or 
obstruction, viral hepatitis other than CMV, etc.):
●ALT or AST > 8 x upper limit of normal (ULN)
●ALT or AST > 5 x ULN for more than 2 weeks
●ALT or AST > 3 x ULN and (total bilirubin [TBL] > 2 x ULN or international 
normalized ratio [INR] > 1.5 x ULN)
●ALT or AST > 3 x ULN with the appearance of fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, fever, rash, and/or eosinophilia (> 5%)
●
BK nephropathy confirmed by renal biopsy (Section 5.5.1.1.5)
●
CMV End Organ Disease (Appendix 12.6)
●
Subjects who develop severe bone marrow suppression as defined by the following in the 
absence of other etiologies (e.g., bleeding, other established causes of neutropenia) and 
have been verified by two (2) consecutive results within 14 days of the first detection 
that occur after Day 28 post-transplant:
●Anemia: Hemoglobin < 6.5 g/dL graded National Cancer Institute Common 
Terminology Criteria for Adverse Events criteria (NCI-CTCAE) Grade 4 and/or
●Agranulocytosis: Absolute Neutrophil Count (ANC) < 100 cells/mm3 graded NCI-
CTCAE Grade 4
●
Subjects who require plasmapheresis for any reason post-initial bleselumab treatment
●
In the subjects’ best interest per Investigator discretion
In addition, if close monitoring for a subject with moderate or severe hepatic laboratory tests 
is not possible, drug should be discontinued.
Reference
Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical Evaluation” 
issued by FDA on July 2009.


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12.3
Common Serious Adverse Events
The following is a list of SAEs that the Sponsor considers to be associated with the disease 
state being studied. The list does NOT change your reporting obligations or prevent the 
need to report an AE meeting the definition of an SAE as detailed in Section 5.4.2,
Definition of Serious Adverse Event (SAE). The purpose of this list is to alert you that 
some events reported as SAEs may not require expedited reporting to the regulatory 
authorities based on the classification of “common SAEs”. You are required to follow the 
requirements detailed in Section 5.5.5, Reporting of Serious Adverse Events (SAE).
For IND safety reporting, single occurrences of the following events may be excluded from 
expedited reporting to the FDA. If aggregate analysis of these events indicates they occur more 
frequently with study drug, an expedited IND safety report may be submitted to the FDA.
1. Kidney Transplant Rejection
2. Kidney allograft loss
3. Blood creatinine increased
4. Diabetes mellitus
5. Hyperglycemia
6. Increase blood glucose


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12.4
Retrospective Pharmacogenetic Sub-Study
INTRODUCTION
Pharmacogenetic research aims to provide information regarding how naturally occurring 
changes in a subject’s gene and/or expression based on genetic variation may impact what 
treatment options are best suited for the subject. Through investigation of pharmacogenetic 
by technologies such as genotyping, gene sequencing, statistical genetics and Genome-Wide 
Association Studies (GWAS), the relationship between gene profiles and a drug’s kinetics, 
efficacy or toxicity may be better understood. As many diseases may be influenced by one or 
more genetic variations, pharmacogenetic research may identify which genes are involved in 
determining the way a subject may or may not respond to a drug.
OBJECTIVES
The pharmacogenetic research that may be conducted in the future with acquired blood 
samples is exploratory. The objective of this research will be to analyze or determine genes 
of relevance to clinical response, pharmacokinetics, and toxicity/safety issues.
By analyzing genetic variations, it may be possible to predict an individual subject’s response 
to treatment in terms of efficacy and/or toxicity.
SUBJECT PARTICIPATION
Subjects who have consented to participate in this study may participate in this 
pharmacogenetic sub-study. As part of this sub-study, subjects must provide separate written 
consent prior to providing any blood samples that may be used at a later time for genetic 
analysis.
SAMPLE COLLECTION AND STORAGE
Subjects who consent to participate in this sub-study will provide one 4 mL tube of whole 
blood per Astellas’ instructions. Each sample will be identified by the unique subject number 
(first code). Samples will be shipped frozen to a designated banking CRO either directly from 
site or via a central laboratory as directed by Astellas.
PHARMACOGENETIC ANALYSIS
Details on the potential pharmacogenetic analysis cannot be established yet. Astellas may 
initiate the pharmacogenetic analysis in case evidence suggests that genetic variants may be 
influencing the drug’s kinetics, efficacy and/or safety.
DISPOSAL OF PHARMACOGENETIC SAMPLES/DATA
All pharmacogenetic samples collected will be stored for a period of up to 15 years following 
study database hard lock. If there is no requirement for analysis, the whole blood sample will 
be destroyed after the planned storage period. The subject has the right to withdraw consent 
at any time. When a subject’s withdraw notification is received, the pharmacogenetic sample 


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will be destroyed. The results of any pharmacogenetic analysis conducted on a sample prior 
to its withdrawal will be retained at Astellas indefinitely.
INFORMATION DISCLOSURE TO THE SUBJECTS
Exploratory pharmacogenetic analysis may be conducted following the conclusion of the 
clinical study, if applicable. The results of the genetic analysis will not be provided to any 
investigators or subjects, nor can the results be requested at a later date. Any information that 
is obtained from the pharmacogenetic analysis will be the property of Astellas.


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12.5
List of Secondary Causes of Focal Segmental Glomerulosclerosis
1.
Familial
a. Mutations in a-actinin 4
b. Mutations in NPHS1 (nephrin)
c. Mutations in NPHS2 (podocin)
d. Mutations in WT-1
e. Mutations in TRPC6
f. Mutations in SCARB2 (LIMP2)
g. Mutations in INF2 (formin)
h. Mutations in CD2-associated protein
i. Mitochondrial cytopathies
2.
Virus associated
a. HIV-associated nephropathy
b. Parvovirus B19
3.
Medication
a. Heroin-nephropathy
b. Interferon-a
c. Lithium
d. Pamidronate/alendronate
e. Anabolic steroids
4.
Adaptive structural-functional responses likely mediated 
by glomerular hypertrophy or hyperfiltration
4.1 Reduced kidney mass
a. Oligomeganephronia
b. Unilateral kidney agenesis
c. Kidney dysplasia
d. Cortical necrosis
e. Reflux nephropathy
f. Surgical kidney ablation
g. Chronic allograft nephropathy
h. Any advanced kidney disease with reduction in functioning 
nephrons
4.2 Initially normal kidney mass
a. Diabetes mellitus
b. Hypertension
c. Obesity
d. Cyanotic congenital heart disease
e. Sickle cell anemia
5.
Malignancy (lymphoma)
6.
Nonspecific pattern of FSGS caused by kidney scarring in 
glomerular disease
a. Focal proliferative glomerulonephritis (IgAN, LN,
pauci-immune focal necrotizing and crescentic GN)
b. Hereditary nephritis (Alport syndrome)
c. Membranous glomerulopathy
d. Thrombotic microangiopathy
Reference
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO 
clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012;2:182.


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12.6
Definition of Cytomegalovirus Disease in Solid Organ Transplant 
Recipients
Disease type
Probable
Definite
CMV syndrome
One or more of the following: 
1. Fever > 38°C for at least 2 days 
2. New or increased malaise 
3. Leukopenia
4. ≥5% atypical lymphocytes 
5. Thrombocytopenia 
6. Elevation of hepatic transaminases (ALT 
or AST) to 2 × upper limit of normal 
(applicable to nonliver transplant recipients) 
plus evidence of CMV in blood by viral 
culture, antigenemia or a DNA/RNA-based 
assay
Clinical and laboratory findings as 
in ‘probable’ case and no other 
cause of symptoms/signs identified
Pneumonia1
Signs and/or symptoms of pulmonary disease in 
the absence of other documented cause plus 
evidence of CMV in blood and/or3
bronchoalveolar lavage (BAL) fluid by viral 
culture, antigenemia or a DNA/RNA-based 
assay
Signs and/or symptoms of 
pulmonary disease plus detection 
of CMV in lung tissue by culture, 
immunohistochemical analysis or 
in situ hybridization4 with or 
without evidence of CMV in blood 
or BAL fluid by viral culture, 
antigenemia (BAL) or a 
DNA/RNA-based assay
Gastrointestinal 
disease
Symptoms of upper or lower gastrointestinal 
disease plus macroscopic mucosal lesions on 
endoscopy plus evidence of CMV in blood or 
biopsy tissue by viral culture, antigenemia or an 
RNA/DNA-based assay
Symptoms or signs of upper or 
lower gastrointestinal disease plus 
detection of CMV in 
gastrointestinal tissue by culture, 
immunohistochemical analysis or 
in situ hybridization4
Hepatitis
Elevation of bilirubin and/or hepatic enzymes 
in the absence 
of other documented cause of hepatitis2 plus 
evidence of CMV in blood by anti-genemia or 
a DNR/RNA-based assay
Elevation of bilirubin and/or 
hepatic enzymes plus detection of 
CMV in liver tissue by culture, 
immunohistochemical analysis or 
in situ hybridization4
CNS disease
CNS symptoms in the absence of other 
documented cause plus evidence for CMV in 
CSF samples by viral culture or DNA-based 
assay
CNS symptoms plus detection of 
CMV in CNS tissue by culture, 
immuno-histochemical analysis or 
in situ hybridization4
Retinitis
Not applicable
Lesions typical of CMV retinitis 
must be confirmed by an 
ophthalmologist
Other tissue invasive 
disease (nephritis, 
cystitis, myocarditis, 
pancreatitis, etc.)
Evidence of organ dysfunction in the absence 
of other documented cause2 plus evidence of 
CMV in blood by viral culture, antigenemia or 
DNA/RNA-based assay
Symptoms/signs of organ 
dysfunction plus detection of CMV 
in affected tissue by culture, 
immunohistochemical analysis or 
in situ hybridization4
BAL= bronchoalveolar lavage; CMV=cytomegalovirus ; CNS=central nervous system; DNA=deoxyribonucleic acid ; 
RNA=ribonucleic acid
Table footnotes appear on next page


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1 Superinfection or coinfection with other pathogens may occur and should be noted when present.
2 If affected organ is the allograft; acute rejection must be excluded as a cause for the clinical 
symptoms.
3 The detection of CMV in both BAL and peripheral blood strengthens the evidence for probable CMV 
pneumonitis.
4 Although, immunohistochemistry and in situ hybridization techniques are more sensitive for the 
detection of CMV-infected cells than morphologic examination, the presence of typical 
cytomegalovirus inclusions should be considered evidence of definite disease.
Reference:
Humar A. American society of Transplantation Recommendations for Screening, Monitoring and 
Reporting of Infectious Complications in Immunosuppression Trials in Recipients of Organ 
Transplantation. Am J Transplantation. 2006;6:262-74.


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12.7
Categories of Post-transplant Lymphoproliferative Disorders
Categories of Post-transplant Lymphoproliferative Disorders (PTLD) are the following:
●
Early Lesions
o Reactive plasmacytic hyperplasia
o Infectious mononucleosis-like
●
Polymorphic PTLD
●
Monomorphic PTLD (classify according to lymphoma classifications)
o B-cell neoplasms
Diffuse large B cell lymphoma (immunoblastic, centroblastic, anaplastic)
Burkitt/Burkitt-like lymphoma
Plasma cell myeloma
Plasmacytoma-like lesions
Maltoma
o T-cell neoplasm
Peripheral T cell lymphoma, unspecified type
Anaplastic large cell lymphoma (T or null cell)
Hepatosplenic gamma-delta T cell lymphoma
Other (i.e., T-NK type)
●
Hodgkin lymphoma and Hodgkin lymphoma-like PTLD
Reference:
AST Infectious Disease Community. Epstein-Barr virus and lymphoproliferative disorders after 
transplantation. Am J Transplantation. 2004;4(Suppl 10):59-65.




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12.9
Short-Form 36 Item Health Survey Score Version 2.0
Refer to your Study Binder for copies of the ePRO device subject-facing screenshots.


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12.10 European Quality of Life 5 Dimensions - 5 Levels Questionnaire
Refer to your Study Binder for copies of the ePRO device subject-facing screenshots.


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12.11 Kidney Transplant Questionnaire
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13
ATTACHMENT 1:  NONSUBSTANTIAL AMENDMENT 2
I. The purpose of this amendment is:
Nonsubstantial Changes
1. Inclusion/Exclusion Criteria clarification
DESCRIPTION OF CHANGE:
The revised language is to clarify the enrollment of subjects who have had a previous kidney 
transplant and indicate that the current graft failure must be due to the rFSGS.
RATIONALE:
A subject’s current graft failure must be due to rFSGS. This was incorrectly documented in 
substantial amendment 2.
II. Amendment Summary of Changes:
IV. Synopsis, Section 3.2 Inclusion Criteria and 3.3 Exclusion Criteria
WAS:
Inclusion:
3. Subject is a recipient of a de novo kidney from a living or deceased donor and has 
biopsy-proven, pFSGS as a cause of ESRD in their native kidneys (initial diagnosing 
biopsy report is required). A subject who has biopsy-proven pFSGS as a cause of ESRD, 
and their prior graft failure(s) is due to the recurrence of FSGS, is eligible.
Exclusion:
3. Subject has previously received any organ transplant including a kidney and the prior 
graft failure(s) is not due to the recurrence of FSGS.
IS AMENDED TO:
Inclusion:
3. Subject is a recipient of a de novo kidney from a living or deceased donor and has 
biopsy-proven, pFSGS as a cause of ESRD in their native kidneys (initial diagnosing 
biopsy report is required). A subject who has biopsy-proven pFSGS as a cause of ESRD, 
and their prior most current graft failure(s) is due to the recurrence of FSGS, is eligible.
Exclusion:
3. Subject has previously received any organ transplant including a kidney and the prior
most current graft failure(s) is not due to the recurrence of FSGS


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III.
Nonsubstantial Amendment Rationale:
Rationale for Nonsubstantial Designation
All revisions made to the protocol are administrative in nature and do not impact the safety 
or scientific value of the clinical study.


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[GPF v4.1]
14
SPONSOR’S SIGNATURES

SAP_001.pdf: 
Sponsor: Astellas Pharma Global Development Inc.
SAP Final Version 2.0
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20-Nov-2019
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STATISTICAL ANALYSIS PLAN
Final Version 2.0, dated 20-NOV-2019
A Phase 2a, Randomized, Open-Label, Active Control, Multi-Center Study to Assess the 
Efficacy and Safety of Bleselumab in Preventing the Recurrence of Focal Segmental 
Glomerulosclerosis in de novo Kidney Transplant Recipients
ISN: 7163-CL-3201
IND number: 100,686
Sponsor name
Astellas Pharma Global Development, Inc. (APGD)
1 Astellas Way
Northbrook, IL 60062
This confidential document is the property of the sponsor.  No unpublished information 
contained in this document may be disclosed without prior written approval of the sponsor.


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Table of Contents
I.
LIST OF ABBREVIATIONS AND KEY TERMS··········································· 5
1
INTRODUCTION·················································································· 9
2
FLOW CHART AND SCHEDULE OF ASSESSMENTS·································10
3
STUDY OBJECTIVE(S) AND DESIGN······················································15
3.1
Study Objective(s) ············································································15
3.1.1
Primary Objective ·······································································15
3.1.2
Secondary Objectives ···································································15
3.1.3
Exploratory Objectives ·································································15
3.2
Study Design···················································································16
3.3
Randomization·················································································17
4
SAMPLE SIZE·····················································································17
5
ANALYSIS SETS ·················································································19
5.1
Full Analysis Set (FAS) ······································································19
5.2
Per Protocol Set (PPS)········································································19
5.3
Safety Analysis Set (SAF) ···································································20
5.4
Pharmacokinetics Analysis Set (PKAS)····················································20
6
ANALYSIS VARIABLES ·······································································20
6.1
Efficacy Endpoints············································································20
6.1.1
Primary Efficacy Endpoint(s)··························································20
6.1.2
Secondary Efficacy Endpoints·························································20
6.1.3
Exploratory Endpoints ··································································21
6.2
Safety Variables···············································································23
6.2.1
Treatment Emergent Adverse Events ·················································24
6.2.2
Anti-bleselumab antibodies, anti-bleselumab neutralizing antibodies and 
bleselumab bi-specific antibodies ·····················································24
6.2.3
Anti CD40 auto-antibody·······························································24
6.3
Pharmacokinetic Variables···································································24
7
STATISTICAL METHODOLOGY ···························································24
7.1
General Considerations·······································································24
7.2
Study Population ··············································································25
7.2.1
Disposition of Subjects ·································································25


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7.2.2
Protocol Deviations ·····································································26
7.2.3
Demographic and Other Baseline Characteristics ···································27
7.2.4
Previous, Concomitant, and other Immunosuppressant Medications ·············30
7.3
Study Drugs····················································································30
7.3.1
Extent of Exposure for Bleselumab ···················································30
7.3.2
Treatment Compliance for Bleselumab···············································31
7.3.3
Extent of Exposure for Basiliximab, Tacrolimus, MMF and steroids·············31
7.3.4
Exposure to Tacrolimus ································································32
7.3.5
Exposure to MMF ·······································································32
7.4
Analysis of Efficacy ··········································································33
7.4.1
Analysis of Primary Endpoint(s) ······················································33
7.4.2
Analysis of Secondary Endpoints ·····················································34
7.4.3
Analysis of Exploratory Endpoints····················································35
7.5
Analysis of Safety·············································································39
7.5.1
Adverse Events ··········································································39
7.5.2
Clinical Laboratory Evaluation ························································42
7.5.3
Vital Signs················································································44
7.5.4
Electrocardiograms (ECGs)····························································45
7.5.5
Viral Load Testing ······································································45
7.5.6
Anti-Bleselumab Antibodies···························································46
7.5.7
Bleselumab bi-specific antibody·······················································46
7.5.8
Incidence of New-onset Diabetes Mellitus after transplantation (NODAT) ·····46
7.6
Analysis of PK·················································································47
7.6.1
Tacrolimus Trough Concentration ····················································47
7.6.2
Bleselumab Concentrations ····························································47
7.7
Analysis of anti-CD40 auto-antibodies·····················································48
7.8
Subgroups of Interest ·········································································48
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)····················48
7.9.1
Interim Data Reviews and the Interim Analysis ·····································48
7.9.2
Data Monitoring Committee (DMC) and Data Analysis Center (DAC)··········49
7.9.3
DMC Open and Closed Sessions ······················································49
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other Information ·········50
7.10.1
Missing Data ·············································································50
7.10.2
Outliers ···················································································50


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7.10.3
Visit Windows ···········································································50
8
DOCUMENT REVISION HISTORY ·························································52
9
REFERENCES ····················································································53
9.1
Appendix 1: Grading of Acute Kidney Allograft Rejection ·····························54
9.2
Appendix 2: Clustered Safety Events·······················································56
9.3
Appendix 3: Liver Safety Monitoring and Assessment···································57
9.4
Appendix 4: Handling of the Human Leukocyte Antigen (HLA) Mismatching·······60
9.5
Appendix 5: Calculation of Dose when Dose Varies within a Visit Interval ··········63
9.6
Appendix 6: Example for Presenting Results for EQ-5D-5L ····························64
9.7
Appendix 7: Protocol Deviation Codes and Sub-codes···································65
9.8
Appendix 8: Key Contributors and Approvers ············································67


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I.
LIST OF ABBREVIATIONS AND KEY TERMS
List of Abbreviations
Abbreviations
Description of abbreviations
ABO
Blood group system (A, AB, B, O)
AE
Adverse event
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase (SGPT)
ANCOVA
Analysis of covariance
ANOVA
Analysis of variance
APGD
Astellas Pharma Global Development, Inc.
AST
Aspartate aminotransferase (SGOT)
BKV
BK virus
BKVAN
BK virus associate nephropathy
BPAR
Biopsy-proven acute rejection
BUN
Blood urea nitrogen
CD
Cluster of differentiation 
Cmax
Maximum concentration
CMV
Cytomegalovirus
CNS
Central nervous system
cPRA
Calculated panel reactive antibody
DCD
Donation after cardiac death
DILI
Drug-induced liver injury
DMC
Data Monitoring Committee
EBV
Epstein-Barr virus
ECD
Extended Criteria Donor
ECG
Electrocardiogram
eCRF
Electronic case report form
eGFR
Estimated glomerular filtration rate
EOT
End of Treatment
EQ-5D-5L
European quality of life – 5 dimensions – 5 levels
ESRD
End stage renal disease
FSGS
Focal segmental glomerulosclerosis
GFR
Glomerular filtration rate
GSD
Geometric Standard Deviation
HBV
Hepatitis B Virus
HbsAg
Hepatitis B surface Antigen
HBc
Hepatitis B core (antigen)
HBcAb IgM
Hepatitis B core antibody IgM
HCV
Hepatitis C Virus 
HLA
Human Lymphocyte Antigen
hx
history
ICH 
International Conference on Harmonization 
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International normalized ratio
IRT
Interactive response technology
LA-CRF
Liver abnormality case report form
LDH
Lactate dehydrogenase


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Abbreviations
Description of abbreviations
LFT
Liver function test 
KTQ
Kidney transplant questionnaire
MDRD
Modification of Diet in Renal Disease
MMF
Mycophenolate mofetil
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse 
Events
NODAT
New Onset of Diabetes after Transplant
PKAS
Pharmacokinetic analysis set
PTLD
Post-transplant lymphoproliferative disorder
rFSGS
Recurrent focal segmental glomerulosclerosis
SAE
Serious adverse event
SAF
Safety analysis set
SOC
Standard of Care
SOC
System Organ Class
TBL
Total bilirubin
TLF
Tables, listings and figures
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal


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List of Key Terms
Terms
Definition of terms
Assigned Treatment Regimen
Arm 1 - Standard of Care regimen (basiliximab 
induction, tacrolimus, steroids and mycophenolate 
mofetil [MMF]).
Arm 2 – Bleselumab regimen (basiliximab induction, 
tacrolimus, steroids and bleselumab).
In this study, when a subject permanently discontinues
or replaces any treatment within in the assigned 
regimen, he/she has reached end of treatment (EOT). 
See EOT term.
Baseline
Time when ‘baseline’ parameters are observed.
The last protocol-defined assessment prior to first dose 
of study drug in the assigned treatment regimen (Days 
-21 to -1, prior to transplant) is considered the baseline 
measurement unless otherwise indicated.
Biopsy-Proven Acute Rejection
Acute rejection episode of which the diagnosis is 
supported by renal allograft histologic evaluation.
Clinically Treated Acute Rejection
Any acute rejection episode that is treated with 
supplemental immunosuppressive agents.
De novo
First line therapy after kidney transplantation. This 
differentiates the “de novo” transplant recipient from a 
stable transplant recipient that is converted from one 
regimen to another (conversion study).
End of Study
(EOS)
End of study (EOS) for each subject has occurred 
when the final, protocol-defined assessment has been 
completed. The last protocol-defined assessment is 
approximately 30 days after the last study drug dose.
If a subject permanently discontinues with the 
assigned treatment regimen AND discontinues
participation in the study, he/she is considered to have 
reached EOS.
Electronic Patient
Reported Outcomes
(ePRO)
An electronic patient-reported outcome (ePRO) is a 
patient-reported outcome that is collected by 
electronic methods. In this study these include the EQ-
5D-5L, the KTQ and the SF-36.
End of Treatment (EOT)
Subjects that permanently discontinue or replace 
bleselumab, tacrolimus or MMF in the post-transplant 
period will be considered to have reached End of 
Treatment (EOT) and are to continue with the 
protocol-defined visit schedule (Table 1: Schedule of 
Assessments – Screening through 12 months Post-
Transplant), for the collection of safety and clinical 
assessment information.


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Terms
Definition of terms
Enroll
The point in time when a subject signs the informed 
consent.
Intervention
The drug, device, therapy or process under 
investigation in a clinical trial which has an effect on 
outcome of interest in a study (e.g., health-related 
quality of life, efficacy and/or safety).
Hepatic enzymes
Also called liver enzymes: Aspartate aminotransferase 
(AST), alanine aminotransferase (ALT) and alkaline 
phosphatase (ALP).
Liver Function Test 
Liver Function Test Includes aspartate 
aminotransferase, (AST), alanine aminotransferase 
(ALT), alkaline phosphatase (ALP) and Bilirubin
Post-transplant Period
Period of time starting on the day of Transplant (Day 
0/post-skin closure) through visit 20/month 12 when a 
subject is on the assigned treatment regimen and fully 
participating in the study.
Randomization
Action to allocate a subject to the treatment group or 
treatment cohort. Randomization is to occur after 
consent has been obtained and the subject has met 
entry criteria, but prior to giving initial dose of study 
drug in any assigned treatment regimen.
Screening
The process for identifying a candidate for the study 
and for evaluation of his/her eligibility to participate 
in the study.
Screen failure
A subject who signs the informed consent and 
undergoes the protocol-specific screening procedures, 
but does not fulfill the protocol inclusion and/or 
exclusion criteria. This subject should not be 
randomized.
Screening Period
The period of time after a subject is enrolled (signs the 
informed consent form) until randomization (assigned 
to a treatment regimen).
Study period
The study will consist of the following study periods: 
screening, transplant and post-transplant.
The entire Study Period includes the time from 
screening (visit 1/Days -21 to 0) through post-
transplant (visit 20/month 12).


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1
INTRODUCTION
This Statistical Analysis Plan (SAP) contains a more technical and detailed elaboration of the 
principal features of the analysis described in the protocol, and includes detailed procedures 
for executing the statistical analysis of the primary and secondary endpoints and other data. 
The SAP is finalized and signed prior to any of the following: study unblinding, database 
hard lock, interim analysis, or accumulation of substantial amount of data in an open-label 
study to ensure lack of bias. 
This statistical analysis is coordinated by the responsible biostatistician of Astellas 
Development Data Science - US. Any changes from the analyses planned in the SAP will be 
justified in the Clinical Study Report (CSR).
Prior to database hard lock, a final review of data and TLFs meeting will be held to allow a 
review of the clinical trial data and to verify the data that will be used for analysis set 
classification. If required, consequences for the statistical analysis will be discussed and 
documented. A meeting to determine analysis set classifications may also be held prior to 
database hard lock.




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Version 1.0
Table 1
Schedule of Assessments– Screening Through 12 Months Post-Transplant
Period
Screening
Transplant
Post-Transplant
Visit
11
21
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21/EOS2
Day
-21 to -1
03
1
4
7
14
28
42
56
70
90
Week
-3 to 1
1
1
1
1
2
4
6
8
10
12
16
20
24
28
32
36
40
44
48
52
Month
1
1
1
1
1
1
2
2
3
3
4
5
6
7
8
9
10
11
12
12
Visit Window (days)
none
none
0
-1
±1
±1
±2
±2
±2
±2
±2
±3
±3
±3
±7
±7
±7
±7
±7
±7
±7
ASSESSMENTS
Informed consent
X
Demographics
X
Physical examination 4
X
X
X
Height and weight 5
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (body temperature, BP and 
HR)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Medical/surgical history 4, 6
X
Medication history and concomitant 
medication
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Chest X-ray
X
X
X
Electrocardiogram
X
X
X
Histocompatibility and cross match
X
Pregnancy test 7
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests (hematology, 
biochemistry and urinalysis) 8
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests – hematology panel and 
hepatic profile 8
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Transplant information 9
X
Verify eligibility criteria
X
Randomization 10
X
Bleselumab dosing 11
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sampling for pharmacokinetics 12
X
X
X
X
X
X
X
X
X
X
X
Anti-bleselumab antibody sampling 12
X
X
X
X
X
X
X
Table continued on next page


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Version 1.0
Period
Screening
Transplant
Post-Transplant
Visit
11
21
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21/EOS2
Day
-21 to -1
03
1
4
7
14
28
42
56
70
90
Week
-3 to 1
1
1
1
1
2
4
6
8
10
12
16
20
24
28
32
36
40
44
48
52
Month
1
1
1
1
1
1
2
2
3
3
4
5
6
7
8
9
10
11
12
12
Visit Window (days)
none
none
0
-1
±1
±1
±2
±2
±2
±2
±2
±3
±3
±3
±7
±7
±7
±7
±7
±7
±7
ASSESSMENTS
Bleselumab bi-specific antibody 
sampling 12
X
X
X
X
X
Auto-Anti-CD40 antibody sampling 12
X
X
X
X
X
X
X
X
X
X
Urine protein-creatinine 13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine albumin-creatinine 13
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Tacrolimus level 14
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Sampling for pharmacogenomics 15
X
Clinical assessment 16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
SF-36s 17
X
X
X
X
X
EQ-5D-5L 18
X
X
X
KTQ 19
X
X
X
X
X
Adverse events 20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Biopsy 21
X
EOT = End of Treatment - If bleselumab is permanently discontinued, subjects in Arm 2 can continue to receive study-supplied Prograf through 12 months post-transplant as
previously assigned; however, any alternate therapy(ies) will not be provided by the Sponsor. Furthermore, subjects that permanently discontinue or replace bleselumab, tacrolimus, or
MMF in the post-transplant period will be considered to have reached EOT and are to continue with the protocol-defined visit schedule for the collection of safety and clinical
assessment information. If a subject declines to be followed upon permanently discontinuing bleselumab, tacrolimus or MMF, the end of study (EOS, visit 21/month 12) procedures are
to be completed within 30 days post-last dose.
EOS = End of Study (visit 21/month 12). EOS for each subject has occurred when the final, protocol-defined assessment has been completed. The last protocol defined assessment is 
approximately 30 days after the last study drug dose. If a subject discontinues with the assigned treatment regimen AND discontinues participation (withdraws consent) in the study, 
he/she is considered to have reached EOS.
Footnotes appear on the next page


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Version 1.0
ABO: absent bed occupant blood group system (A, AB, B and O); AE: adverse event; ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; 
BKV: BK polyomavirus; BP: blood pressure; BUN: blood urea nitrogen; CD40: cluster of differentiation 40; CMV: cytomegalovirus; CPK: creatine phosphokinase; EBV: Epstein-
Barr virus; EQ-5D-5L: European Quality of Life-5 Dimensions–5 Levels; HBcAb IgM (or Anti-HBc IgM): hepatitis B core antibody IgM; HbsAg: hepatitis B surface antigen; HBV: 
hepatitis B virus; HCV: hepatitis C virus; HDL: high-density lipoprotein; INR: international normalized ratio; KTQ: Kidney Transplant Questionnaire; LDH: lactate dehydrogenase; 
LDL: low-density lipoprotein; HDL: high density lipoprotein; MMF: mycophenolate mofetil; PR: pulse rate; PRA: panel reactive antibodies; rFSGS: recurrence of focal segmental 
glomerulosclerosis; RBC: red blood cells; SAE: serious adverse event; SF-36s: Short Form 36-Item Health Survey Score; WBC: white blood cells.
1.
Visits 1 (screening [days -21 to -1]) and 2 (day 0/transplant) can be combined as one.
2.
Also unscheduled visit. Unscheduled visit assessments to be conducted are at the discretion of the Investigator. Urine protein-creatinine and urine albumin-creatinine must be 
collected at all unscheduled visits.
3.
The day of Transplant (day 0) is day/date of transplant completion (skin closure). For transplants that span midnight, assessments may be conducted on day -1.
4.
The screening physical examination includes significant, ongoing medical conditions. Any changes between screening and Randomization are to be captured in the 
Medical/Surgical History.
5.
Height will be measured one time at screening ONLY. Weight will be collected AT ALL VISITS.
6.
Medical/Surgical history includes: diagnosis for renal failure, duration and severity of renal disease at Randomization, and Screening medications (30 days prior to Transplant).
7.
Serum pregnancy test at screening is to be collected on admission to the hospital or within 7 days prior to transplant. All subsequent urine pregnancy tests are to be collected prior 
to continued treatment.
8.
Laboratory tests –
ABO blood-typing at screening ONLY.
Coagulation/thrombotic pathway (prothrombin time, activated partial thromboplastin time, INR). Lipid profile (total cholesterol [including LDL, HDL and triglycerides]).
Hematology includes: hemoglobin, hematocrit, RBC, WBC with differential and bands (where available), and platelet count. Biochemistry includes: phosphorous, total protein,
serum creatinine, BUN, albumin, CPK, LDH, amylase, electrolytes (sodium, potassium, calcium, magnesium, bicarbonate, chloride), and fasting glucose.
The Hematology panel and Hepatic profile (total bilirubin, direct bilirubin, AST, ALT and ALP) are to be collected at EVERY visit. For subjects not making urine at screening,
urinalysis for BKV will not be required.
Recipient viral serologies (i.e., antibodies [e.g., HBV, HCV, CMV and EBV]) performed > 1 year prior to transplant are to be repeated within the screening period (up to 21 days
prior to transplant). Results do not need to be available for randomization. Post-screening testing is to be conducted at day 90/month 3 and month 12/EOS.
If HBsAg is positive, HBcAb IgM and envelope (HBe) antigens are to be analyzed. If the subject has previously been tested for antibodies to HBsAg and the results are positive,
then HBsAg testing does not need to be repeated at screening.
If HCV is positive, quantitative HCV ribonucleic acid is to be analyzed. If the screening results indicate the presence of antibodies, no further testing is required during the study. If
the screening results are negative, testing needs to be repeated at day 90/month 3 and month 12/EOS.
Recipient viral load testing (CMV, BKV [serum an urine] and EBV) is to be conducted at screening, days 14, 28, 56 and 90/month 3, and months 4, 5, 6 and 12/EOS, ONLY if
recipient viral serologies were positive at any time.
Footnotes appear on the next page


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Version 1.0
9.
Transplant information to be collected includes: donor demographics (age, sex, race), donor viral serology (HBV, HCV, CMV and EBV, if available), type of transplant (living 
related, living non-related, or deceased donor), total ischemia time, length of surgery, and most recent PRA results prior to transplant. A copy of the donor kidney biopsy report is 
to be collected where available.
10. Randomization will occur once subject has met ALL entry criteria and prior to initial dose of study drug. Randomization should occur on day 0, or the day prior to skin closure, but 
not more than 4 days prior to transplant start.
11. Bleselumab dosing is to be initiated on day 0 (intravenous intra-operatively and prior to revascularization of the allograft) and may continue during reperfusion; days 7, 14, 28, 42, 
56, 70 and 90/month 3, and once per month through month 12/EOS as a single, 30-minute infusion.
12. SUBJECTS IN ARMS 1 AND 2
Auto-anti-CD40 antibody samples are to be collected at screening, and prior to each infusion at baseline (day 0), visit days 7, 14, 28, 56, 90/month 3, and months 6, 9 and 12/EOS.
SUBJECTS IN ARM 2 ONLY
Pharmacokinetic (bleselumab blood concentration) samples are to be collected within 30 minutes or less pre-initial, and post-initial, intraoperative, bleselumab infusion at baseline
(day 0). Two single, pharmacokinetic samples are to be collected at each subsequent 30-minute intravenous infusion: one within 30 minutes or less prior to the infusion (trough
concentration), and the other at the end of the infusion (peak concentration) up through visit day 28. After that only trough concentrations (within 30 minutes or less pre-infusion)
are to be collected up through day 90/month 3, and months 6, 9 and 12/EOS visits.
Anti-bleselumab antibody samples are to be collected prior to each infusion at baseline (day 0), visit days 14, 28, 90/month 3, and months 6, 9, and 12/EOS.
Bleselumab bi-specific antibody samples are to be collected prior to each infusion at baseline (day 0), visit day 90/month 3, and months 6, 9, and 12/EOS..
13. Urine collection via a spot urine is to occur within 72 hours prior to transplant.
14. Whole blood trough samples are to be drawn 11 - 13 hours’ post-initial tacrolimus dose and immediately prior to all subsequent doses.
15. Sample to be collected one time, preferably prior to first dose on day 0; however, can be collected any time during the study.
16. Clinical assessment is to include: BPAR, clinically-treated acute rejection episodes, graft and patient survival, and rFSGS.
17. SF-36s, version 2.0. Subjects are to complete the questionnaire at screening, days 14 and 90/month 3, and months 6 and 12/EOS
18. EQ-5D-5L. The baseline EQ-5D-5L is to be completed by the subject at screening (or at any visit up through day 10) and 90/month 3, and month 12/EOS.
19. KTQ. Subjects are to complete the KTQ at screening, days 14 and 90/ month 3, and months 6 and 12/EOS.
20. All AEs will be recorded from the time of consent through 30 days post-last dose. The transplantation that occurs on day 0 is not considered an AE or an SAE. Planned surgical 
procedures such as removal of venous catheter or peritoneal catheter, post-transplant, are not considered an AE or an SAE.
21. All subjects who have not had a biopsy with a diagnosis of rFSGS by 3 months post- transplant will have a protocol-defined biopsy at the day 90/month 3 visit. There are no other 
protocol-required biopsies. Biopsies other than the protocol-indicated one at day 90/month 3 will be considered ‘for cause’ only. All images for electron microscopy (EM) and 
slides for light microscopy (LM) utilized for local pathological review for evaluation of possible BPAR and/or rFSGS are to be forwarded for a blinded, central review by an 
independent pathologist to assess (via EM and LM) rFSGS.


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Version 2.0
3
STUDY OBJECTIVE(S) AND DESIGN
3.1
Study Objective(s)
3.1.1
Primary Objective
The primary objective of the study is to assess the efficacy of the bleselumab regimen 
(basiliximab induction, tacrolimus, steroids and bleselumab) compared with the Standard of 
Care (SOC) regimen (basiliximab induction, tacrolimus, steroids and mycophenolate mofetil 
(MMF)) in the prevention of the recurrence of Focal Segmental Glomerulosclerosis (FSGS). 
FSGS recurrence is defined as nephrotic range proteinuria with protein-creatinine ratio
(> 3.0 g/g) through 3 months post-transplant. Death, graft loss or lost to follow-up will be 
imputed as recurrent FSGS (rFSGS).
3.1.2
Secondary Objectives
The secondary objectives include:
●
To assess the incidence of nephrotic range proteinuria with protein-creatinine ratio 
(> 3.0 g/g) through 6 and 12 months’ post-transplant. Death, graft loss or lost to
follow-up will be imputed as rFSGS.
●
To assess the incidence of Biopsy-proven acute rejection (BPAR) (Banff Grade ≥ 1; 
local read) through 3, 6 and 12 months’ post-transplant
●
To assess the incidence of efficacy failure defined as BPAR (Banff Grade ≥1; local
read), death, graft loss or lost to follow-up through 12 months post-transplant
●
To assess the incidence of biopsy-proven (blinded, central read) recurrence of FSGS 
through 3, 6 and 12 months’ post-transplant.
●
To assess the safety of the bleselumab regimen compared with the SOC regimen
3.1.3
Exploratory Objectives
●
To assess graft and patient status through 12 months post-transplant.
●
To assess the Glomerular Filtration Rate (GFR, based on Modification of Diet in Renal 
Disease [MDRD] criteria) through 12 months post-transplant.
●
To assess the incidence of FSGS defined as nephrotic range proteinuria with protein-
creatinine ratio (≥3.0 g/g).
●
To assess the time to rFSGS defined as nephrotic range proteinuria with protein-
creatinine ratio (≥3.0 g/g).
●
To assess the time to rFSGS defined as nephrotic range proteinuria with protein-
creatinine ratio (≥3.0 g/g) or initiation of plasmapheresis.
●
To assess the time to rFSGS defined as recurrence of nephrotic range proteinuria with 
protein-creatinine ratio (≥3.0 g/g), death, graft loss or lost to follow-up. 
●
To assess the time to recurrence of biopsy-proven (blinded, central read) FSGS.
●
To assess the time to first BPAR (Banff Grade ≥1, local read).
●
To assess the urine protein-creatinine ratio through 6 and 12 months post-transplant.
●
To assess the urine albumin-creatinine ratio through 3, 6 and 12 months post-transplant.
●
To assess the change in anti-CD40 autoantibodies from baseline.


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●
To assess the change in patient-reported outcomes from baseline (Short Form 36-Item
Health Survey Score [SF-36s]), European Quality of Life-5 Dimensions-5 Levels
[EQ-5D-5L], and Kidney Transplant Questionnaire [KTQ]).
3.2
Study Design
This is a Phase 2a, randomized, open-label, active control, multi-center study to assess the 
efficacy and safety of bleselumab in preventing the recurrence of FSGS in de novo kidney 
transplant subjects.
The study will consist of the following periods:
●
Screening (Days -21 to -1)
●
Transplant (Day 0)
●
Post-Transplant (Day 0/post skin closure through 12 months’ post-transplant)
Prior to any study-related assessment, the subject will sign the informed consent form 
(ICF)/authorization (visit 1). All subjects will enter into a screening period (Days -21 to -1 prior 
to transplant), undergo a transplant (Day 0) and will be followed for up to 12 months in the 
post-transplant period (Day 0 / post-skin closure through 12 months post-transplant) for efficacy 
and safety.
Randomization can occur up to 4 days prior to or on Day 0 (prior to transplant). Subjects will be 
assigned in a 1:1 ratio to open-label treatment of one of two arms as follows:
●
Arm 1 - SOC regimen (basiliximab induction, tacrolimus, steroids and MMF)
●
Arm 2 – Bleselumab regimen (basiliximab induction, tacrolimus, steroids and 
bleselumab)
All subjects who have not had a biopsy with a diagnosis of rFSGS by 3 months post-
transplant will have a protocol-defined biopsy at the Day 90/month 3 visit. There are no other 
protocol-defined biopsies. Biopsies other than the protocol-indicated one at Day 90/month3 
will be considered ‘for cause’ only. All episodes of kidney dysfunction based on clinical 
signs and symptoms will be evaluated for possible BPAR and/or rFSGS. All subjects should 
have a biopsy confirmation of a rejection episode prior to the initiation of treatment for 
rejection, or within 48 hours of initiation of treatment for acute rejection. BPAR (T- or 
B-cell) will be determined via local review at the study center using the 2007 Banff criteria.
All images for electron microscopy (EM) and slides for light microscopy (LM) reviewed by 
the local pathologist to evaluate possible BPAR and/or rFSGS will be forwarded for a 
blinded, central assessment of rFSGS by an independent pathologist.
If bleselumab is permanently discontinued, subjects in Arm 2 can continue to receive
study-supplied tacrolimus through 12 months post-transplant as previously assigned; 
however, any alternate therapy (ies) will not be provided by the Sponsor. 
Subjects that permanently discontinue bleselumab, tacrolimus or MMF in the post-transplant 
period will be considered to have reached End of Treatment (EOT) and are to continue with 
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safety and clinical assessment information. If a subject declines to be followed upon 
permanently discontinuing bleselumab, tacrolimus or MMF, the End of Study (EOS, visit 
20/month 12) procedures are to be completed within 30 days post-last treatment.
Data reviews by an independent Data Monitoring Committee (DMC) were planned as 
follows for the following time points during the study:
●
50% of the subjects have completed 3 months’ post-transplant follow-up
●
100% of the subjects have completed 3 months’ post-transplant follow-up
●
100% of the subjects have completed 6 months’ post-transplant follow-up.
A separate DMC Charter has been created providing the details and the output needed for 
each of the reviews.
An interim analysis was planned when all subjects completed 3 months’ post-transplant 
follow-up. The purpose of the interim analysis was to evaluate treatment differences for the 
recurrence of FSGS to support strategic decision making for future project development and 
study design. Instead, due to slow enrollment the first 50 subjects transplanted and dosed will 
be analyzed and the results used to support strategic decisions. The interim analyses that were 
planned once all 60 subjects completed 3 months of follow-up and 6 months of follow-up 
will not occur. The final analysis will occur once all subjects have been followed through 
12 months. 
The first subject was enrolled in May 2017. There are 50 subjects transplanted and dosed as 
of mid July 2019 with an additional 10 subjects planned. Due to the slow enrollment Astellas 
and the development partner, Kyowa Kirin Co., Ltd. (KKC) plan to follow these 50 subjects 
for three months (the time of the primary endpoint), and conduct an interim analysis to 
evaluate response in the two treatment groups. This interim analysis will serve as the 
foundation for a Briefing Document to support a Type C meeting with the FDA, if the results 
merit a go forward decision. TLFs from this interim analysis will be discussed in an open 
session with the members of the DMC.
3.3
Randomization
Subjects who meet the inclusion criteria and exhibit none of the exclusion criteria will be 
randomly assigned to receive one of two study treatments using a 1:1 ratio. Randomization 
will be central with treatment assignments balanced between the two study arms.  There will 
be no stratification by site since an individual site is expected to enroll a small number of 
subjects; balancing within a site could lead to selection bias. Randomization will be stratified 
by previous transplant (yes, no). Randomization will be performed via Interactive Response 
Technology (IRT) from Cenduit LLC. 
4
SAMPLE SIZE
The primary aim of this study is to assess the rFSGS defined as nephrotic range proteinuria 
with protein-creatinine ratio (≥ 3.0 g/g) through 3 months post-transplant. Death, graft loss or
lost to follow-up will be imputed as rFSGS.


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This proof of concept study will provide an estimate of the effect size for the difference in the
rFSGS between the standard of care and the experimental group and provide estimates of the 
recurrence rates for each treatment group. The estimate of the effect size will be needed to
plan a future study.
The following table provides a subset of estimates and the 95% confidence interval for the
FSGS recurrence rate with 30 subjects per treatment group. The width of these confidence
intervals varies between 17% and 36% indicating the limit of the precision for the estimate.
Proportion (%)
95% Confidence Interval with 30 subjects (%)
3.3  (1/30)
0.1 - 17.2*
16.7 (5/30)
3.4 - 30.0
33.3 (10/30)
16.4 - 50.2
50.0 (15/30)
32.1 - 67.9
66.7 (20/30)
49.8 - 83.6
83.3 (25/30)
70.0 - 96.6
96.7 (29/30)
82.8 - 99.9*
*Exact binomial confidence interval using Clopper-Pearson (Exact method based on the Beta distribution); for
all others the normal approximation was used to calculate the intervals.
Literature estimates show that the expected FSGS recurrence rate for the SOC group is 
between 30% and 50% with most occurring by three months post-transplant. Imputing death, 
graft loss or lost to follow-up as rFSGS is not anticipated to have a sizeable impact on the 
rFSGS estimates. In a previous study that included two of the treatment arms planned for the 
current study, there were 4/48 in the SOC group and 3/44 in the ASKP1240 (Bleselumab) 
+Tac group who experienced death, graft loss or lost to follow-up by 6 months.  Literature
estimates of rFSGS were used to examine the precision of the treatment difference provided 
with 30 subjects per treatment group.
Bleselumab was assumed to decrease the recurrence rate in the experimental arm by 20% to 
60% relative to SOC. The following table provides the difference in the observed rates and 
the associated two-sided 95% confidence interval with 30 subjects per group. The width of 
the confidence interval for the difference between the two treatment groups ranges between 
47% and 57%. The width of the confidence interval provides the precision of the estimate for 
the difference in recurrence between the two groups.
Bleselumab Rate
SOC Rate
50%
(15/30)
40%
(12/30)
30%
(9/30)
60% Reduction from SOC
0.20
(6/30)
0.167
(5/30)
0.133
(4/30)
Difference in rates and 95% 
CI
(2-sided)
0.30
0.038 to 0.562
0.233
-0.021 to 0.487
0.167
-0.07 to 0.404
50% Reduction from SOC
0.267
(8/30)
0.20
(6/30)
0.167
(5/30)
Table continued on next page


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Bleselumab Rate
SOC Rate
50%
(15/30)
40%
(12/30)
30%
(9/30)
Difference in rates and 95% 
CI
(2-sided)
0.233
-0.039 to 0.505
0.20
-0.06 to 0.46
0.133
-0.112 to .355
40 % Reduction from SOC
0.30
(9/30)
0.267
(8/30)
0.20
(6/30)
Difference in rates and 95% 
CI
(2-sided)
0.20
-0.068 to .434
0.133
-0.137 to 0.40
0.10
-0.151 to 0.351
30% Reduction from SOC
0.367
(11/30) 
0.30
(9/30)
0.23
(7/30)
Difference in rates and 95% 
CI
(2-sided)
0.133
-0.149 to 0.415
0.10
-0.173 to 0.373
0.07
-0.186 to 0.326
20 % Reduction from SOC
0.40
(12/30)
0.333
(10/30)
0.267
(8/30)
Difference in rates and 95% 
CI
(2-sided)
0.10
-0.184 to 0.384
0.067
-0.21 to 0.344
0.033
-0.228 to 0.294
5
ANALYSIS SETS
In accordance with International Conference on Harmonization (ICH) recommendations in 
guidelines E3 and E9, the following analysis sets will be used for the analyses. Unless 
otherwise stated, the Full Analysis Set (FAS) will be used for analysis of efficacy data and 
the Safety Analysis Set (SAF) will be used for analysis of safety data. The PK Analysis Set 
(PKAS) will be used for analysis of pharmacokinetic parameters. 
5.1
Full Analysis Set (FAS)
The Full Analysis Set (FAS) consists of all subjects who are randomized, receive at least one 
dose of study drug and receive a transplanted kidney. Subjects who enroll in the study and 
later documentation reveals that the subject does not have primary FSGS, will not be 
included in the FAS since they are not included in the population of interest, primary FSGS, 
and are not at risk for recurrence of their primary FSGS. The FAS will be the primary 
analysis set for efficacy analyses. 
5.2
Per Protocol Set (PPS)
No Per Protocol Set (PPS) is planned for this study. However, exploratory analyses excluding 
certain subjects may be performed if clinically meaningful. These analyses, if performed, are 
for the purpose of gaining additional insight. 


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5.3
Safety Analysis Set (SAF)
The Safety Analysis Set (SAF) consists of all randomized subjects who received at least one 
dose of study drug, and will be used for safety analyses. Study drug includes basiliximab, 
tacrolimus, MMF and bleselumab.
5.4
Pharmacokinetics Analysis Set (PKAS)
The Pharmacokinetics Analysis Set (PKAS) consists of subjects from the SAF who have at 
least one measurable peak or trough pharmacokinetic concentration. The PKAS will be used 
for summaries and exploratory analysis of the pharmacokinetic data. 
6
ANALYSIS VARIABLES
6.1
Efficacy Endpoints
6.1.1
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the percentage of subjects who have rFSGS defined as
nephrotic range proteinuria with protein-creatinine ratio (≥ 3.0 g/g) through 3 months
post-transplant. Death, graft loss or lost to follow-up will be imputed as rFSGS. Subjects with 
a protein-creatinine ratio (≥ 3.0 g/g) on Day 0 only (day of skin closure) will not be 
considered to have a recurrence if this is the only day with the elevated ratio and subsequent 
values do not meet this limit. This specification for Day 0 will apply to all rFSGS endpoints. 
6.1.2
Secondary Efficacy Endpoints
The following secondary efficacy endpoints will be assessed:
●
Recurrence of FSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(> 3.0g/g) through 6 and 12 months’ post-transplant. Death, graft loss or lost to 
follow-up will be imputed as rFSGS.
●
BPAR (Banff Grade ≥1, local read) through 3, 6 and 12 months post-transplant. 
●
Efficacy failure defined as BPAR (Banff Grade ≥ 1; local read), death, graft loss or lost 
to follow-up through 12 months post-transplant.
●
Biopsy-proven (blinded, central read) rFSGS through 3, 6 and 12 months post-transplant.
6.1.2.1 Blinded, Central Read for Recurrence of Focal Segmental Glomerulosclerosis
All episodes of kidney dysfunction based on clinical signs and symptoms will be evaluated
for recurrence of FSGS and for possible rejection after exclusion of other causes. A sample of
the biopsy will be sent to a central pathology lab and read without knowledge of the subject’s 
treatment regimen by an independent pathologist to determine if FSGS has recurred.
Subjects who have not had a biopsy with a diagnosis of rFSGS by three months post-
transplant will have a protocol-defined biopsy at the Day 90 / 3 month visit. If there is an 
earlier biopsy indicating rFSGS, then the protocol-defined biopsy at 3 months is not required. 
Biopsies after the protocol-defined biopsy at three months will be for-cause only.  There will 
are no additional protocol-defined biopsies required at 6 and 12 months post-transplant.


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6.1.2.2 Biopsy Proven Acute Rejection
All episodes of kidney dysfunction based on clinical signs and symptoms will be evaluated 
for possible rejection. The pathologist at the clinical site will grade all biopsies using the 
2007 Banff criteria (Section 9.1).  The date of the first positive biopsy for an event will 
constitute the start of the BPAR event. 
6.1.3
Exploratory Endpoints
The following exploratory endpoints will be assessed:
Efficacy
●
Graft and subject status through 12 months’ post-transplant
●
GFR, based on MDRD criteria through 12 months’ post-transplant
●
Recurrence of FSGS defined as nephrotic range proteinuria with protein-creatinine ratio
(≥ 3.0 g/g); there is no imputation for death, graft loss, or lost to follow-up for this 
endpoint.
●
Recurrence of FSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(≥ 3.0 g/g) or initiation of plasmapheresis.
●
Time to rFSGS defined by nephrotic range proteinuria with protein-creatinine ratio 
(> 3.0g/g) 
●
Time to rFSGS defined by nephrotic range proteinuria with protein-creatinine ratio 
(> 3.0g/g) or initiation of plasmapheresis.
●
Time to rFSGS defined by nephrotic range proteinuria with protein-creatinine ratio 
(> 3.0g/g), death, graft loss or lost to follow-up
●
Time to biopsy-proven (blinded, central read) rFSGS
●
Time to first BPAR (Banff Grade ≥ 1, local read)
●
Urine protein-creatinine ratio through 3, 6 and 12 months’ post-transplant
●
Urine albumin-creatinine ratio through 3, 6 and 12 months’ post-transplant
●
Change in anti-CD40 auto-antibodies (protocol term: auto-anti-CD40 antibody) from 
baseline; the anti-CD40 auto-antibodies obtained prior to the first dose of ASKP1240, at 
screening or on Day 0, will be the baseline value. Anti-CD40 auto-antibodies will be 
assessed for both treatment groups.
●
Change in patient-reported outcomes from baseline (Short Form-36 Item Health Survey
[SF-36s], European Quality of Life - 5 Dimensions - 5 Levels [EQ-5D-5L] and Kidney 
Transplant Questionnaire [KTQ]); baseline will be obtained prior to transplant for all 
patient reported outcomes.
Safety
●
Adverse events (AEs) graded by National Cancer Institute Common Terminology 
Criteria for Adverse Events criteria (NCI CTCAE)
●
Vital sign measurements.
●
Clinical laboratory tests.
●
Viral serology (hepatitis B virus [HBV], hepatitis C virus [HCV], CMV, BK 
polyomavirus [BKV] and EBV).


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●
Viral load testing (CMV, BKV and EBV).
●
Anti-bleselumab antibodies.
●
Bleselumab bi-specific antibodies
●
NODAT (New Onset Diabetes Mellitus after Transplant)
●
Bleselumab pharmacokinetics
6.1.3.1 Patient Survival
Patient survival is defined as any subject who does not have a fatal event during the study. 
6.1.3.2 Graft Survival
Graft survival is defined as any subject who does not experience graft loss during the study. 
Graft loss is defined as subject death, re-transplant, nephrectomy, or return to permanent 
dialysis (greater than 30 days).
6.1.3.3 Estimated Glomerular Filtration Rate
Estimated glomerular filtration rate (eGFR) will be calculated using the Modification of Diet 
in Renal Disease criteria. eGFR = 186 x Serum Creatinine-1.154 x Age-0.203 x [1.212 if Black] x 
[0.742 if Female], where Serum Creatinine is in mg/dL and Age is in integer years at study 
baseline. Baseline eGFR will be calculated using the serum creatinine obtained on Day 28 
post-transplant. 
6.1.3.4 Urine Protein-Creatinine Ratio and Urine Albumin-Creatinine Ratio
Urine protein-creatinine ratio and albumin-creatinine ratio, will be summarized by visit and 
treatment group and compared between treatment groups.  Higher values indicate worsening 
kidney function. These data are usually right-skewed and will be log-transformed to achieve 
a normal distribution. Values of 0, if any, will have 0.5 added to enable calculation of the 
log-transformation.  The transformed data will be analyzed and back-transformed to provide 
the summaries.
6.1.3.5 Short Form-36 Item Health Survey
The SF-36 Version 2.0 is a measure of health status. The SF-36 provides scores for each of 
the eight health domains, a psychometrically-based physical component summary (PCS) and 
mental component summary (MCS). The eight domains are the weighted sums of questions 
in their section. Each domain is directly transformed into a 0 -100 scale on the assumption 
that each question carries equal weight. The higher the score the less disability (i.e., a score 
of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability). 
Subjects will complete this self-assessment at baseline, Day 14, month 3, 6 and 12/EOS. 
6.1.3.6 European Quality of Life - 5 Dimensions - 5 Levels
The EQ-5D-5L is an international standardized non-disease specific (i.e., generic) instrument 
for describing and valuing health status. 


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This questionnaire consists of two parts:
●
5-dimensions (EQ-5D-5L): mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. For each dimension there are 5 levels (i.e., scores 1 to 5) to classify 
the severity the dimension, ranging from no problems to inability to do things
●
VAS, where 0 represents the worst imaginable health state and 100 the best imaginable 
health state.
For the total VAS Score, change from baseline at Month 3 and 12/EOS will be defined as the 
Month 3, or Month 12/EOS Visit value minus the baseline value obtained at Screening. 
6.1.3.7 Kidney Transplant Questionnaire
The KTQ is a 25-item questionnaire designed specifically for use with kidney transplant 
patients that includes five domains for subscales (i.e., physical symptoms, fatigue, 
uncertainty/fear, appearance, and emotional). A mean score ranging from 1 to 7 is reported
for each of the five subscales, with higher scores representing better functioning, well-being, 
or fewer problems [Laupacis et al, 1993]. 
Subjects are to complete this self-assessment at the baseline, Day 14, month 3, 6 and 12/EOS. 
6.2
Safety Variables
Safety will be assessed by evaluation of the following variables:
●
Treatment-emergent adverse events (TEAE) by: frequency, severity graded by NCI 
CTCAE criteria, relationship to bleselumab, relationship to tacrolimus, relationship to 
MMF, relationship to basiliximab, seriousness, and outcome.
●
Vital signs (systolic and diastolic blood pressure, heart rate, oral temperature, height and 
weight, body mass index)
●
Clinical laboratory variables 
○
Hematology
○
Biochemistry
○
Coagulation/thrombotic pathway (prothrombin time, activated partial 
thromboplastin time, INR)
○
Hepatic profile
○
Lipid profile
○
Urine quantitative
○
Urinalysis
○
Pregnancy Testing
●
Viral serology (HBV, HCV, CMV, BKV and EBV)
●
Viral load testing (CMV, BKV and EBV)
●
Anti-bleselumab antibodies, anti-bleselumab neutralizing antibodies
●
Bleselumab Bi-specific antibodies
●
NODAT (New Onset of Diabetes after Transplant)


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6.2.1
Treatment Emergent Adverse Events
TEAE is defined as an adverse event observed after starting administration of bleselumab or 
MMF. If the adverse event occurs on Day 0 (day of skin closure) and the onset check box is 
marked “Onset after first dose of study drug” or the onset check box is left blank, then the 
adverse event will be considered treatment emergent. If the adverse event occurs on Day 0
and the onset check box is marked “Onset before first dose of study drug”, then the adverse 
event will not be considered treatment emergent. If a subject experiences an event both 
during the pre-investigational period and during the investigational period, the event will be 
considered as TEAE only if it has worsened in severity. All adverse events collected that 
begin within 30 days after taking the last dose of study drug will also be counted as TEAE.
6.2.2
Anti-bleselumab antibodies, anti-bleselumab neutralizing antibodies and 
bleselumab bi-specific antibodies
Samples for anti-bleselumab, anti-bleselumab neutralizing and bleselumab bi-specific 
antibodies will be collected only for subjects treated with bleselumab. 
Anti-bleselumab antibody samples are to be collected prior to each infusion at baseline (Day 
0), visit Days 14, 28, 90/month 3, and months 6, 9, and 12/EOS. If the antibody sample is 
positive with a titer, the sample will be tested to determine if it is neutralizing. 
Bleselumab bi-specific antibody samples are to be collected prior to each infusion at baseline 
(Day 0), visit Day 90/month 3, and months 6, 9, and 12/EOS.
6.2.3
Anti CD40 auto-antibody
Anti-CD40 auto-antibodies are present in the serum of rFSGS subjects and pre-transplant 
elevation of anti-CD40 auto-antibody is reported to be associated with the risk of rFSGS 
post-transplant.  Samples for anti-CD40 auto-antibody will be collected from both treatment 
groups at screening, and prior to each infusion at baseline (Day 0), visit Days 7, 14, 28, 56, 
90/month 3, and months 6, 9 and 12/EOS.
6.3
Pharmacokinetic Variables
Bleselumab samples for trough concentrations (30 minutes or less prior to infusion) will be 
collected on visit Days 0, 7, 14, 28, 42, 56, 70, 90 and months 6, 9 and 12/EOS. Samples for 
peak concentrations (at the Bleselumab infusion completion) will be collected on visit Days 
0, 7, 14 and 28.
7
STATISTICAL METHODOLOGY
7.1
General Considerations
For continuous variables, descriptive statistics will include the number of subjects (n), mean, 
standard deviation, median, minimum and maximum. When needed, other percentiles, (10%, 
25%, 75% and 90%) will be provided. Frequencies and percentage will be displayed for 
categorical data by treatment group. Percentages by category will be based on the number of 
subjects with no missing data. Subjects with missing data will be treated as a separate 


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category and not included in the denominator, unless specific methods for imputation are 
stated. 
If there are a sufficient number of subjects with a second transplant in each of the treatment 
groups then the analysis will be modified to include 2nd transplant (yes, no) as a factor or 
stratification variable. For an analysis of variance (ANOVA) or analysis of covariance 
(ANCOVA), previous kidney transplantation (no, yes) will be included as a factor in the 
model if there are a sufficient number of subjects with second transplants. Endpoints 
analyzed with Fisher’s Exact test may be analyzed with a CMH test stratifying by previous 
kidney transplantation (no, yes) if there are a sufficient number of subjects with second 
transplants and the outcome does not produce a missing row for the strata of second 
transplants. For time-to-event endpoints, Cox regression will be used comparing the two 
treatment groups and will include previous kidney transplantation (no, yes) in the model.
All statistical comparisons will be made using two-sided test at α=0.05 significance level
with no adjustments for multiplicity unless specifically stated otherwise. All null hypotheses 
will be of no treatment difference. All hypotheses testing will be two-sided. 
The primary analysis will be the comparison between standard of care regimen (Arm 1) and 
the bleselumab regimen (Arm 2). 
For purpose of data presentation and analyses, Study Day is defined relative to the day of 
skin closure (Day 0) and unless specifically stated otherwise, the term baseline will refer to 
the last assessment/evaluation up to and including Day 0. 
There is a slight modification for defining Day 0 for patients given Bleselumab 
intraoperatively on the day prior to the day of skin closure. Subjects may have their transplant 
surgery initiated before midnight and end after midnight on the next day. Assigning Day 0 as 
skin closure results in the appearance that study drug was given prior to Day 0. Subjects who 
are given Bleselumab on the day prior to skin closure with their transplant spanning midnight 
will have Day 0 defined as the day surgery is initiated.
All data processing, summaries, and analyses will be performed using SAS® Version 9.1.3 or 
higher on Unix. Specifications for table, figures, and data listing formats can be found in the 
TLF specifications for this study.
7.2
Study Population
7.2.1
Disposition of Subjects
Disposition will include the number of subjects in the following categories:
●
subjects completing informed consent, 
●
subjects discontinued prior to randomization, 
●
subjects randomized, 
●
subjects dosed (received any study drug: bleselumab, tacrolimus, MMF, steroids, or 
basiliximab) and 
●
subjects dosed and transplanted.


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The following subject data will be summarized and presented for each treatment group and 
for the total:
●
Number and percentage of subjects in each analysis set (Randomized; and Safety, Full, 
Pharmacokinetic Analysis Sets);
●
Screening Disposition: number and percentage of all subjects who signed the informed 
consent by screening status (Screen Failure, Primary Screening Status (Completed, 
Screen Failure)). 
●
Treatment Disposition: number and percentage all randomized subjects by treatment 
discontinuation (Yes, No). For those who did not complete the regimen, the number and 
percentage for each reason will be given (adverse event, death, lack of efficacy, lost to 
follow-up, protocol deviation, withdrawal by subject, non-compliance with study drug 
and other). 
●
Number and percentage of all randomized subjects by study completion status, i.e.,
completed 12 months on the study regardless of assigned treatment status (Yes, No). For 
those who did not complete the study, the number and percentage for each reason will be 
given (adverse event, death, lost to follow-up, protocol deviation, withdrawal by subject, 
non-compliance with study drug and other). 
A listing of screen failures will be provided by investigative site. Subject listings will be 
produced by investigative site and treatment group for the following: 
●
Randomization information 
●
Treatment discontinuations
●
Study discontinuations
●
Dates of First and Last Evaluations
●
Inclusion/Exclusion from analysis sets for subjects excluded from at least one analysis 
set and the reason for exclusion, if applicable. 
7.2.2
Protocol Deviations
Protocol deviations as defined in the study protocol (Section 8.1.6 Protocol Deviations) will 
be assessed for all randomized subjects. The number and percentage of subjects meeting any 
protocol deviation criteria (PD1-PD5) will be summarized for each criterion and overall, by
treatment group as well as by study site. See Appendix 7 for a list of the sub-codes and their 
definition.
Subjects deviating from a criterion more than once will be counted once for the 
corresponding criterion. Any subjects who have more than one protocol deviation will be 
counted once in the overall summary. A listing of the protocol deviation definitions will be 
provided and a listing of subjects who had protocol deviations will be provided by site and 
subject.   
The protocol deviation criteria will be uniquely identified in the summary table and listing. 
The unique identifiers will be as follows:


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PD1 - Entered into the study even though they did not satisfy entry criteria, 
PD2 - Developed withdrawal criteria during the study and was not withdrawn,
PD3 - Received wrong treatment or incorrect dose,
PD4 - Received excluded concomitant treatment. 
PD5 - SAE was not submitted in the required time frame.
At the time of the 3-month analysis of the primary endpoint, a summary of protocol 
deviations will be provided and upon completion of the study a summary for the full study 
period will be provided.
7.2.3
Demographic and Other Baseline Characteristics
7.2.3.1 Recipient Demographic 
Recipient demographics will be summarized by descriptive statistics and compared between 
treatment groups using Fisher’s Exact Test or a one-way ANOVA with treatment as the 
factor. The safety analysis set will be summarized and if different, the full analysis set will be 
summarized.  A summary will be provided for the screen failures. Recipient demographic 
variables are gender, age in years, age categories (<65, >65 to <=75 and >75), race (white, 
black or African American, Asian, American Indian or Alaska native, native Hawaiian or
other Pacific Islander, and other) and (African-American vs. Others), ethnicity, weight, 
height and BMI. Summary statistics will also be given for the total.
7.2.3.2 Baseline Characteristics Related to FSGS and the Native Kidney 
Baseline characteristics related to FSGS and native kidney status will be summarized by 
treatment group and overall for the full analysis set, and for the safety analysis set (SAF), if 
different from the FAS. Duration variables are:
●
duration of FSGS (Date of skin closure – Date of Primary FSGS Diagnosis)+1, 
●
duration of pathology-confirmed FSGS (Date of skin closure – Date of Pathology-
confirmed FSGS)+1 and 
●
duration of End Stage Renal Disease, ESRD (Date of skin closure – Date of ESRD 
Diagnosis)+1.  
Other variables and their categories (where applicable) are:
●
panel reactive antibody (PRA in %), 
●
panel reactive antibody (%) categories (<=0%, >0% - 20%, >20% - 50%, >50%),
●
dialysis prior to transplant (Yes, No), 
●
making urine prior to transplant (Yes, No),
●
reason for dialysis (fluid overload, uremia, hyperkalemia, metabolic acidosis, other 
and other specify) and
●
plasmapheresis prior to transplant (Yes, No). 


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The means for continuous variables will be compared between treatment groups using an 
analysis of variance (ANOVA) with treatment group as the factor. For categorical variables, 
comparisons between treatment groups will be performed using Fisher’s exact test. 
These variables will be listed by investigative site and treatment group.
7.2.3.3 Donor Demographic and Other Baseline Characteristics
Donor demographic data (age, sex, race, height, weight and BMI) will be summarized by 
treatment group and overall for the full analysis set. The source of the kidney to be 
transplanted (living related, living non-related or deceased donor), and specific detailed 
information for deceased donors will be summarized by treatment group and overall. 
Detailed information for deceased donors includes:
●
cause of death (anoxia, cerebrovascular /stroke, head trauma, CNS tumor, 
other/specify),
●
terminal serum creatinine (mg/dL), 
●
history of hypertension (yes, no) 
●
history of diabetes (yes, no), 
●
Deceased donor criteria (DCD: Donation After Cardiac Death; ECD: Expanded 
Criteria Donor; SCD: Standard Criteria Donor)
●
ECD Donor age category (50-59, > 60) and
●
deceased donors aged 50-59 with
o
death by cerebrovascular accident (yes), 
o
history (hx) of hypertension (yes), 
o
terminal serum creatinine >1.5 mg/dL (yes), 
●
controlled DCD (yes, no, unknown). 
Detailed information for the donated kidney will include:
●
longest primary organ preservation method (pump, cold storage)
●
cold ischemia time (hours)
●
cold ischemia time (hours) for living donors
●
cold ischemia time (hours) for deceased donors
●
warm ischemia time (hours)
●
total ischemia time (hours) 
Continuous variables will be compared between treatment groups using an analysis of 
variance (ANOVA) with treatment group as a factor. Categorical variables will be compared 
between treatment groups using Fisher’s exact test. 
Listings will be provided by investigative site and treatment group for the variables above. 
7.2.3.4 Transplant Surgery Information
Listings will be provided by investigative site and treatment for variables related to the 
transplant surgery, specifically,


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●
admission/discharge day, 
●
making urine prior to transplant (yes or no), 
●
length of surgery, 
●
complications, and if yes, the specific complications, 
●
hemodynamically unstable during surgery (yes or no), 
●
dialysis within 7 days following skin closure (No, Yes).
Summaries by treatment group and overall will be provided for the longest primary 
preservation method for the donated organ, warm ischemia time, cold ischemia time and total 
ischemia time using the FAS. 
7.2.3.5 Crossmatch of Histocompatibility, ABO Type and Serology
7.2.3.5.1
Histocompatibility
The total number of Human Lymphocyte Antigen (HLA) mismatches between the donor and 
recipient will be calculated for the Full Analysis Set. The number and percent of patients with 
0, 1, 2, etc. mismatches will be displayed. The broad type designations will be provided for 
HLA A, HLA B and HLA DR. These are 2 numeric values for each of the HLA antigens. A 
mismatch between a donor and a recipient exists if the donor has an antigen which doesn’t 
appear in the recipient.
For complete details on how to determine the number of HLA mismatches, see Appendix 4. 
7.2.3.5.2
ABO Type
ABO Type will be categorized as identical, compatible or not recorded.  Identical is defined 
as the donor and recipient have the same blood type. Compatible is defined as the recipient 
has blood type A or B and the donor has O or the recipient is type AB and the donor is A, B 
or O. The number and percent of patients within each treatment group and overall will be 
displayed for the FAS. 
7.2.3.5.3
Recipient and Donor Viral Serology 
Patient and donor status (negative or positive) will be determined for each of the following 
serology parameters using the definitions provided below.  
●
Hepatitis B surface antibody (Hepatitis B Surface Antibody is positive if any of the 
following are positive: Hepatitis B Surface Antibody (HBSAB), Hepatitis B Surface 
Antibody IgG (HBSIGG) or Hepatitis B Surface Antibody IgM (HBSIGM)).
●
Hepatitis B core antibody (Hepatitis B Core Antibody is positive if any of the following 
are positive: Hepatitis B Core Antibody (HBCOREAB), Hepatitis B Core Antibody IgG 
(HBCIGG) or Hepatitis B Core Antibody IgM (HBCIGM)). 
●
Hepatitis B surface antigen (Hepatitis B Surface Antigen (HBsAG) is a stand-alone lab 
result).
●
Hepatitis B Virus E antigen (Hepatitis B E Antigen (HBeAG) is a stand-alone lab result.)
●
Hepatitis C antibody (Hepatitis C Antibody is positive if any of the following are 
positive: Hepatitis C Surface Antibody (HCAB), Hepatitis C Antibody IgG 
(HCVIGGAB) or Hepatitis C Antibody IgM (HCVIGMAB)). 


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●
Epstein-Barr virus antibody (Epstein Barr Virus is positive if any of the following are 
positive: Epstein - Barr virus Antibody (EBVAB), Epstein - Barr virus Antibody IgG 
(EBVIGGAB) or Epstein-Barr Virus Antibody IgM (EBVIGMAB)). 
●
Cytomegalovirus antibody (Cytomegalovirus is positive if any of the following are 
positive: Cytomegalovirus Antibody (CMVAB), Cytomegalovirus Antibody IgG 
(CMVIGGAQ), or Cytomegalovirus Antibody IgM (CMVIGMAB)).
Counts and percentages will be provided for each recipient/donor combination with 
D=Donor, R=Recipient, +=Positive, -=Negative, U=Unknown (D+/ R+, D+/R-, D+/RU, D-
/R+, D-/R-, D-/RU, DU/R+, DU/R-, and DU/RU). The data will be summarized by treatment 
group and overall for the FAS.
7.2.3.6 Country and Investigative Site
The number and percent of subjects will be provided for the SAF by treatment group and 
total number for each investigative site and by country.
7.2.3.7 Medical History
Medical history and targeted medical history is coded with MedDRA. Medical history and 
targeted medical history will be summarized by System Organ Class and Preferred Term by 
treatment group and total for the SAF. The number and percent of subjects will be presented. 
7.2.4
Previous, Concomitant, and other Immunosuppressant Medications
Previous, concomitant and other immunosuppressant medications will be coded with WHO-
DD or WHO-DRL(immunosuppressant medications), and a table will be created for each 
category with summaries provided by chemical subgroup (ATC 4th level) and preferred 
WHO name by treatment group for the SAF. Previous medications are those initiated prior to 
the first dose of bleselumab for those assigned to the bleselumab regimen and those that 
occur prior to the first dose of MMF for those on the SOC regimen. This definition is 
consistent with the definition of treatment emergent.
Subjects taking the same medication multiple times will be counted once per medication. A 
medication, which can be classified into several chemical and/or therapeutic subgroups, will 
be presented in all chemical and therapeutic subgroups.
The following listings will be provided by investigative site and treatment group. 
●
Previous and Concomitant Medications
●
Non-Medication Therapy
●
Immunosuppressant Medications Other than Study Medication. 
7.3
Study Drugs
Descriptive statistics will be used to characterize duration of dosing (measured in days) and 
exposure to drug by treatment group and overall. These summaries will be based on the SAF. 
7.3.1
Extent of Exposure for Bleselumab
Duration of exposure will be summarized for bleselumab in two ways.


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●
Descriptive statistics of duration (days) of exposure = ‘Date of last dose of study drug’ –
‘Date of first dose of study drug’ + 1.
●
Exposure time will be categorized by month according to the following categories:
○
≤1month
○
> 1month, ≤2 months
○
> 2 months, ≤3 months
○
> 3 months, ≤4 month
○
> 4 months, ≤5 month
○
> 5 months, ≤6 month
○
> 6 months, ≤7 month
○
> 7 months, ≤8 month
○
> 8 months, ≤9 month
○
> 9 months, ≤10 month
○
> 10 months, ≤11 month
○
> 11 months, ≤12 month
○
> 12 months
Counts and percentages of subjects in each of these categories will be summarized for the 
SAF.
7.3.2
Treatment Compliance for Bleselumab
During the treatment period, overall compliance with the dosing schedule will be examined 
for subjects in the SAF whose total study drug infusion count is known. Compliance = (total 
number of study drug infusions received in the treatment period/total number of infusions 
planned for the treatment period) x 100. Patients randomized to receive bleselumab are 
scheduled to receive a single infusion on the following days (i.e., target days) of the study 
Days 0, 7, 14, 28, 42, 56, 70, 90 and monthly for months 4 through 12.
Percent overall compliance will be summarized in two ways for the SAF:
●
Descriptive statistics will be presented.
●
Percent compliance will be categorized according to the following categories:
○
< 50%
○
> 50% to < 70%
○
> 70% to < 90%
○
> 90%.
A listing of study drug exposure for bleselumab will be provided by investigative site.  
7.3.3
Extent of Exposure for Basiliximab, Tacrolimus, MMF and steroids
The total dose of basiliximab (mg) will be summarized by treatment group for the initial dose 
and for the post-transplant dose given on Day 3, 4 or 5. The duration of dosing for 
tacrolimus, MMF and steroids will each be summarized by treatment group for the SAF in 
two ways.
●
Descriptive statistics of Duration (days) of exposure = ‘Date of last dose of study drug’ –
‘Date of first dose of study drug’ + 1.


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●
Exposure time will be categorized by month according to the following categories:
○
< 1 month
○
> 1 month, ≤2 months
○
> 2 months, ≤3 months
○
> 3 months, ≤4 month
○
> 4 months, ≤5 month
○
> 5 months, ≤6 month
○
> 6 months, ≤7 month
○
> 7 months, ≤8 month
○
> 8 months, ≤9 month
○
> 9 months, ≤10 month
○
> 10 months, ≤11 month
○
> 11 months, ≤12 month
○
> 12 months.
Counts and percentages of subjects in each of these categories will be summarized for the 
SAF.
7.3.4
Exposure to Tacrolimus
7.3.4.1 Tacrolimus Dosing
Descriptive statistics will be used to summarize tacrolimus total daily dose at each scheduled 
visit. The summary at each visit will be for that visit only and will not be cumulative.
If multiple levels of a dose were received by a subject within a visit, the subject’s mean total 
daily dose (including intermittent doses of 0 mg) within the visit window will be used for 
analysis. The mean total daily dose within a visit window will be calculated as a cumulative 
dose (within the window) divided by total duration (including intermittent doses of 0 mg) of 
tacrolimus dosing within the visit window; only the doses from first dose day through last 
dose day will be considered for the calculation. For a detailed description of the calculations 
involved, see Appendix 5, Section 9.5. 
The analysis described above will be performed for both mg and mg/kg units, separately. 
When needed, a subject’s weight assessment from the vital signs CRF that is closest to the 
start of a dosing stint will be used to convert from one unit to another (i.e., mg to mg/kg or 
mg/kg to mg). If there are two weight measurements that are equidistant from the start of the 
dosing stint (e.g., values on Days 2 and 4 for a dose on Day 3), the earlier weight 
measurement will be used. 
The total daily dose, and the duration of exposure (calculated as last dose day – first dose day 
+ 1) will also be summarized by treatment group. 
7.3.5
Exposure to MMF
The total daily dose of MMF (mg/day) will be summarized using descriptive statistics at each 
scheduled visit. The summary at each visit will be for that visit only and will not be 
cumulative. 


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So that subjects are counted only once at each time point, each subject’s mean total daily 
dose (including doses of 0 mg/day) within a visit window will be calculated and used for 
analysis. The mean total daily dose within a visit window will be calculated as cumulative 
dose (within the window) divided by total duration (including intermittent doses of 0 mg) of 
MMF dosing within the visit window; only the doses from first dose day through last dose 
day will be considered for the calculation. For a detailed description of the calculations 
involved, see Appendix 5, Section 9.5. 
The duration of exposure (calculated as last dose day – first dose day +1) will also be 
summarized. 
o
For subjects that switch from MMF to Myfortic, the MMF equivalent of Myfortic 
(1 mg of MMF = 1000/720 mg of Myfortic) will be used in all analyses of MMF. 
7.4
Analysis of Efficacy 
The objective in this study is to compare the efficacy of the bleselumab regimen (Arm 2) 
relative to the SOC regimen (Arm 1) for the prevention of FSGS recurrence post-transplant.
All efficacy summaries for the comparison of interest will be based on the FAS. Since many 
analyses are performed for specific time periods (e.g., Month 3), analyses of event data by 
time period will first consider all visits within the defined visit window and then select the 
visit closest to the target day for the analysis. Displays will be cumulative unless otherwise 
specified. For example, a summary at 6 months will include all events up through six months.
In addition, listings by investigator and treatment group will be provided for all data used in 
efficacy analyses. 
7.4.1
Analysis of Primary Endpoint(s)
The primary endpoint is recurrence of FSGS defined by nephrotic range proteinuria with 
protein-creatinine ratio (> 3.0g/g) through 3 months’ post-transplant. Death, graft loss or lost 
to follow-up will be imputed as rFSGS. The percentage of subjects who have recurrence of 
FSGS will be computed along with a two-sided 95% confidence interval (CI) for each of the 
treatment groups and for the treatment difference (Arm 2 – Arm 1). A positive difference 
indicates a higher recurrence rate in the bleselumab regimen compared to the SOC regimen. 
Confidence intervals for the incidence of rFSGS for each treatment group will be obtained 
using the Normal Approximation {p ± Z.025 (1 −)/}.
The formula for the two-sided 95% CI for the difference is:
 − ± .(1 −)  +
⁄
(1 −) 
⁄
where  and  are the proportion of FSGS recurrence and the sample size in Bleselumab 
regimen, respectively,  and  and are the proportion of FSGS recurrence and the sample 
size in SOC regimen, respectively. Fishers’ exact will also be used to test for treatment 
differences.


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7.4.1.1 Subgroup Analysis of Recurrence of FSGS determined by Nephrotic Range 
Proteinuria 
For each treatment group, incidence of FSGS recurrence will be calculated for following 
subgroups: age (<65, ≥ 65), gender, race (African-American vs. Others), donor types 
(deceased donors vs. others), and donor relationship (living related vs. living non-related). 
The incidence of FSGS recurrence by first or repeat transplant will be provided by treatment 
group.
7.4.2
Analysis of Secondary Endpoints 
7.4.2.1 Recurrence of FSGS through 6 and 12 Months determined by Nephrotic Range 
Proteinuria 
The percentage of subjects with rFSGS through 6 and 12 months’ post-transplant will be 
analyzed as described for the primary endpoint. Death, graft loss or lost to follow-up will be 
imputed as rFSGS. The percentage of subjects who have rFSGS through 6 and 12 months, a 
95% CI for each of the treatment-group estimates, the treatment difference (Bleselumab 
regimen – SOC regimen) and a 95% CI for the difference will be provided. Fishers’ exact test 
will also be used to test for treatment differences.
7.4.2.2 Biopsy-Proven Acute Rejection
Summaries by treatment group will be given for the incidence of BPAR (Banff Grade ≥ 1, 
local read) through 3, 6 and 12 months. P-values comparing the two groups will be obtained 
using Fisher’s exact. A two-sided 95% CI will be constructed for each of the treatment 
groups and for the treatment difference [see Section 7.4.1 for the formulas].  Subjects who 
drop out of the study prior to each of the defined time points (3, 6 or 12 months), if any, 
without having a BPAR by local review will not be counted as having a BPAR.  Subjects 
who have met the criteria for a BPAR and drop out of the study prior to each of the defined 
time points will be included in the BPAR count.  
In a second set of analyses, subjects who drop out of the study without having a BPAR by 
local review will be counted as a recurrence. The same set of summaries will be computed as 
described in the previous paragraph.
7.4.2.3 Efficacy Failure
Incidence of efficacy failure defined as death, graft loss, BPAR (Banff Grade ≥ 1, local read), 
or lost to follow up through 12 months’ post-transplant will be summarized by treatment 
group. A two-sided 95% CI will be constructed for each of the treatment groups and for the 
treatment difference (see Section 7.4.1 for the formulas). 
For each treatment group, Kaplan-Meier estimates will be used to estimate efficacy failure at 
one year. The treatment difference will be computed as Arm 2 – Arm 1. A two-sided 95% CI 
will be constructed for the treatment difference using Greenwood’s formula for standard 
error. A Wilcoxon test will be used to compare survival curves.


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7.4.2.4 Biopsy-Proven rFSGS through 3, 6 and 12 Months determined by Independent 
Blinded Review of the Biopsy Slides
Biopsy slides will be provided for all subjects after the appearance of symptoms for rejection 
or rFSGS, or at the Day 90/month 3 visit, if there has not been a previous biopsy indicating 
rFSGS in the transplanted kidney. The blinded, central reader will objectively assess 
podocyte changes to identify those with rFSGS. Subjects who drop out of the study and do 
not provide a biopsy for slide review will not be included in the analysis of biopsy-proven 
rFSGS. Any biopsies after 3 months are for-cause only and there are no other protocol-
defined biopsies.
The percentage of subjects who have biopsy-proven rFSGS will be computed along with a 
two-sided 95% confidence interval (CI) for each of the treatment groups and for the treatment 
difference (Arm 2 – Arm 1). Fishers’ exact test will also be used to test for treatment 
differences.
The method used to confirm rFSGS (light microscopy, electron microscopy) will be 
summarized, n(%), by treatment group. Summaries, n (%), will be provided for the rFSGS 
histologic classification (perihiliar variant, cellular variant, tip variant, collapsing variant and 
not otherwise specified) by treatment group. Treatment differences for rFSGS confirmation 
method (LM, EM) and distribution of histologic type will be assessed using Fisher’s Exact 
Test.
7.4.3
Analysis of Exploratory Endpoints 
7.4.3.1 Patient Survival and Graft Survival
Patient and graft status through 12 months’ post-transplant will be summarized by treatment 
group. Patient status is defined as alive or deceased. Graft status is defined as graft loss 
determined by subject death, re-transplant, nephrectomy, or return to permanent dialysis 
(> 30 days) or graft survival determined as the absence of any of the above. Patient and graft 
status will be summarized by treatment group with a two-sided 95% CI for each treatment 
group and a two-sided 95% CI for the treatment difference (see Section 7.4.1 for the 
formulas). There will be no imputation for lost to follow-up for one display. In a second 
display of patient and graft survival, lost to follow-up will be counted as an event (graft loss 
or patient death).
Summaries (counts and percentages) will be provided by treatment for the FAS. Fisher’s 
Exact Test will be used to compare the two treatment groups for one analysis. 
In a second analysis, Kaplan-Meier estimates will be used to estimate patient survival and 
graft survival at one year. Any drop-outs prior to one-year will be censored at the time of 
drop-out. The treatment difference will be computed as Arm 2 – Arm 1. A two-sided 95% CI 
will be constructed for the treatment difference using Greenwood’s formula for standard 
error. A Wilcoxon test will be used to compare survival curves. In kidney transplant studies 
efficacy failure tends to occur early and the Wilcoxon test is more powerful test in detecting 
differences early in time.


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7.4.3.2 Estimated Glomerular Filtration Rate
Summaries for the mean eGFR value based on MDRD criterion will be given for Day 56, 
Day 90 and at 4, 5, 6 and 12 months and analyzed at each time point using an analysis of 
covariance (ANCOVA) with treatment as the factor and the week 4 value as a covariate. A 
summary and comparison of the results for the two treatment groups at three months will 
provide kidney function information at the time of the three-month interim analysis. 
Sample SAS code is provided below.
PROC GLM data=dsetname;
CLASS TREAT;
MODEL MGFR = AVISITN TREAT Week4 /SOLUTION;
LSMEANS TREAT / STDERR PDIFF DIFF CL;
RUN;
The mean change in eGFR value from week 4 (e.g., Month 6 value minus Week 4 value) will 
also be similarly analyzed for each time point (Day 56, Day 90 and months 4, 5, 6 and 12). 
Also, incidence of GFR < 40 mL/min and the incidence of a decrease of GFR ≥ 10% from 
week 4 to each time point (Day 56, 90, months 4, 5, 6, and 12) will be analyzed using Fisher’s 
exact test. The difference from the standard of care for ASKP1240+Tac will be shown with a 
95% CI.
Descriptive statistics (n, mean, sd, min, median, and max) will be provided by study visit 
beginning at week 4. Summaries for change will be calculated with week 4 as the baseline 
value.  
7.4.3.3 Recurrence of FSGS with no Imputation for Death, Graft Loss or Lost to 
Follow-up
Incidence of rFSGS defined as nephrotic range proteinuria with protein-creatinine ratio 
(> 3.0 g/g) cumulatively up to 3, 6 and 12 months post-transplant will be summarized by 
treatment group. There will be no imputation for death, graft loss or lost to follow-up in this 
display. A two-sided 95% CI will be constructed for each of the treatment group and for the 
treatment difference. Fishers’ exact will also be used to test for treatment differences.
7.4.3.4 Time to rFSGS
For each treatment group, Kaplan-Meier estimates will be used to estimate FSGS recurrence. 
The treatment difference will be computed as Arm 2 – Arm 1. A two-sided 95% CI will be 
constructed for the treatment difference using Greenwood’s formula for standard error. A 
Wilcoxon test will be used to compare survival curves and will be displayed on the graph.
This analysis will be conducted for
●
FSGS recurrence (defined by nephrotic range proteinuria with protein-creatinine ratio 
(> 3.0g/g))
●
FSGS recurrence (defined by nephrotic range proteinuria with protein-creatinine ratio 
(> 3.0g/g) or initiation of plasmapheresis)


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●
FSGS recurrence (defined by nephrotic range proteinuria with protein-creatinine ratio 
(> 3.0g/g), death graft loss or lost to follow-up
●
Biopsy proven (blinded, central read) FSGS recurrence 
Those who drop out of the study prematurely without sufficient information to determine 
recurrence will be censored at the time of withdrawal with the exception of bullet 3.
7.4.3.5 Time to First BPAR
Kaplan-Meier estimates will be used to estimate the time to first BPAR by treatment group. 
The treatment difference will be computed as ASKP1240+Tac - SOC. A two-sided 95% CI 
will be constructed for the treatment difference using Greenwood’s formula for standard 
error. A Wilcoxon test will be used to compare survival curves and will be provided on the 
graph. Those who drop out of the study prematurely without sufficient information to 
determine recurrence will be censored at the time of withdrawal.
7.4.3.6 Urine Protein-Creatinine Ratio and the Urine Albumin-Creatinine Ratio
The urine protein-creatinine ratio, the change from week 1 (Day 7) for collections up to week 
4, and the change from week 4 for collections after week 4 will be summarized for each 
scheduled collection time. The urine protein-creatinine ratio collected up to week 4 will be 
analyzed with an ANCOVA with treatment group as the factor of interest and the first 
available post-transplant value as the covariate. The urine protein-creatinine ratio after week 
4 will be analyzed with an ANCOVA with treatment as a factor and the week 4 value as a 
covariate. These data are usually right-skewed and will be transformed using the natural 
logarithm (ln) to produce data that more closely conforms to a normal distribution. Values of 
0, if any, will have 0.5 added to enable calculation of the ln transformation.  The 
ln-transformed data will be analyzed and then back-transformed using the exponential 
transformation to provide the summaries.
The urine albumin-creatinine ratio will be analyzed and summarized as described for the 
urine protein-creatinine ratio.
7.4.3.7 Patient-Reported Outcomes
7.4.3.7.1
Short Form Health Survey
The Short Form 36-Item Health Survey Scores Version 2.0 (SF-36, v2) provides scores for 
each of eight health domains (physical functioning, bodily pain, role limitations due to 
physical health problems, role limitations due to personal or emotional problems, emotional 
well-being, social functioning, energy/fatigue, and general health perceptions). The items for 
an individual domain are averaged to obtain a mean score.  Items that are left blank are not 
included in the calculations. Each domain is directly transformed into a 0 - 100 scale with the 
assumption that each question carries equal weight. Once transformed a score represents a 
percentage of the total possible score for an item. Lower scores indicate greater disability 
(i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to 
no disability).
The eight subscales are summarized into two scores, the physical component summary (PCS) 
and mental component summary (MCS) scores. The PCS is an average of the mean scores for 


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the physical domains and the MCS is an average of the mean scores for the mental domains. 
The PCS and MCS are transformed to norm-based scores with a mean of 50 and a SD of 10. 
A two-point difference in the PCS and a three-point difference in the MCS are considered 
clinically meaningful.
Descriptive statistics (n, mean, median, sd, min and max) will be provided for each of the 
eight domains and the PCS and MCS. In this study, SF-36v2 scale scores, PCS and MCS will 
be calculated by QualityMetric and a report of the results will be provided.
7.4.3.7.2
EuroQol-5 dimensions-5 levels 
The EuroQol-5 dimensions-5 levels (EQ-5D-5L) is an international and standardized 
non-disease specific instrument for describing and valuing health status. This questionnaire 
consists of two parts:
●
5-dimensions (EQ-5D-5L): mobility, self-care, usual activities, pain/discomfort and 
anxiety/depression. For each dimension there are 5 levels (i.e., scores 1 to 5) to classify 
the severity of the dimension, ranging from no problems to extreme problems or inability 
to perform the specified activity
●
VAS, where 0 represents the worst imaginable health state and 100 the best imaginable 
health state.
The number of responses (%) for each of the 5 categories within a dimension will be 
summarized by visit and treatment. Fisher’s exact test will be used to compare the 
distribution of responses between the two treatment groups at each visit. 
The following SAS code may be used:
PROC FREQ data=dataset;
TABLE treatment * dimension / Exact;
Output out=pvalue exact;
RUN;
For each dimension, the percentage of patients who respond with no issue, slight, moderate, 
severe, and unable to function will be graphically displayed (Appendix 6).  If applicable, the 
percentage who do not respond will be shown on the graph. The absolute value for the VAS 
and the change from baseline to the Month 3, and 12/EOS Visit in the VAS score will be 
summarized by treatment group and visit. The change from baseline will be defined as the 
Month 3, 12/EOS Visit value minus the baseline value. The change from baseline for the 
VAS Score will be analyzed by using an analysis of covariance (ANCOVA) model with
treatment group as a fixed factor and the baseline VAS score as a covariate.
The following SAS code may be used:
    PROC GLM data=dataset;
          CLASS treat;
          MODEL VAS=visit treat base / solution;
            lsmeans treat / stderr diff cl;
   run;


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7.4.3.7.3
Kidney Transplant Questionnaire
The score for each of the five domains of the KTQ (i.e., physical symptoms, fatigue, 
uncertainty/fear, appearance, and emotional) is obtained by summing the values for all of the 
items in the dimension and dividing by the number of items in that dimension. Dimension 
scores range from 1 (worst possible score) to 7 (best possible score). Instructions to 
determine the score for each of the dimensions are given below.
●
Physical Symptoms: Sum the 6 patient specific items and divide by 6.
●
Fatigue: Sum items 8 (weak), 25 (low level of energy), 12 (sluggish), 23 (increased 
tiredness) and 14 (very little strength) and divide by 5.
●
Uncertainty/Fear: Sum items 21 (protective of transplant), 15 (fear of panic related to 
rejection), 16 (uncertain about the future), and 17 (worried) and divide by 4.
●
Appearance: Sum items 18 (excessive hair growth), 7 (excessive appetite), excessive 
weight (19), acne (20) and divide by 4.
●
Emotional: Sum items 22 (irritable, difficult to get along with), 10 (depressed), 13 
(anxious), 24 (frustrated), 11 (stubborn), 9 (impatient) and divide by 6.
In the event that one of the items does not have a response, sum the items with a 
response and divide by the number of responses. 
The change from baseline in the score for each of the 5 domains at 3 and 12 months will be 
analyzed using ANCOVA with treatment as a factor and baseline as a covariate.
7.5
Analysis of Safety
All analyses of safety will be presented by treatment group for SAF, unless otherwise 
specified. 
7.5.1
Adverse Events
Summaries and listings of SAEs and Serious TEAEs include SAEs upgraded by the sponsor 
based on a review of the Sponsor’s list of Always Serious terms if any upgrade was done. 
The coding dictionary for this study will be the Medical Dictionary for Regulatory Activities 
(MedDRA v19.0). It will be used to summarize adverse events (AEs) by system organ class 
(SOC) and preferred term (PT). All adverse event summaries will display frequencies and 
percentages by treatment group.
An overview of the incidence of treatment emergent adverse events and death by treatment 
group will be provided for the 3- and 12-month treatment periods. Adverse events will be 
collected up to 30 days after the last dose and will be represented in the AE overview. The 
overview table will include the following details by treatment group:
●
Number and percentage of subjects with TEAEs,
●
Number and percentage of subjects with drug-related TEAEs 
o
related to any drug, 
o
related to bleselumab, 


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o
related to tacrolimus, 
o
related to MMF, or 
o
related to basiliximab,
●
Number and percentage of subjects with Serious TEAEs, 
●
Number and percentage of subjects with Drug-related serious TEAEs,
o
related to any drug, 
o
related to bleselumab, 
o
related to tacrolimus, 
o
related to MMF, or 
o
related to basiliximab,
●
Number and percentage of subjects with TEAE Leading to Death (i.e. outcome=fatal),
●
Number and percentage of subjects with TEAE Leading to Permanent 
Discontinuation of Study Drug,
●
Number and percentage of subjects with Drug-Related TEAE Permanent 
Discontinuation of Study Drug,
o
related to any drug, 
o
related to bleselumab, 
o
related to tacrolimus, 
o
related to MMF, or 
o
related to basiliximab,
●
Deaths.
The number and percentage of subjects with TEAEs, classified by SOC and PT will be 
summarized by treatment group for:   
●
TEAEs,
●
Drug-related TEAEs,
●
Serious TEAEs,
●
Drug-related serious TEAEs, 
●
TEAE Leading to Death (i.e. outcome=fatal),
●
TEAE Leading to Permanent Discontinuation of Study Drug,
●
Drug-Related TEAE Permanent Discontinuation of Study Drug,
●
Deaths.
For each of the drug-related summaries, there will be a summary for: 
o
related to any drug, 
o
related to bleselumab, 


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o
related to tacrolimus, 
o
related to MMF, or 
o
related to basiliximab.
In the subject count, if a subject has multiple TEAEs with the same SOC or PT, but with 
differing severity or relationship, then the subject will be counted only once with the worst 
severity and highest degree of relationship. If any of the severity or relationship values are 
missing, the subject will be counted as having the greatest severity and the event will be 
considered to be related. If an adverse event has multiple classifications, it will be included in 
each classification category. All adverse events data will be displayed in a listing. 
A listing of infections and post-transplant lymphoproliferative disorder (PTLD), if any, will 
also be provided. If there are no PTLDs, the listing will have the phrase, ‘No Data Available 
for this Report’.
Clusters of adverse events associated with tacrolimus, MMF or bleselumab will be 
summarized by treatment group.  These clusters are hepatic events, BK infection, cardiac 
events, cardiovascular events, cytomegalovirus, diarrhea, dyspepsia, gastroenteritis, G.I. 
disturbances, G.I. pain/ discomfort, glucose abnormality, hypertension, lipids, malignancy, 
MMF GI specific, MMF hematologic, MMF lower GI, MMF upper GI, MMF other GI, 
neurotoxicity, opportunistic infections, renal events, respiratory tract infections, upper GI 
complex, urinary tract infections, and viral and fungal infections.
7.5.1.1 Potentially Excessive Toxicities
The following set of defined toxicities, monitored on a continuous basis, will be summarized 
by treatment group. These will be provided for the DMC review:
●
Deaths
●
Graft Loss
●
Acute Rejection (BPAR> 2A Banff T cell and/or > Banff 1 AMR)
●
Severe Anemia (NCI-CTCAE Grade 4: Two consecutive Hemoglobin < 6.5 g/dL 
taken within 14 days of first detection after Day 28 post-transplantation)
●
Agranulocytosis (NCI-CTCAE Grade 4: Two consecutive absolute Neutrophil Count  
< 100 cells/mm3 taken within 14 days of first detection after Day 28 post-
transplantation)
●
BK Virus-Associated Nephropathy: (BKVAN) (excludes BK viremia or viuria alone)
●
Cytomegalovirus Tissue Disease: (CMV) (excludes CMV syndrome, viremia alone, 
viuria alone) 
●
Malignancies (Excludes non-melanoma skin malignancies and PTLD)
●
BK Virus Infection
●
CMV Virus Infection
●
Post-Transplant Lymphoproliferative Disease (PTLD) 


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7.5.2
Clinical Laboratory Evaluation
Clinical laboratory variables (hematology, biochemistry, urinalysis, coagulation/thrombotic 
pathway, hepatic profile, and fasting lipid profile) will be summarized using mean, standard 
deviation, minimum, maximum and median for each treatment group at each visit. 
Additionally, a within-subject change will be calculated as the post-baseline measurement 
minus the baseline measurement and summarized in the same manner. For renal tests (serum 
creatinine, blood urea nitrogen, eGFR, urine protein/creatinine ratio, urine albumin/creatinine 
ratio), the latest assessment in the Day 28 visit window will be serve as baseline for values 
collected after Day 28. For the urine/protein and urine/creatinine ratios, post-transplant 
changes after week 1 the first post-transplant. 
Shift tables will also be used to summarize the change from baseline to worst value 
post-transplant for the select laboratory parameters. Table 2 lists the cut points used for these 
analyses. 
Table 2
Cut Points Used for Laboratory Shift Tables
Laboratory Parameter
Shift Categories
Fasting glucose (mg/dL)
<70, 70-100, >100-<126, 126-200, >200
Create a shift to greatest for this parameter.
Magnesium (mg/dL)
<0.9, 0.9-<1.2, 1.2-<1.7, 1.7-2.7, >2.7-4.9, >4.9-7.0, >7.0
Create a shift to least for this parameter.
Potassium (mmol/L)
<2.5, 2.5-<3.5, 3.5-5.1, >5.1-6.5, >6.5-8, >8.0
Create a shift to least and shift to greatest for this parameter.
SGPT (U/L)
<35, 35-105, >105-175, >175-280, >280-350, >350-700, >700-1000, >1000
Create a shift to greatest for this parameter.
SGOT (U/L)
<35, 35-105, >105-175, >175-280, >280-350, >350-700, >700-1000, >1000
Create a shift to greatest for this parameter.
WBC (109/L)
<1.5, 1.5-3.0, >3.0-4.5, >4.5-11.0, >11.0-15.0, >15.0
Create a shift to least for this parameter.
Platelets (109/L)
<25, 25-<50, 50-<100, 100-<130, 130-<400, >=400
Create a shift to least for this parameter.
Hematocrit (%)
Male and female: <24, 24-<30, 30-<33, 33-<36, 36-<45, >=45
Create a shift to least for this parameter.
Hemoglobin (g/dL)
Male and female: < 8, 8-<10, 10-<11, 11-<12, 12-<15, >=15
Create a shift to greatest for this parameter.
Total cholesterol (mg/dL)
<200, 200-239, >239
Create a shift to greatest for this parameter.
LDL cholesterol (mg/dL)
<100, 100-129, 130-159, 160-189, >=190
Create a shift to greatest for this parameter.
HDL cholesterol (mg/dL)
<40, 40-60,>=60
Create a shift to least for this parameter.
Triglycerides (mg/dL)
<150, 150-199, 200-499, >=500
Create a shift to greatest for this parameter.
Table continued on next page


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Laboratory Parameter
Shift Categories
Serum creatinine (mg/dL)
<0.6, 0.6-1.2,>1.2-1.5, >1.5-2, >2-2.5, >2.5-3, >3
Create a shift to greatest for this parameter.
GFR (MDRD) 
(mL/min/1.73m2)
<15, 15-29,>29-59, >59-89, >89
Create a shift to least for this parameter.
Blood urea nitrogen (mg/dL)
<8, 8-18, >18-50, >50-75, >75
Create a shift to greatest for this parameter.
Total bilirubin (mg/dL)
0.3-1.0, >1.0-2.0, >2.0
Create a shift to greatest for this parameter.
Alkaline phosphatase (U/L)
<35, 35-105, >105-175, >175-280, >280-350, >350-700, >700-1000, >1000
ANC (cells/µL)
<500, 500-<1000, 1000-<2000, 2000-<8000, >=8000
Create a shift to lowest for this parameter.
7.5.2.1 Liver Enzymes and Total Bilirubin
The following potentially clinically significant criteria for liver tests – defined as Alkaline 
Phosphatase (ALP), Alanine Transaminase (ALT), total bilirubin, Aspartate Transaminase 
(AST) and their combination are defined. The subject’s highest value during the 
post-transplant period will be used. 
Parameter
Criteria
ALT
> 3xULN
> 5xULN
> 10xULN
> 20xULN
AST
> 3xULN
> 5xULN
> 10xULN
> 20xULN
ALT or AST
> 3xULN
Total Bilirubin
> 2xULN
ALP
> 1.5xULN
ALT and/or AST AND Total Bilirubin(*)
(ALT and/or AST > 3xULN) and 
total bilirubin > 2xULN
(*) Combination of values measured within same sample
The number and percentage of subjects with potentially clinically significant values in liver 
enzyme and total bilirubin tests during the post-transplant period will be presented by 
treatment group.


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The following data will be presented graphically by treatment group: 
●
eDISH Plot of Peak AST/ALT (xULN) against Peak Total Bilirubin (xULN)
7.5.2.2 Potentially Clinical Significant Values in Select Laboratory Tests
The number and percentage of subjects with potentially clinically significant (PCS) values in 
select laboratory tests will be summarized by treatment group using the cutoffs in both sets of 
units given below. For each laboratory parameter, the incidence of patients that met the 
relevant criteria will be tabulated and treatment group will be compared using Fisher’s exact 
test. Table 3 describes the laboratory parameter and PCS criteria to be used in analyses. 
Table 3
Potentially Clinically Significant (PCS) Criteria for Analyses of Select 
Laboratory Parameter
Laboratory Parameter
PCS Criteria
PCS Criteria in SI Units
Fasting glucose
>200 mg/dL
>11.0 mmol/L
SGOT/AST
>175 U/L
>175 U/L
SGPT/ALT
>175 U/L
>175 U/L
WBC
<1.5 109/L
< 1500 106/L
Platelets
<100 109/L
<100 109/L
Hematocrit
<24%
0.24 (fraction of 1)
Hemoglobin
<8.0 g/dL
<80 g/L
Total cholesterol
>239 mg/dL
>6.19 mmol/L
LDL cholesterol
≥190 mg/dL
>4.92 mmol/L
Triglycerides
≥500 mg/dL
>5.65 mmol/L
Serum creatinine
Female: >2.0 mg/dL,
Male: >2.5 mg/dL
Female: > 176.8 µmol/L;
Male >221 µmol/L
eGFR (MDRD)
≤ 29 mL/min/1.73m2
≤ 29 mL/min/1.73m2
Total bilirubin
> 2.0 mg/dL
> 34.21 µmol/L
7.5.3
Vital Signs
Vital signs (systolic blood pressure, diastolic blood pressure and pulse rate) will be 
summarized using mean, standard deviation, minimum, maximum and median by treatment 
group and visit. Additionally, a within-subject change will be calculated by visit as the 
post-baseline measurement minus the baseline measurement and summarized by treatment 
group and visit.  The baseline value will be obtained at screening. 
7.5.3.1 Potentially Clinically Significant Values in Select Vital Signs
The number and percentage of subjects with potentially clinically significant vital signs will 
be summarized by treatment group. 
Tables for potentially clinically significant vital signs will be generated using the baseline 
value and highest value obtained post baseline for each subject for each treatment group.
The following potentially clinically significant criteria are defined for each parameter:


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Vital Sign Variable
Criteria
SBP
≥160 mmHg AND ≥20 mmHg change from baseline
DBP
≥100 mmHg AND ≥15 mmHg change from baseline
Pulse Rate
≥100 bpm AND ≥15 bpm change from baseline
7.5.3.2 Clustered Safety Events
The following clusters of safety events, based on adverse events, laboratory values, and vital 
sign values will be summarized: BK infection, cardiac, cardiovascular, cytomegalovirus, 
diarrhea, dyspepsia, gastrointestinal (GI) disturbances, gastroenteritis, GI pain/discomfort, 
glucose abnormality, hepatic events, hypertension, lipids, malignancy, neurotoxicity, 
opportunistic infections, renal events, respiratory tract infections, upper GI complex, urinary 
tract infections, infections and infestations. Details of the specific adverse events, vital values 
and laboratory values that compose each cluster are described in Section 9.2. The final set of 
preferred terms for each cluster will be updated based on the actual reported terms for the 
study. The subset of the infections and infestations that were determined to be viral infections 
or fungal infections will each be analyzed as separate clustered safety events. 
The incidence of treatment emergent clustered safety events will be summarized by treatment 
group and overall. 
7.5.4
Electrocardiograms (ECGs)
A 12-lead ECG will be performed as part of screening, month 3 and 12. Number and 
percentage of subjects with normal, not clinically significant abnormal and clinically 
significant abnormal results as assessed by the investigator for the 12 lead ECG will be 
tabulated by treatment group at each treatment visit and time point. 
7.5.5
Viral Load Testing
The cumulative number and percentage of subjects with a positive test result for CMV, EBV 
and BKV will be summarized by visit. Absolute non-zero serum viral loads (log10 IU/ml) for 
CMV, EBV and BKV and urine BK viral loads (copies/ml) will be summarized by visit and 
treatment group. Results for subjects who are negative at baseline will be shown in a second 
set of tables (cumulative positive by visit, viral loads).
The cumulative number and percentage of subjects with a CMV, EBV and BKV infections 
will be tabulated. The categories and sub-categories to be tabulated by visit, if they occur, are 
shown below:
●
CMV Infection
o
CMV Active Infection
o
CMV Disease

CMV Syndrome Symptoms


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
Pneumonia

Gastrointestinal Disease

Hepatitis

CNS Disease

Retinitis

Other Tissue Invasive Disease 
●
EBV Infection 
o
EBV Infection
o
EBV Disease
●
BK Virus Infection
o
BKVAN
7.5.6
Anti-Bleselumab Antibodies
The number of and percentage of subjects with Anti-Bleselumab antibodies will be 
summarized for treatment arm 2 by visit (Days 0, 14, 28, 90, months 6, 9, 12/EOS) and a 
total will be provided. The results of the screening assay and the confirmation assay will be 
tabulated. Descriptive statistics will be used to summarize anti-Bleselumab titers at each 
scheduled visit (n, GM, GSD, Min, Max). Subjects with anti-bleselumab antibodies will have 
an additional test to determine if the antibodies are neutralizing.  The number and percentage 
of subjects with neutralizing antibodies will be provided by visit.
7.5.7
Bleselumab bi-specific antibody 
The Bleselumab bi-specific antibody measures whether a portion of the Bleselumab molecule 
has formed a new antibody with the endogenous anti-CD40 antibody. Antibody concentration 
levels (ng/mL) will be summarized (n, GM, GSD, Min, Max,) by visit. The LLOQ for the 
assay is 100 ng/mL. 
7.5.8
Incidence of New-onset Diabetes Mellitus after transplantation (NODAT)
Subjects who are at risk for experiencing NODAT are those without diabetes at skin closure. 
For these analyses, subjects will be considered at risk if they did not have diabetes (type I or 
II, or NODAT with prior transplant) present at skin closure, and did not have any pre-
transplant (lab Day < 0) fasting glucose value > 200 mg/dL. In addition, subjects on 
antidiabetic medication (e.g. insulin or oral hypoglycemic) for ≥ 30 pre-transplant days that 
did not end that stint more than 7 days prior to transplant will not be considered at risk. These 
subjects should be noted as having a history of diabetes on the Targeted Medical History 
CRF.
For at-risk subjects, any of the following events constitutes a NODAT event within the 
post-transplant period.


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●
Two, post-transplant, high (≥ 126 mg/dL) fasting plasma glucose ≥ 30 days apart. If
the subject had a major event (died, experienced graft loss, was lost to follow-up, or 
discontinued study) but didn’t have two high values ≥ 30 days apart he/she will still 
be counted as a NODAT event if the last fasting plasma glucose value was high.
●
Use of insulin for ≥ 30 consecutive days. If a subject had a major event, he will be 
counted as a NODAT event if he was on insulin at the time of the major event.
●
Use of oral hypoglycemics for ≥ 30 consecutive days during the study. If a subject 
had a major event, he will be counted as a NODAT event if he was on an oral 
hypoglycemic agent at the time of the major event.  
●
Use of other antidiabetic medications for ≥ 30 consecutive days during the study. If a 
subject had a major event, he will be counted as a NODAT event if he was on another 
antidiabetic medication at the time of the major event.  
Antidiabetics and high laboratory (fasting glucose) values prior to skin closure are not 
considered. In addition, high laboratory values and antidiabetic medications that started after 
a major event are not considered. All at-risk subjects who do not have an event as described 
above will be counted as non NODAT.
The number and percentage of patients with NODAT through Study Months 3, 6, and 12 will 
be summarized by treatment group. The percentage will be calculated from the at risk 
population (patients with no history of diabetes mellitus) and compared among treatment 
groups using Fisher’s exact test.
7.6
Analysis of PK
7.6.1
Tacrolimus Trough Concentration
Descriptive statistics will be used to summarize tacrolimus trough concentration (ng/ml) by 
treatment group and scheduled collection visit. The serum concentration at trough (Ctrough) 
(Day 1: 11-13 hours post-dose, 4, 7, 14, 28, 42, 56, 70, 90, months 4 – 12, EOS) for 
tacrolimus will be listed and summarized using descriptive statistics (n, mean, SD, %CV, 
Min, Median, Max, GM, Geo %CV) at each scheduled collection time point for subjects in 
both regimens. 
For the purpose of analyses, the trough concentration within each visit window that is closest 
to the target scheduled collection day will be used. If there are two concentration values 
within a specified visit window that are equidistant from the target day (e.g., values on 
Days 2 and 4 for collection Day 3), the latter will be used. 
7.6.2
Bleselumab Concentrations
The serum concentration at peak (Cmax) (Day 0, 7, 14, 28), trough (Ctrough) (Day 0, 7, 14, 28, 
42, 56, 70 90, months 6, 9, 12) and the peak to trough ratio for bleselumab will be listed and 
summarized using descriptive statistics (n, mean, SD, %CV, Min, Median, Max, GM, 
Geo %CV) at each scheduled collection time point for subjects in bleselumab regimen. 


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7.7
Analysis of anti-CD40 auto-antibodies
Titers for the anti-CD40 auto-antibodies will be provided for both treatment groups and 
summarized for the FAS. Titers below the LLOQ will be assigned ½ LLOQ. This antibody 
data will be analyzed after normalizing the data using a natural log transformation (SAS LOG 
function). Summaries for this data will include n, the geometric mean, geometric standard 
deviation and the minimum and maximum values. After obtaining the summary statistics for 
the log transformed values, the mean and standard deviation will be exponentiated to obtain 
the geometric mean and the geometric standard deviation.  
Log-transformed anti-CD40 auto-antibody titers will be compared between the treatment 
groups at each post-baseline visit (Day 7, Day 14, Day 28, Day 56, Day 90, Month 6, 9 and 
12) using a mixed model repeated measures analysis with the baseline value as the covariate. 
The variability of antibody values usually decreases with increasing values of antibody levels 
(heteroscedasticity). The model will assume heteroscedasticity and that the regression lines 
for the two treatment groups are parallel (no baseline by treatment group interaction). The 
SAS code for this model is shown below:
proc mixed;
model postCD40=trtgrp baseCD40 / solution;
repeated / local=exp(baseCD40  baseCD402);
run;
7.8
Subgroups of Interest 
The primary efficacy endpoint will be summarized by the treatment group for the subgroups 
as defined in Section 7.4.1.1.
7.9
Interim Analysis (and Early Discontinuation of the Clinical Study)
7.9.1
Interim Data Reviews and the Interim Analysis 
Interim data reviews by a DMC (Data Monitoring Committee) were originally planned as 
follows:
●
50% of the subjects have been enrolled, completed and cleaned through Month 3 
●
100% of subjects have been enrolled, completed and cleaned through Month 3 
(Interim Analysis), 
●
100% of subjects have been enrolled, completed and cleaned through Month 6.
An interim analysis was planned when all subjects completed 3 months’ post-transplant 
follow-up. The purpose of the interim analysis was to evaluate treatment differences for the 
recurrence of FSGS to support strategic decision making for future project development and 
study design. Instead, due to slow enrollment, the first 50 subjects transplanted and dosed 
will be analyzed and the results used to support strategic decisions. 
The first subject was enrolled in May 2017 with 50 subjects transplanted and dosed as of mid 
July 2019. The additional 10 subjects are planned to be enrolled. Due to the slow enrollment 


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Astellas and the development partner, Kyowa Kirin Co., Ltd. (KKC) plan to follow these 
50 subjects for three months (the time of the primary endpoint), and conduct an interim 
analysis to evaluate response in the two treatment groups. This interim analysis will serve as 
the foundation for a Briefing Document to support a Type C meeting with the FDA, if the 
results merit a go forward decision. TLFs from this interim analysis will be discussed in an 
open session with the members of the DMC.
7.9.2
Data Monitoring Committee (DMC) and Data Analysis Center (DAC)
A Data Monitoring Committee (DMC) and an independent Data Analysis Center (DAC) will 
be established. A charter for the DMC (Data Monitoring Committee) has been created and 
contains all of the definitions of the outputs that will be provided. A charter for the DAC will 
be created.
The DAC will provide the aggregated by-treatment summaries using the correct treatment 
assignment to the DMC members. The displays will initially be created by the study 
programmer(s) and provided to the study team using a dummy randomization. The study 
team will review for format and content and the study programmer will make any requested 
modifications. Once finalized, the DAC will use the programs and datasets created by the 
study programmer(s) and populate the TLFs using the actual treatment randomization. The 
displays will be kept in a secure directory on the Astellas Unix until the study has been
locked. Once the study has been locked the security controls will be removed for the 
sub-directory.  
For the interim analysis of the 50 subjects transplanted, dosed and followed through at least 
three months, the unblinded TLFs will be produced by a representative of Astellas rather than 
by the independent DAC.  
7.9.3
DMC Open and Closed Sessions
There will be an open and closed session for the DMC (Data Monitoring Committee) 
meetings. The open session will be attended by members of the DMC and Astellas study 
team members. Aggregated by-treatment data summaries for disposition, baseline 
characteristics, recipient and donor demographics, recipient and donor baseline 
characteristics and baseline characteristics related to FSGS and kidney transplantation will be 
available to the study team and presented during the open session. All other displays 
described in the DMC charter will be provided by the DAC to the DMC using the treatment 
randomization and discussed during the closed session.  Aggregated efficacy and safety data 
before the interim analysis at three months and after the interim analysis at three months will 
not be available to the study team until the data has been locked following completion of the 
study.
The display(s) for the planned interim analysis at three months and other aggregated efficacy 
and safety results for data through 3 months post-transplantation will be provided to the study 
team and shared with the DMC. These results will be discussed during the open session 
between members of Astellas and the DMC. 


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For the interim analysis of the 50 subjects transplanted, dosed and followed through three 
months, there will be a single open session since the TLFs with the treatment assignment can 
be viewed by the study team after database cutoff.  A discussion of the results with the 
experts on the DMC will help the study team to understand the results of this study. The 
results will not be shared with the sites until the study has been completed and the database 
locked.
7.10
Handling of Missing Data, Outliers, Visit Windows, and Other 
Information
7.10.1
Missing Data
A subject will be considered lost to follow up (i.e., unknown outcome) if the subject has not 
had the event of interest and does not have a study assessment within 30 days prior to the 
target day (see Section 7.10.3) for analysis.
Imputation for missing start and stop dates and times for adverse events and concomitant 
medications should use the following algorithm. If time is missing, then 00:00 will be 
assigned for start time and 24:00 for stop time. If day is missing, then the first day of the 
month will be assigned for a start day and the last day of the month for stop day. If month is 
missing, then the first month of the year will be assigned for start month and the last month 
of the year as the stop month. However, if the imputation rules lead to impossible dates, then 
the algorithm may be revised. The imputed data will be used to determine whether or not an 
adverse event is treatment emergent, whether or not a medication is concomitant. Listings of 
adverse events and concomitant medications will present the actual dates; imputed dates will 
not be shown. 
For PK analyses, if at least half of the individual data in a group are 0, the standard deviation 
and %CV will not be calculated. If one or more values are below the LLOQ (lower limit of 
quantitation), the geometric mean will not be calculated.
Any additional consideration for handling missing data is addressed in relevant sections. 
7.10.2
Outliers
Unless otherwise specified, analyses will use all available data. 
7.10.3
Visit Windows
For the purpose of data presentation and analyses, study Day is defined relative to the day of 
skin closure (Day 0) and unless specifically stated otherwise, the term baseline will refer to 
the last assessment/evaluation up to and including Day 0. 
The visit windows defined in the table below will apply for analyses by visit. For data 
collected at every visit the following visit windows will apply.


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Visit Name 
(time period)
Week
Target Day
Visit Window
(study Day)
Target Window (Day) for 
ASKP1240 Infusion
Screening
-
< 0
Baseline
0
< 0
Day 0
1
0
0
0
Day 1
1
1
1 – 2
Day 4
1
4
3 – 5
Day 7
1
7
6 – 10
6-8
Day 14
2
14
11 – 21
13-15
Day 28
4
28
22 – 35
26-30
Day 42
6
42
36 – 49
40-44
Day 56
8
56
50 – 63
54-58
Day 70
10
70
64 – 80
68-72
Day 90/Month 3
12
90
81 – 115
88-92
Month 4
16
120
116 – 135
117-123
Month 5
20
150
136 – 166
147-153
Month 6
24
182
167 – 197
179-185
Month 7
28
212
198 – 227
205-219
Month 8
32
242
228 – 257
235-249
Month 9
36
272
258 – 287
265-279
Month 10
40
302
288 – 317
295-309
Month 11
44
332
318 – 347
325-339
Week 48/ Month 12
48
362
348 – 377
358-372
Week 52/ EOS
52
392
378-407
No dosing


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8
DOCUMENT REVISION HISTORY 
Version
Date
Changes
Comment/rationale for change
1.00
24-JAN-2018
NA
Document finalized
2.00
19-NOV-2019
Description of 
interim analyses was 
updated.
Definition of Full 
Analysis Set was 
updated.
Definition of primary 
efficacy endpoint was 
updated.
Pharmacodynamic 
Analysis Set was 
removed.
Added descriptions 
for analyses of 
several endpoints.
Added analysis of 
New Onset of 
Diabetes after 
Transplant (NODAT)
Additional changes to 
correct typographical 
errors or add clarity
Specifications of the timing of an 
interim analysis were changed. The 
procedures of interim analysis were 
revised.
Subjects who enroll in the study but 
don’t have primary FSGS, will not be 
included in the FAS, since they are not 
included in the population of interest, 
primary FSGS, and are not at risk for 
recurrence of their primary FSGS.
Subjects with a protein-creatinine ratio 
(≥ 3.0 g/g) on Day 0 only (day of skin 
closure) will not be considered to have a 
recurrence if this is the only day with 
the elevated ratio and subsequent values 
do not meet this limit.
Per team decision.
Added detailed analysis for Anti-
bleselumab antibodies, anti-bleselumab 
neutralizing antibodies, bleselumab bi-
specific antibodies, and anti-CD40 auto-
antibodies.
Per DSMB request.
To easily understand the text in the 
document.


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9
REFERENCES
ICH Harmonized Tripartite Guideline E 3. Structure and Content of Clinical Study Reports, 
November 1995. (www.ich.org; Guidelines; "Efficacy" Topics)
ICH Harmonized Tripartite Guideline E 9. Statistical Principles for Clinical Trials, February 1998. 
(www.ich.org; Guidelines; "Efficacy" Topics)
Laupacis A, Pus N, Muirhead N, Wong C, Ferguson B, Keown P. Disease-Specific Questionnaire for 
Patients with a Renal Transplant. Nephron. 1993; 64: 226-231.


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9.1
Appendix 1: Grading of Acute Kidney Allograft Rejection
2007 Update to the Banff 97 Diagnostic Categories for Renal Allograft Biopsies
Category
Global Assessment
Histopathological Findings
1
Normal
2
Antibody-mediated 
changes 
(may coincide with 
categories 3, 4 and 5 
and 6)
Due to documentation of circulating anti-donor antibody, and C4d or 
allograft pathology 
C4d depletion without morphologic evidence of active rejection
Cd4+, presence of circulating anti-donor antibodies, no signs of acute 
or chronic TCMR or ABMR (i.e., g0, cg0, ptc0, no ptc lamination).  
Cases with simultaneous borderline changes or ATN are considered 
indeterminate
Acute antibody-
mediated rejection1
Cd4+, presence of circulating anti-donor antibodies, morphologic 
evidence of acute tissue injury, such as (Type/Grade):
Grade I
ATN-like minimal inflammation
Grade II
Capillary and/or glomerular inflammation (pct/g >0) and/or 
thromboses
Grade III
Arterial – v3
Chronic active 
antibody-mediated 
rejection1
Cd4+, presence of circulating anti-donor antibodies, morphologic 
evidence of chronic tissue injury, such as glomerular double contours 
and/or peritubular capillary basement membrane multi-layering and/or 
interstitial fibrosis/tubular atrophy and/or fibrous intimal thickening in 
arteries
3
Borderline 
(may coincide with 
categories 2 and 5 and 
6)
“Suspicious” for acute T-cell-mediated rejection 
This category is used when no intimal arteritis is present, but there are 
foci of tubulitis (t1, t2, or t3) with minor interstitial infiltrate (i0 or i1) 
or interstitial infiltrate (i2, i3) with mild (t1) tubulitis 
4
T-cell mediated 
rejection (TCMR, 
may coincide with 
categories 2 and 5 and 
6)
Acute T-cell-mediated 
rejection 
(Type/Grade)
Grade IA
Cases with significant interstitial infiltration (>25% of parenchyma 
affected, i2 or i3) and foci of moderate tubulitis (t2) 
Grade IB
Cases with significant interstitial infiltration (>25% of parenchyma 
affected, i2 or i3) and foci of severe tubulitis (t3)
Grade IIA
Cases with mild-to-moderate intimal arteritis (v1)
Grade IIB
Cases with severe intimal arteritis comprising >25% of the luminal 
area (v2)
Grade III
Cases with “transmural” arteritis and/or arterial fibrinoid change and 
necrosis of medial smooth muscle cells with accompanying 
lymphocytic inflammation (v3)
Chronic active T-cell-
mediated rejection
“Chronic allograft arteriopathy” (arterial intimal fibrosis with 
mononuclear cell infiltration in fibrosis, formation of neo-intima)


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Category
Global Assessment
Histopathological Findings
5
Interstitial fibrosis 
and tubular atrophy
No evidence of specific etiology (may include nonspecific vascular 
and glomerular sclerosis, but severity graded by tubulointersitial 
features)
Grade I
Mild interstitial fibrosis and tubular atrophy (<25% cortical area)
Grade II
Moderate interstitial fibrosis and tubular atrophy (26-50% of cortical 
area)
Grade III
Severe interstitial fibrosis and tubular atrophy/loss (>50% of cortical 
area)
6
Other
Changes not considered to be due to rejection-acute and/or chronic (for 
diagnosis see full article Table 14; may include isolated g, cg or cv 
lesions and coincide with categories 2, 3, 4 and 5) 
1 Suspicious for antibody-mediated rejection if C4d (in the presence of antibody) or alloantibody (C4d+) 
not demonstrated in the presence of morphologic evidence of tissue injury.  
For complete description, please refer to the below reference. 
Reference:
Solez K, Colvin RB, Racusen LC, et al. Banff ’07 classification of renal allograft pathology: updates 
and future directions.  Am J Transplant 2008;8: 753-60.    


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9.2
Appendix 2: Clustered Safety Events
Adverse Events, Laboratory Values, and Vital Sign Values That Constitute Clusters
Example
Cluster
Events (adverse events‡, lab values, and vitals) that compose the 
cluster
BK Infection
BK virus infection
Polyomavirus associated 
nephropathy    
Cardiac  
Acute myocardial infarction
Angina pectoris
Aortic valve incompetence
Arrhythmia
Atrial fibrillation
Atrioventricular block first degree
Bradycardia
Cardiac arrest
Cardiac failure congestive
Cardiac murmur
Cardiomegaly
Chest discomfort
Chest pain
Coronary artery disease
Dyspnoea exertional
Electrocardiogram change
Endocarditis
Extrasystoles
Heart rate increased
Labile blood pressure
Mitral valve stenosis
Myocardial infarction
Myocardial ischaemia
Palpitations
Sinus bradycardia
Sinus tachycardia
Supraventricular tachycardia
Tachycardia
Troponin increased
Ventricular extrasystoles
Ventricular tachycardia
Cardiovascular
Arterial thrombosis limb
Arteriosclerosis
Arteriovenous fistula
Arteriovenous fistula site 
haemorrhage
Arteriovenous fistula thrombosis
Deep vein thrombosis
Dyslipidaemia
Pelvic venous thrombosis
Peripheral vascular disorder
Pulmonary embolism
Pulmonary oedema
Vasodilatation
Cytomegalovirus
Cytomegalovirus colitis
Cytomegalovirus infection
Cytomegalovirus test positive
Cytomegalovirus viraemia
…
…
…
‡ The complete list of adverse events that define each cluster will be finalized after the final 
data review. The list of potential adverse event terms for the defined clusters is greater than 
1200 and will not be listed here. There is a dataset that has been created with the targeted 
terms and is periodically updated.  A set of programs references this dataset with a standard 
set of terms and provides the adverse events within each cluster for an individual study.


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9.3
Appendix 3: Liver Safety Monitoring and Assessment
If laboratory testing for a subject enrolled in study and receiving study drug reveals an increase 
of serum aminotransferases (AT) to > 3X ULN, or bilirubin > 2X ULN, at least all four of the 
usual serum hepatic measures (ALT, AST, ALP, and TBL) should be repeated. Testing should 
be repeated within 48-72 hours of notification of the test results. For studies for which a central 
laboratory is used, alerts will be generated by the central lab regarding moderate and marked 
liver abnormality to inform the investigator, study monitor and study team. Subjects should be 
asked if they have any symptoms suggestive of hepatobiliary dysfunction.
Definition of Liver Abnormalities
Confirmed abnormalities will be characterized as moderate and marked where ULN:
ALT or AST
Total Bilirubin
Moderate
> 3 x ULN
or
> 2 x ULN
Marked
> 3 x ULN
and
> 2 x ULN
In addition, the subject should be considered to have marked hepatic abnormalities for any of 
the following:
●
ALT or AST > 8X ULN
●
ALT or AST > 5X ULN for more than 2 weeks
●
ALT or AST > 3X ULN and INR > 1.5
●
ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
The investigator may determine that abnormal liver function results, other than as described 
above, may qualify as moderate or marked abnormalities and require additional monitoring and 
follow-up.
Follow-up Procedures
Confirmed moderate and marked abnormalities in hepatic functions should be thoroughly 
characterized by obtaining appropriate expert consultations, detailed pertinent history, physical 
examination and laboratory tests. The site should complete the Liver Abnormality Case Report 
Form (LA-CRF) or an appropriate document. Subjects with confirmed abnormal liver function 
testing should be followed as described below.
Confirmed moderately abnormal LFTs should be repeated 2-3 times weekly then weekly or 
less if abnormalities stabilize or the study drug has been discontinued and the subject is 
asymptomatic.  
Marked hepatic liver function abnormalities, in the absence of another etiology, may be 
considered an important medical event and reported as a Serious Adverse Event (SAE). The 
sponsor should be contacted and informed of all subjects for whom marked hepatic liver 
function abnormalities possibly attributable to study drug are observed.


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To further assess abnormal hepatic laboratory findings, the investigator is expected to:
●
Obtain a more detailed history of symptoms and prior or concurrent diseases. Symptoms 
and new onset-diseases should be recorded as ’adverse events’ on the AE page of CRF. 
Illnesses and conditions such as hypotensive events, and decompensated cardiac disease 
that may lead to secondary liver abnormalities should be noted. Non-alcoholic 
steatohepatitis (NASH) is seen in obese hyperlipoproteinemic, and/or diabetic patients 
and may be associated with fluctuating aminotransferase levels. The investigator should 
ensure that the medical history form captures any illness that pre-dates study enrollment 
that may be relevant in assessing hepatic function. 
●
Obtain a history of concomitant drug use (including non-prescription medication, 
complementary and alternative medications), alcohol use, recreational drug use, and 
special diets. Medications, should be entered on the concomitant medication page of 
CRF.  Information on alcohol, other substance use, and diet should be entered on the LA-
CRF or an appropriate document.
●
Obtain a history of exposure to environmental chemical agents
●
Based on the subject’s history, other testing may be appropriate including: 
○
acute viral hepatitis (A,B, C, D, E or other infectious agents). 
○
ultrasound or other imaging to assess biliary tract disease
○
other laboratory tests including INR, direct bilirubin
●
Consider gastroenterology or hepatology consultations
●
Submit results for any additional testing and possible etiology on the LA-CRF or an 
appropriate document.
Study Discontinuation
In the absence of an explanation for increased LFTs, such as viral hepatitis, pre-existing or 
acute liver disease or exposure to other agents associated with liver injury, the subject may be 
discontinued from the study. The investigator may determine that it is not in the subject’s 
best interest to continue study enrollment. Discontinuation of treatment should be considered 
if:
●
ALT or AST > 8X ULN
●
ALT or AST > 5X ULN for more than 2 weeks
●
ALT or AST > 3X ULN and (TBL > 2X ULN or INR > 1.5)
●
ALT or AST > 3X ULN with the appearance of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash and/or eosinophilia (> 5%). 
In addition, if close monitoring for a subject with moderate or marked hepatic laboratory tests 
is not possible, drug should be discontinued.


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References
(1) Guidance for Industry titled “Drug-Induced Liver Injury: Premarketing Clinical 
Evaluation” issued by FDA on July 2009.
(2) Ware JE Jr, Kosinski M, Dewey JE. How to Score Version Two of the SF-36 Health 
Survey. Lincoln, RI: Quality Metric, Incorporated, 2000.
(3) Ware JE Jr, Bjorner JB, Kosinski M. SF-36 Health Survey: Manual and Interpretation 
Guide. 2nd ed. Lincoln, RI: Quality Metric, 2007.


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9.4
Appendix 4: Handling of the Human Leukocyte Antigen (HLA) 
Mismatching
The HLA antigens are located on the cell surface. The genes encoding the HLA antigens are 
on chromosome 6 and have co-dominant expression: both alleles of one gene locus result in a 
surface HLA antigen. HLA class I antigens consist of a heavy chain and a β2m unit and 
include the HLA-A, HLA-B and HLA-C antigens, while HLA class II antigens are 
constituted by two heavy chains and include the HLA-DR, HLA-DP and HLA-DQ antigens. 
All HLA genes (loci) are very polymorphic: each has various alleles (variants) that can be 
distinguished by DNA sequencing of gene DNA or by serological techniques for detection of 
the gene products (the HLA antigens on the cell surface): HLA typing. 
The HLA types for HLA-A, HLA-B and HLA-DR are entered in the eCRF. Broad HLA 
types comprise of several fine specificities, the narrow types, but it is only the broad type 
codes (roughly equivalent to the serologically defined antigen or serotype (allotype)) that are 
entered into the eCRF.
Example:
Donor:
HLA A
HLA B
HLA DR
A11
A66
B5
-
DR5
DR6
Recipient:
HLA A
HLA B
HLA DR
A25
A32
B12
B5
DR5
DR7
Both codes for a locus will be considered identical (homozygote) if only one code is entered. 
In this case, the investigator will either enter the code twice or put a dash for the second entry 
(or leave the second entry blank). The order of the entries is unimportant. A mismatch 
between a donor and a recipient exists if the donor has an antigen which doesn’t appear in the 
recipient.
Calculation of the number of HLA mismatches:
For the comparison of the HLA types between the donor and the recipient, the following 
steps should be done to calculate the number of HLA mismatches:
1.  If the entry for a locus is a numeric code and a dash (or missing), then the dash for that 
locus is to be replaced (for calculation only) by the numeric code (homozygote).
2.  The following rules should be applied when calculating the number of mismatches within 
a HLA A, B, and DR locus:
●
If both codes are missing in either the donor or recipient, the number of mismatches is 
unknown (missing)


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●
If the two codes are non-missing and identical for the recipient and the donor (without 
regard to the order) or the donor is homozygote and the donor code matches either 
one of the recipient’s codes, then the number of mismatches is 0.
Examples:
Donor
Recipient
Mismatch
A1   A2
A2   A1
0
A2   A2
A2   A1
0
●
If one code from the donor exists in the recipient but the other code is different 
between the donor and recipient or the donor has identical codes (homozygote) but 
they do not match either code in the recipient, then the number of mismatches is 1. 
Examples:
Donor
Recipient
Mismatch
A2   A3
A2   A1
1
A2   A3
A2    A2
1
A2   A2
A3   A4
1
A2   A2
A1   A1
1
●
If the donor is not homozygote and all codes are different between the donor and the 
recipient, then the number of mismatches is 2.
Example:
Donor
Recipient
Mismatch
A1   A2
A3   A4
2
3.  If the number of mismatches from any of the three loci is missing, then total number of 
HLA mismatches is missing.  Otherwise, the total number of HLA mismatches is the sum of 
the mismatches from the three loci.


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An example following rules 1-4 above is provided below:
Donor:
(broad types)
HLA A
HLA B
HLA DR
A11
A10
B5
B5
DR5
DR6
Recipient:
(broad types)
HLA A
HLA B
HLA DR
A10
A19
B12
B5
DR5
DR7
Mismatch:
HLA A
HLA B
HLA DR
Total
1 
0 
1
2


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9.5
Appendix 5: Calculation of Dose when Dose Varies within a Visit 
Interval
Here are 3 examples for the Day 90 visit which has a window from 81 to 115.
        Last    --------Dose---------   
        Dose              Start    Stop     
Pt#   Day    Level  Day     Day    
---- ------   -------  ------   ------
1      110         5       1       100         
1      110         0     101     105
1      110        10    106     110
2      500         5       1       100         
2      500         0     101     105
2      500        10    106     500
3      500         5       1       100         
3      500         0     101     105
3      500        10    106     110
3      500          0    107     120
3      500          7    121     500
Mean dose for Pt 1 at Day 90 is calculated as:
[5mg*(100-81+1) + 0mg*(105-101+1)+ 10mg*(110-106+1)]/[110-81+1]=5mg/day
Mean dose for Pt 2 at Day 90 is calculated as:
[5mg*(100-81+1) + 0mg*(105-101+1)+ 10mg*(115-106+1)]/[115-81+1]=5.71mg/day
Mean dose for Pt 3 at Day 90 is calculated as:
[5mg*(100-81+1) + 0mg*(105-101+1)+ 10mg*(110-106+1)+0mg(115-111+1)]/[115-
81+1]=4.29mg/day


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9.6
Appendix 6: Example for Presenting Results for EQ-5D-5L
This example was created using excel. The final graphs will be created using SAS and the 
legend will be contained within the graph rather than located to the right of the graph.