Clinical trial NCT03744910
Conditions: Antibody-mediated Rejection
Keywords: Chronic Active Antibody-mediated Rejection (AMR)
Sponsor: CSL Behring
Start date: 2019-10-14; Completion date: 2024-04-08
Enrollment: 194 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This trial investigates the efficacy and safety of clazakizumab \[an anti-interleukin (IL)-6 monoclonal antibody (mAb)\] for the treatment of CABMR in recipients of a kidney transplant.

Detailed description:

Arms: arm 1: Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6 that is administered subcutaneously. arm 2: Physiologic saline solution that is administered subcutaneously.
Interventions: intervention 1: Clazakizumab intervention 2: Physiologic saline solution
Intervention descriptions: intervention 1: Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that binds to human IL-6 intervention 2: Normal saline

Protocol documents:
Prot_000.pdf: 
CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 1 of 185 
Date 10 July 2023 
Confidential 
CLINICAL STUDY PROTOCOL 
 
A Pivotal Phase 3 Trial to Evaluate the Safety and Efficacy of Clazakizumab for the 
Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Transplant 
Recipients 
Study Number: 
CSL300_3001 (Formerly VKTX01) 
Study Product: 
Clazakizumab (CSL300) 
Development Phase: 
3 
Short Title: 
A Trial to Evaluate the Safety and Efficacy of Clazakizumab for 
the Treatment of Chronic Active Antibody-Mediated Rejection 
in Kidney Transplant Recipients 
Sponsor: 
CSL Behring, LLC 
1020 First Avenue 
King of Prussia, PA 19406 
Protocol Version: 
Amendment 9 
EudraCT Number: 
2018-003682-34 
IND Number: 
134376 
Protocol Date: 
10 July 2023 
Compliance: 
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council 
for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use) and all applicable national and 
local regulations.  
Commercial in Confidence. This document and the information contained herein are proprietary and 
confidential. This document and the contained information are intended for disclosure to and use by those 
personnel who are under an obligation of confidentiality by a signed agreement with Sponsor (“CSL Behring”). 
This document and the contained information may be disclosed and used only to the extent necessary to conduct 
the clinical study. Reproduction or disclosure of this document or its contained information is forbidden unless 
at the express request or with the written consent of CSL Behring. 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 2 of 185 
Date 10 July 2023 
Confidential 
LIST OF PERSONNEL AND ORGANIZATIONS RESPONSIBLE FOR CONDUCT 
OF THE STUDY 
A list of personnel and organizations responsible for the conduct of the study will be supplied 
to study sites as part of the Investigator’s Study File. This list will be updated by CSL 
Behring (or delegate) and provided to the study sites as needed. 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 3 of 185 
Date 10 July 2023 
Confidential 
REVISION HISTORY 
Date 
Version  
Summary of Changes 
22 October 2018 
Original 
Not applicable 
7 December 2018 
Amendment 1 
1. Investigational product dose was changed 
from 25 mg/mL to 12.5 mg/mL 
2. Belatacept added to allowed medications 
(only if already taking at screening) 
3. Clarification that CNI levels should reach 
target levels during Screening, if possible, 
and then maintained 
4. Requirement for prophylactic treatment of 
pneumocystis jiroveci pneumonia (PJP) for 
the first year of the study (ie, from 
Screening up to and including Week 52), 
and thereafter at the discretion of the 
investigator. 
5. Treatments for ABMR (including 
CABMR) or T cell-mediated rejection 
(TCMR), are not allowed within 3 months 
of the start of Screening 
6. Prior exposure to all IL-6 / IL-6R blockers, 
including, tocilizumab or other IL-6 / IL-
6R blockers, in addition to excluded 
clazakizumab, added as exclusions 
7. Spot urine albumin creatinine ratio 
(UACR) ≥ 2200 mg/g (≥ 220 mg/mmol) 
replaces urine protein creatinine ratio 
(UPCR) ≥ 3000 mg/g (≥ 300 mg/mmol) as 
an exclusion criterion 
8. ABO-incompatible transplant recipient, 
severe hypogammaglobulinemia (defined 
as immunoglobulin G (IgG) < 400 mg/dL) 
and prior exposure to proteasome inhibitors 
(eg, bortezomib) added as exclusion criteria 
9. Extent of monitoring for liver function test 
(LFT) abnormalities, neutropenia and 
thrombocytopenia was clarified 
10. Monitoring for hypogammaglobulinemia 
was added and timing of monitoring 
provided and in the case of severe 
hypogammaglobulinemia (IgG 
< 400 mg/dL), reduction of background 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 4 of 185 
Date 10 July 2023 
Confidential 
immunosuppression and treatment with 
IVIG is be permitted 
11. Subjects who prematurely discontinue 
investigational treatment with 
clazakizumab / placebo, and who have not 
reached an endpoint of allograft loss will 
be required to continue in the study, attend 
regular clinic visits and undergo all 
assessments per the Schedule of Events 
(SOE) (up to and including Visit 68, if 
possible) and must comply with all aspects 
of the protocol (including prohibited 
medications). 
12. Stratification by baseline proteinuria 
parameters changed from (UACR 
< 1000 mg/g (< 100 mg/mmol) or UACR 
≥ 1000 mg/g (≥ 100 mg/mmol)) changed to 
(UACR < 300 mg/g (< 30 mg/mmol) or 
UACR ≥ 300 mg/g (≥ 30 mg/mmol) 
6 February 2019 
Amendment 2 
1. Reduction of investigational drug dose 
2. Updates to exclusion criteria 
3. Updates to risks/precautions 
4. Treatment of hypogammaglobulinemia and 
routine monitoring of IgG levels 
5. Updates to concomitant medications 
6. Prophylactic treatment for PJP 
7. Editorial changes 
29 October 2019 
Amendment 3 
1. Inclusion Criterion 3 has been amended to 
clarify that a window of +3 weeks is 
allowed with respect to screening 
biopsy/donor-specific antibodies (DSA) 
results 
2. Exclusion Criterion 2 was clarified to 
specify that recipients of multiple previous 
kidney transplants are eligible for the study. 
3. Exclusion Criterion 11 was broadened to 
exclude subjects with a known 
hypersensitivity to clazakizumab or any 
constituent of the drug product. 
4. Exclusion Criterion 18 was clarified to 
specify that the “mismatch” refers to the 
status at the time of transplantation. 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 5 of 185 
Date 10 July 2023 
Confidential 
5. Exclusion Criterion 19 was amended to 
allow subjects with fully excised 
diverticular disease to enter the study as 
this risk factor will have been surgically 
removed. 
6. Exclusion Criterion 23 was amended to 
clarify that active infection is defined as 
any polymerase chain reaction (PCR) value 
above the lower limit of quantification 
(LLOQ). 
7. Exclusion Criterion 33 was changed to 
only exclude subjects exposed to 
proteasome inhibitors within 2 years of the 
start of Screening. 
8. The requirement for subjects to use “highly 
effective methods of contraception” was 
amended as requested by multiple 
European health authorities to also allow 
“acceptable methods” as defined in the 
European “Heads of Medicines Agencies” 
2014 Clinical Trial Facilitation Group 
(CTFG) document “Recommendations 
related to contraception and pregnancy 
testing in clinical trials.” 
9. Throughout the protocol, the terminology 
with respect to discontinuation of 
investigational drug was clarified so that 
the term “discontinuation” now refers to 
permanent discontinuation and the term 
“withholding” refers to temporary 
discontinuation. Accordingly, Section 5.6 
was amended to clarify permanent 
discontinuation versus withholding of 
investigational drug. In addition, the 
instructions to stop treatment with 
investigational drug due to severe LFT 
abnormalities, severe neutropenia, and/or 
severe thrombocytopenia were amended to 
state that treatment with investigational 
drug should be “withheld or permanently 
discontinued.” 
10. The dose modification guidelines were 
clarified and expanded throughout the 
protocol. Recommendations to consider 
“stopping” investigational drug were 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 6 of 185 
Date 10 July 2023 
Confidential 
amended to specify withholding and/or 
discontinuing investigational drug (as 
appropriate). The instructions to “stop 
investigational drug” in the event of severe 
LFT abnormalities, severe neutropenia, 
and/or severe thrombocytopenia were 
amended to “withhold or discontinue 
investigational drug and contact the 
Medical Monitor.” 
11. Recommendations regarding concomitant 
background immunosuppression were 
clarified to explicitly state that subjects are 
expected to be on background 
immunosuppression per standard of care. 
12. The first planned formal safety review by 
the Data and Safety Monitoring Board 
(DSMB) was changed to occur after 
50 subjects (instead of 100 subjects) have 
been randomized and received at least 
1 dose of investigational drug. 
13. The guidelines for subjects with severe 
hypogammaglobulinemia were amended to 
add a 4-week waiting period after reduction 
of background immunosuppression 
followed by a re-check of IgG levels before 
implementing treatment with intravenous 
immunoglobulin. 
14. Home health visits were added as a 
potential option for certain visits in order to 
reduce the burden on study subjects. The 
required in-clinic visits were specified 
along with a recommended in-clinic visit 
schedule. 
15. Changes were made to clarify the process 
for reporting preexisting medical 
conditions that meet the definition of a 
serious adverse event (SAE).  


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 7 of 185 
Date 10 July 2023 
Confidential 
11 December 2019 Amendment 4 
1. Inclusion Criterion 3 has been amended to 
clarify that a window of +3 weeks is 
allowed with respect to Screening biopsy/ 
DSA results. 
2. Exclusion Criterion 2 was clarified to 
specify that recipients of multiple previous 
kidney transplants are eligible for the study. 
3. Exclusion Criterion 11 was broadened to 
exclude subjects with a known 
hypersensitivity to clazakizumab or any 
constituent of the drug product. 
4. Exclusion Criterion 18 was clarified to 
specify that the “mismatch” refers to the 
status at the time of transplantation. 
5. Exclusion Criterion 19 was amended to 
allow subjects with fully excised 
diverticular disease to enter the study as this 
risk factor will have been surgically 
removed. 
6. Exclusion Criterion 23 was amended to 
clarify that active infection is defined as any 
PCR value above the lower limit of 
quantification (LLOQ). 
7. Due to the potential confounding long-term 
effects of proteasome inhibitors on the 
immune system, subjects with any prior 
exposure to proteasome inhibitors are 
currently excluded from the study. 
8. The requirement for subjects to use “highly 
effective methods of contraception” was 
amended as requested by multiple European 
health authorities to also allow “acceptable 
methods” as defined in the European 
“Heads of Medicines Agencies” 2014 
Clinical Trial Facilitation Group (CTFG) 
document “Recommendations related to 
contraception and pregnancy testing in 
clinical trials.” 
9. Throughout the protocol, the terminology 
with respect to discontinuation of 
investigational drug was clarified so that the 
term “discontinuation” now refers to 
permanent discontinuation and the term 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 8 of 185 
Date 10 July 2023 
Confidential 
“withholding” refers to temporary 
discontinuation. 
10. The dose modification guidelines were 
clarified and expanded throughout the 
protocol. Recommendations to consider 
“stopping” investigational drug were 
amended to specify withholding and/or 
discontinuing investigational drug (as 
appropriate). 
11. Recommendations regarding concomitant 
background immunosuppression were 
clarified to explicitly state that subjects are 
expected to be on background 
immunosuppression per standard of care. 
12. To further ensure subject safety and to be 
consistent with the DSMB charter, the first 
planned formal safety review by the DSMB 
was changed to occur after 50 subjects 
(instead of 100 subjects) have been 
randomized and received at least 1 dose of 
investigational drug. 
13. For consistency with standard clinical 
practice of some investigators, the 
guidelines for subjects with severe 
hypogammaglobulinemia were amended to 
add a 4-week waiting period after reduction 
of background immunosuppression followed 
by a re-check of Immunoglobulin G (IgG) 
levels before implementing treatment with 
intravenous immunoglobulin. 
14. Home health visits were added as a potential 
option for certain visits in order to reduce 
the burden on study subjects. The required 
in-clinic visits were specified along with a 
recommended in-clinic visit schedule. 
15. Changes were made to clarify the process 
for reporting preexisting medical conditions 
that meet the definition of a SAE. 
16. The appearance of Clazakizumab Drug 
Product in 12.5 mg/mL vials was corrected 
to state “clear, colorless solution.” Text 
related to drug preparation and blinding was 
amended to remove reference to “masked” 
syringes which are not required given that 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 9 of 185 
Date 10 July 2023 
Confidential 
within syringes, clazakizumab 12.5 mg/mL 
is indistinguishable from placebo. 
17. The telephone numbers for the 24-hour SAE 
reporting lines were updated. 
18. With the exception of pulse steroid 
treatment for acute TCMR (see Protocol 
Section 7.6.2), treatments for ABMR 
(including CABMR) and TCMR are not 
allowed during the study. As a point of 
clarification, T cell depleting agents were 
added to the list of prohibited therapies and 
medications as these agents may confound 
the effects of clazakizumab. 
19. Minor editorial changes were implemented 
for clarification and/or correction of 
typographical errors.  
1 June 2020 
Amendment 5 
1. Exclusion Criterion 19 was amended to 
allow for subjects with fully excised 
ulcerative colitis to enter the study as this 
risk factor will have been surgically 
removed. 
2. In order to minimize the risk to subjects and 
study personnel participating in the study 
the protocol was revised to include 
coronavirus disease 2019 (COVID-19) PCR 
testing at screening and an additional 
exclusion criterion was added to exclude 
subjects with an active COVID-19 infection. 
3. The processing of blood samples for 
pharmacokinetic (PK) and anti-drug 
antibody (ADA) analysis requires a 
refrigerated centrifuge, which is not 
available to the home health providers. In 
order to address this, and ensure all tests are 
completed per the SOE, the schedule of 
mandatory in-clinic visits was amended. 
4. The rescreening procedures were amended 
so that a subject being rescreened does not 
require a repeat chest X-ray for tuberculosis 
(TB) screening if the first screening chest 
X-ray was normal and conducted within 
6 months from the start date of rescreening. 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 10 of 185 
Date 10 July 2023 
Confidential 
5. The prohibited medications section was 
amended to recommend that the 
administration of live vaccines (eg, measles, 
mumps, and rubella; varicella zoster) should 
be avoided during the course of the study. 
6. Minor editorial changes were implemented 
for clarification and/or correction of 
typographical errors. 
04 February 2021 
Amendment 6 
1. Inclusion Criterion 3 updated to diagnosis of 
CABMR based on kidney biopsy and the 
presence of human leukocyte antigen (HLA) 
DSA using single-antigen bead-based 
assays. Diagnosis of CABMR with 
histopathologic and serologic diagnostic 
criteria consistent with Banff 2015 criteria. 
2. Exclusion Criterion 2 updated to no longer 
exclude simultaneous kidney-pancreas or 
previous multiple kidney transplants. 
3. Exclusion Criterion 6 updated to “biopsy 
indicating predominant cause of renal 
dysfunction caused by pathology other than 
CABMR”. 
4. Exclusion Criterion 9 updated to no longer 
allow collection of a 24-hour urine to 
confirm nephrotic range if urine albumin 
creatinine ratio (UACR) is above defined 
limits. 
5. In Exclusion Criterion 19, diverticular 
disease is now defined as clinically 
significant diverticulosis (except if disease 
has been fully excised) 
6. In Exclusion Criterion 34, screening of 
subjects with prior COVID-19 has been 
clarified. 
7. The definition, End of Treatment (EOT) has 
been added to the SOE and throughout the 
protocol, and the definition of End of Study 
(EOS) has been likewise updated. 
8. A pharmacokinetic / pharmacodynamic 
substudy has been added to better capture 
clazakizumab exposures and relate these to 
IL-6 and hsCRP levels. 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 11 of 185 
Date 10 July 2023 
Confidential 
9. Patient-reported outcome assessments have 
been added. 
10. Sponsor changed to CSL Behring, LLC. 
11. Editorial, style and formatting changes 
made through the document. 
30 April 2021 
Amendment 7 
1. Clarified the required timing of the biopsy 
required to determine study eligibility after 
the end of any prior treatment for ABMR 
(including CABMR) or TCMR, in order to 
show continuing CABMR and presence of 
HLA DSA. 
2. Corrected Table 4 to reflect administration 
of subcutaneous clazakizumab. 
3. Corrected an inconsistency in the timing of 
interim analyses. 
4. Removed an exploratory healthcare 
utilization endpoint. 
5. Outlined that patient-reported outcome 
assessments would not be performed for 
subjects randomized prior to the deployment 
of an electronic clinical outcome assessment 
solution. 
12 July 2022  
Amendment 8 
1. The overall study design and treatment 
duration was changed from up to 260 weeks 
(or until allograft loss or death) to until the 
subject permanently discontinues IP, 
withdraws from the study, experiences 
allograft loss, dies, or reaches the common 
treatment end date. 
2. The duration of an individual subjects was 
defined as 5.5 years on average. 
3. The frequency of procedures in Years 2 to 
End of Study was decreased in order to 
maintain appropriate safety monitoring yet 
ease the burden on subject’s participation. 
4. The study procedures were updated based 
upon the changes to the Schedule of Events 
in Years 2 to End of Study. 
5. A new secondary objective (To evaluate the 
effects of clazakizumab on loss of allograft 
function [defined as a 40% decline in eGFR 
from Baseline that is sustained for at least 
60 days]) was added to the study. 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 12 of 185 
Date 10 July 2023 
Confidential 
6. A corresponding new secondary endpoint 
(Incidence and time to loss of allograft 
function as defined by a 40% decline in 
eGFR from Baseline) was added to the 
study. 
7. A description of the common treatment end 
date criteria was added throughout the 
protocol. 
8. Text that is currently described in the 
Investigator Brochure was removed from the 
protocol. 
9. Access to study product after the end of the 
study will now be available at the discretion 
of the treating physician and offered to 
subjects as agreed upon in their respective 
country. 
10. Subjects who receive IVIG will undergo PK 
assessments. 
11. The inclusion and exclusion criteria were 
modified to increase the number of subjects 
who may be eligible to participate in the 
study, ie. age range for inclusion into the 
study was increased from 70 to 75 years old, 
the screening window for kidney biopsy was 
increased from 6 to 12 months (±3 weeks). 
12. Clarifications to exclusion criteria were 
added ie, Nephrotic range proteinuria 
defined as spot UACR ≥ 2200 mg/g 
(≥ 248.4 mg/mmol) and Neutropenia 
(< 1500/mm3) or thrombocytopenia 
(< 75,000/mm3). 
13. Text from the Clinical Trials Facilitation and 
Coordination Group was added to the 
adequate contraception language. 
14.  Subjects who permanently discontinue IP 
will remain in the study until the common 
treatment end date. 
15. Text regarding unblinding procedures was 
amended to provide clear directions in the 
case of a SUSAR. 
16. Text describing dose, administration, 
storage, accountability, and destruction of IP 
was deleted from the protocol as this 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 13 of 185 
Date 10 July 2023 
Confidential 
information is provided in the IMP and / or 
pharmacy manual. 
17. Text regarding allowed concomitant 
medications / interventions was updated to 
allow treatment with Lymphocyte immune 
globulin / anti-thymocyte globulin therapy 
for TCMR Banff ≥ IIa, V1 lesion. 
18. Text regarding prohibited concomitant 
medications / interventions was expanded to 
prohibit the use of IVIG and PLEX for any 
reason for 3 months prior to the start of 
Screening and can only be administered 
during the study for 
hypogammaglobulinemia or if the subject 
meets the 40% decline in eGFR endpoint. 
19. Recommendations for immunizations within 
6 weeks prior to the start of Screening was 
added to the protocol. 
20. A detailed description of End of Study 
procedures was provided for subjects who 
complete the study, subjects who 
permanently discontinue IP, subjects who 
withdraw from the study, and subjects who 
are on treatment when the primary endpoint 
of the study is reached. 
10 July 2023 
Amendment 9 
1. The primary objective was revised to 
include “or irreversible loss of allograft 
function”. 
2. The primary composite efficacy endpoint 
and associated footnote were revised to 
include “a sustained (≥ 60 days) 40% 
decline in eGFR from Baseline”. 
3. The “End of Study” (EOS) visit terminology 
was revised to the “Safety Follow-up Visit” 
(SFV) or the “Common Treatment End Visit 
(CTEV)”, where applicable. 
4. Testing methodology for COVID-19 was 
expanded to include rapid antigen testing. 
5. Minor corrections and clarifications, 
including word modifications and 
administrative changes. 
6. Protocol text under the synopsis subsection 
entitled “Guidelines for Dose Modification, 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 14 of 185 
Date 10 July 2023 
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Withholding or Discontinuation of 
Investigational Product, and / or 
Modification of Background 
Immunosuppression” was deleted. 
7. Protocol text under the synopsis subsection 
entitled “Post-treatment Follow-up 
(5 months after the last dose of IP)” was 
deleted. 
8. “Secondary Safety Endpoints” was revised 
to “Safety Endpoints”. 
9. The text describing the confirmatory 
measurement requirements for subjects who 
met the primary efficacy endpoint by the 
one component of eGFR of 
< 15 mL/min/1.73 m2 was revised. 
10. Protocol text was revised to outline the 
sequence of assessments (kidney biopsy and 
DSA analysis) required if treatment (other 
than steroids) for ABMR or TCMR was 
administered prior to the start of Screening. 
Details regarding the acceptable dosing 
regimen of steroids was also provided. 
11. Protocol text was revised regarding how to 
manage study subjects who remain in the 
study after permanently discontinuing IP. 
12. An exploratory objective and corresponding 
exploratory endpoints were added to the 
protocol. 
13. Text describing calcineurin inhibitor (CNI) 
monitoring was revised. 
14. “Acceptable” methods of contraception 
were removed from the protocol. 
15. The secondary objectives were revised to 
include the previous primary efficacy 
objective as the first secondary objective. 
The remaining secondary objectives were 
adjusted in position after the new first 
secondary objective. 
16. The order of the secondary objectives was 
revised to list the “evaluation of the effects 
of clazakizumab on the histology of kidney 
biopsies” before the “evaluation of the 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 15 of 185 
Date 10 July 2023 
Confidential 
effects of clazakizumab on the incidence of 
acute rejection episodes (TCMR and 
ABMR)”. 
17. A statement regarding how to manage study 
subjects who reach the endpoint of “a 
sustained (≥ 60 days) 40% decline in eGFR 
from Baseline” was added to the text of the 
protocol. 
18. Protocol text regarding how to manage 
study subjects who withdraw from the study 
was clarified. 
19. The number of participating study sites was 
increased from 135 to 155. 
20. Exclusion criterion 11 was revised to “a 
history of anaphylaxis or known 
hypersensitivity related to IP”. 
21. Exclusion criterion for COVID-19 was 
clarified. 
22. Exclusion criterion 35 was revised to 
confirm the dose of anti-hypertensive agents 
has been stable for at least 2 months prior to 
the start of Screening. 
23. The timing for initiating pneumocystis 
jiroveci pneumonia (PJP) prophylactic 
therapy has been revised to a Sponsor 
recommendation. 
24. Protocol text regarding the administration of 
live vaccines was revised to prohibited 
during the study. Administration of live 
vaccines is allowed during the 5-month 
safety Follow-up period following the last 
dose of IP after careful consideration of 
risk / benefit profile evaluated by a health 
care provider. 
25. The dose range of mycophenolate mofetil 
(MMF) and mycophenolic acid (MPA) 
(allowed concomitant medications) was 
revised. 
26. Based upon the revised primary composite 
efficacy endpoint and a relative risk 
reduction of 31%, the graft survival rate was 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 16 of 185 
Date 10 July 2023 
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increased from 24.7% to 38.3% over 
4 years. 
27. The original primary efficacy endpoint is 
now listed as the first secondary efficacy 
endpoint. The remaining secondary 
endpoints were adjusted in position after the 
new first secondary endpoint. 
28. The original first secondary efficacy 
endpoint is now the second secondary 
efficacy endpoint and now includes 
“irreversible loss” of allograft function. 
29. The original second secondary efficacy 
endpoint is now the third secondary efficacy 
endpoint and includes the new endpoint 
component of “a sustained (≥ 60 days) 40% 
decline in eGFR from Baseline”. 
30. The order of the secondary endpoints was 
revised to align with the revised secondary 
objectives. “The change in Banff lesion 
grading score of pre-treatment to post-
treatment kidney biopsies” is now listed 
before the “incidence of acute rejection 
episodes (TCMR and ABMR) from Baseline 
to EOT”. 
31. Two footnotes (D and E) were added to the 
Study Schema regarding the Safety 
Follow-up Visit, the common treatment end 
date visit, and study subjects who 
permanently discontinue IP. 
32. A “Q6 month (Q6M) after DC of IP” visit 
and a “common treatment end date visit” 
and their respective assessment schedules 
were added to the Schedule of Events 
(Table 1 and Table 2). 
33. The definition of Baseline eGFR was added 
where needed. 
34. The procedure entitled “MPA levels” was 
revised to “as clinically indicated per 
investigator discretion” in the Schedule of 
Events (Table 1 and Table 2). 
35. The order of presented information was 
revised to align with the title of this section. 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 17 of 185 
Date 10 July 2023 
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36. Protocol text regarding subjects who 
discontinue IP due to pregnancy was 
revised. 
37. Protocol text describing withholding or 
discontinuing IP due to AE, abnormal LFTs, 
neutropenia and / or thrombocytopenia, and 
BKV, CMV, or EBV viral infection was 
revised. 
38. Protocol text describing emergency 
unblinding of IP was revised. 
39. Drug product description was updated to 
“Clear to slightly opalescent, colorless to 
yellow colored solution”. 
40. Protocol text describing studies in Crohn’s 
disease and rheumatoid arthritis was deleted 
from the protocol. A statement was added to 
the protocol text to refer the reader to the 
CSL300 Investigator’s Brochure. 
41. The subsection under potential risks entitled 
“autoimmunity” was deleted from the 
protocol. 
42. The sample collection timepoints for several 
of the test types in Table 8 now includes the 
SFV, the Q6M (or Q12M) visit, and / or the 
CTEV, where applicable. 
43. The protocol text for the following 
procedures was updated with the appropriate 
visit(s) schedule: viral monitoring, 
monitoring for hypogammaglobulinemia, 
eGFR, DSA titers and MFI scores, Plasma 
hsCRP, Plasma IL-6, serum clazakizumab, 
immunogenicity, MPA levels, standard 
12-lead electrocardiogram, and the health-
related qualify of life. 
44. The timing of the DSA analysis and renal 
biopsy was revised. 
45. Protocol text was revised to allow a study 
subject to rescreen if they screen failed for 
either clinical or administrative reasons. 
46. The following visits were added to Table 10 
(Schedule of Mandatory In-Clinic Visits): 


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SFV, Q6 months after DC of IP visit, and 
CTEV. 
47. Visit 16 (Week 52) was deleted from 
Table 11 (Schedule of “Mandatory In-clinic” 
Visits that may be Completed as Remote 
Visits During Extraordinary Circumstances). 
48. The list of site visits that are not permitted 
to be completed remotely was revised. 
49. Section title clarified to apply to study 
subjects who met any of the other non-fatal 
composite all-cause allograft loss endpoints. 
Additional assessments that are now 
required at the SFV were added to this 
subsection of the protocol text. 
50. Additional text was added to the protocol 
regarding how to manage study subjects 
once the common treatment end date for the 
study has been reached. 
51. The telephone number for the serious 
adverse event hotline was removed from the 
protocol. The email address was moved 
before the fax number. 
52. The summary table of all scheduled study 
visits (Appendix 2) was revised to include 
the SFV, the Q6M visit (for study subjects 
who permanently DC IP), and the CTEV. 


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PROTOCOL SYNOPSIS 
Title 
A Pivotal Phase 3 Trial to Evaluate the Safety and Efficacy of Clazakizumab for the 
Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Transplant 
Recipients 
Sponsor 
CSL Behring 
Study Code 
CSL300_3001 (Formerly VKTX01) 
Study Name 
IMAGINE (Interleukin 6 Blockade Modifying Antibody-Mediated Graft INjury and 
eGFR Decline) 
Development 
Phase 
3 
Number of Sites 
Approximately 155 study sites planned in North America, Europe, Asia, and Australia 
Rationale 
Active antibody-mediated rejection (ABMR), especially chronic active antibody-
mediated rejection (CABMR), is now recognized as the most common cause of allograft 
failure after a successful kidney transplant. Current standard of care antirejection 
treatments target cellular-mediated (ie, T cell-mediated rejection [TCMR]) processes and 
do not affect this antibody-mediated process. Currently, there are no approved or 
effective treatments for active ABMR, including CABMR. 
Interleukin 6 (IL-6) appears to be a critical cytokine involved in ABMR. It promotes the 
development and maturation of B cells to plasma cells that produce donor-specific 
antibodies (DSA) targeting the allograft. These DSA damage the allograft via 
complement and non-complement mediated pathways and induce graft endothelial cells 
to produce inflammatory (eg, p-selectin, vascular cell adhesion molecule 1 [VCAM-1]) 
and pro-thrombotic (eg, von Willebrand factor) molecules. Furthermore, IL-6 shapes the 
T cell immune response resulting in promotion of long-lived pro-inflammatory T helper 
(Th) cells (eg, follicular Th cells Th17, Th1, Th2 cells) and inhibition of immune 
regulatory T (Treg) cells that promote allograft tolerance. 
This trial investigates whether clazakizumab (an anti-IL-6 monoclonal antibody [mAb]) 
may be beneficial for the treatment of CABMR in recipients of a kidney transplant by 
inhibiting the production of DSA and re-shaping T cell alloimmune responses.  
Indication 
Treatment of CABMR in kidney transplant recipients. 
Study Design 
Randomized, double-blind, parallel-group, placebo-controlled, phase 3 multicenter study. 
Subjects will receive treatment with either 12.5 mg clazakizumab (n = 175) or placebo 
(n = 175) by SC injection Q4W until permanent discontinuation of Investigational 
Product (IP), withdrawal from the study, allograft loss, death, or the common treatment 
end date (CTED) is reached, whichever occurs first). The CTED is the date when the 
primary efficacy endpoint is achieved, ie, the date the target number of primary 
composite all-cause allograft loss or irreversible loss of allograft function events (221) 
has been reached.  
Primary Objectives 
 
1. To evaluate the efficacy of clazakizumab in preventing all-cause allograft loss 
(including death) or irreversible loss of allograft function, due to CABMR. 


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2. To evaluate the efficacy of clazakizumab in slowing / preventing the progressive loss 
of kidney function (as measured by eGFR using the Modification of Diet in Renal 
Disease 4 [MDRD4] equation [Interim Analysis #2 {IA #2}]). 
3. To evaluate the safety of clazakizumab. 
Secondary 
Objectives 
 
1. To evaluate the efficacy of clazakizumab in preventing all-cause allograft loss 
(including death) due to CABMR. 
2. To evaluate the effects of clazakizumab on loss of allograft function (defined as a 
40% decline in eGFR from Baseline that is sustained for at least 60 days). 
3. To evaluate the effects of clazakizumab on death-censored allograft loss. 
4. To evaluate the effects of clazakizumab on albuminuria. 
5. To evaluate the effects of clazakizumab on DSA titers and mean fluorescence 
intensity (MFI) scores. 
6. To evaluate the effects of clazakizumab on the histology of kidney biopsies 
according to the Banff 2015 lesion grading scores. 
7. To evaluate the effects of clazakizumab on incidence of acute rejection episodes 
(TCMR and ABMR). 
8. To evaluate the effects of clazakizumab on overall subject survival. 
9. To evaluate the PK of clazakizumab following subcutaneous (SC) injection in kidney 
transplant recipients with CABMR (for those subjects in the Pharmacokinetic [PK] / 
Pharmacodynamic [PD] Substudy only). 
10. To evaluate the immunogenicity of clazakizumab in kidney transplant recipients with 
CABMR. 
Exploratory 
Objectives 
1. To evaluate the PD of clazakizumab (serum IL-6 [total and free] and / or high-
sensitivity C-reactive protein [hsCRP]) following SC injection in kidney transplant 
recipients with CABMR (for those in the PK / PD Substudy only). 
2. To explore the relationship between clazakizumab PK and PD parameters (serum 
IL-6 [total and free] and / or hsCRP [for those in the PK / PD Substudy only]). 
3. To evaluate the effects of clazakizumab on health-related quality of life (HRQoL) 
associated with the treatment of antibody-mediated rejection to Week 52 as well as to 
the Safety Follow-up Visit (SFV). 
4. To evaluate the efficacy of clazakizumab in slowing / preventing the progressive loss 
of kidney function up to the EOT (as measured by eGFR using the MDRD4 
equation). 
Number of 
Subjects / Events 
It is estimated that approximately 350 subjects randomized to clazakizumab 12.5 mg SC 
injection once every 4 weeks (Q4W) (175 subjects) or placebo SC injection Q4W 
(175 subjects) will be required to accrue at least 221 composite all-cause allograft loss or 
irreversible loss of allograft function events over approximately 5 to 8 years. 
A subset of 44 subjects (out of the 350 enrolled in the main study) will have the option to 
participate in a PK / PD Substudy. Subjects enrolled in the PK / PD Substudy will 
provide consent for additional blood samples for the purpose of PK / PD analyses.  


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Investigational 
Treatment 
IP: clazakizumab single-dose vials (12.5 mg/mL) for SC injection. 
Clazakizumab (12.5 mg) will be administered Q4W by SC injection for approximately 
260 weeks (5 years) on average. Each 12.5 mg dose will be administered as a 1 mL 
injection of clazakizumab (12.5 mg/mL). 
In the case of dose reductions directed by protocol-defined safety parameters, each 
6.25 mg dose will be administered as a 0.5 mL injection of clazakizumab (12.5 mg/mL). 
Placebo Control: normal saline for injection. 
Placebo will be administered Q4W by SC injection, for approximately 260 weeks 
(5 years) on average. Each dose of placebo (for subjects on target dose) will be 
administered as a 1 mL injection of normal saline. Each dose of placebo for subjects on a 
reduced dose as described above will be administered as a 0.5 mL injection of normal 
saline. 
Concomitant 
Medications / 
Interventions 
Allowed: antidiabetic agents (eg SGLT2 inhibitors), anti-hypertensive agents 
(eg, angiotensin-converting enzyme inhibitors [ACEIs], angiotensin II receptor blockers 
[ARBs]), azathioprine (AZA), calcineurin inhibitors (CNIs), low dose corticosteroids 
(prednisone / prednisolone ≤ 10 mg/day), belatacept (only if already taking at Screening) 
and mycophenolate mofetil (MMF) / mycophenolic acid (MPA) or equivalent after 
approval by the Medical Monitor. 
If the subject is on an ACEI or ARB or starting these drugs, the dose should be stable for 
at least 2 months prior to the start of Screening Visit and not planned to be increased. 
Subjects are expected to be on background immunosuppression per standard of care. 
Recommended AZA / MMF / MPA dose and CNI target trough blood levels: 
• 
AZA dose: 1.0 to 2.0 mg/kg/day. 
• 
MMF dose: 1.0 to 2.0 g/day. 
• 
MPA dose: 720 to 1440 mg/day. 
• 
Target tacrolimus plasma trough levels: 5 to 8 ng/mL. 
• 
Target cyclosporine plasma trough levels: 50 to 150 ng/mL. 
Note: Given the potential for drug-drug interactions between clazakizumab and CNIs, 
CNI trough levels will be monitored at Year 1: Visits 2 (Baseline) through 6, 8, 10, 12, 
14, and 16; Year 2 through EOT: every second visit (Q8W) starting with Visit 18 through 
the EOT / Early Withdrawal Visit (for subjects taking a concomitant CNI). CNIs will 
also be monitored Q2W following a change in CNI dose, withholding, discontinuation, or 
restarting of IP until target CNI trough levels are achieved. 
After Year 1, CNI levels may be checked per local practice through local laboratories, 
including being a part of evaluating any significant changes in creatinine. Locally drawn 
CNI levels may qualify for monitoring if drawn within the specified interval of ± 
2 weeks. Routine monitoring of CNI levels is summarized in the Schedule of Events 
(SOE). 
With prior alignment and permission from CSLB, CNI monitoring may be conducted 
locally during Year 1. If monitored locally during Year 1,CNI monitoring should be 
conducted at the same laboratory throughout the study, ie beginning from and including 
the Baseline CNI level. Also, if CNI monitoring is conducted locally in Year 1, a sample 


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should be drawn and submitted to the central laboratory each time CNI levels are 
assessed as per the schedule described in the SOE (see Table 1 and Table 2). 
• 
Investigators should attempt to achieve recommended CNI target trough 
levels within the Screening Period and maintain these levels throughout the 
study. 
Lymphocyte immune globulin / anti-thymocyte globulin therapy is allowed for TCMR 
Banff ≥ IIa, V1 lesion. The next administration of IP and any DSA testing as per the SOE 
should occur ≥ 2 weeks after lymphocyte immune globulin / anti-thymocyte globulin 
therapy. 
Pneumocystis jiroveci pneumonia (PJP) prophylaxis: 
• 
All subjects will be required to take prophylactic treatment for PJP. For the 
first year of the study (ie, from Screening up to and including Week 52), 
subjects should take trimethoprim / sulfamethoxazole as single-strength pill 
(80 mg as trimethoprim) daily or double-strength pill (160 mg as 
trimethoprim) 3 times per week. It is recommended that treatment with 
trimethoprim / sulfamethoxazole should be started approximately 1 week 
before the Day 1 Baseline Visit (Visit 2) or 1 week before Screening if 
already taking it. If a subject is already receiving a suitable 
Investigator-approved alternative PJP prophylactic therapy, the subject should 
remain on that therapy and not start trimethoprim / sulfamethoxazole. 
Subjects who are intolerant to trimethoprim / sulfamethoxazole and not 
already receiving an Investigator-approved alternative should be started on 
atovaquone (mepron), inhaled pentamidine, or oral dapsone approximately 
1 week before the Day 1 Baseline Visit (Visit 2) based on consultation with 
the Medical Monitor. In the event of acute kidney injury (AKI [eg, interstitial 
nephritis]) considered related to trimethoprim / sulfamethoxazole, 
prophylactic treatment with this drug should be discontinued, and the subject 
should be started on another Investigator-approved antibiotic therapy (see 
Section 7.1.3.2). In the event of other serious adverse reactions, the Medical 
Monitor should be consulted with respect to discontinuing prophylactic 
treatment or switching to another prophylactic treatment. 
• 
For the remainder of the study (ie, after Week 52), PJP prophylaxis should be 
continued at the discretion of the Investigator. 
Treatment for acute TCMR allowed: 
• 
Pulse steroid (eg, IV methylprednisolone 1000 mg, or oral prednisone 
200 mg/day [or equivalent] and taper to Baseline level over 2 weeks). 
• 
Lymphocyte immune globulin / anti-thymocyte globulin therapy is allowed 
for TCMR Banff ≥ IIa, V1 lesion. 
Treatment with oral valganciclovir or intravenous (IV) ganciclovir is permitted for 
cytomegalovirus (CMV) infection (see “Monitoring for polyoma BK virus [BKV], CMV, 
and Epstein-Barr virus [EBV] infection”). 


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In general, the use of herbal and homeopathic medicines (eg, St. John’s Wort, echinacea, 
goldenseal, Schisandra sphenanthera extracts) is strongly discouraged. 
Prohibited: 
Treatments for ABMR (including CABMR) and TCMR are not allowed within 3 months 
prior to the start of Screening with the exception of steroids. Subjects who received these 
treatments at any time prior must have both a renal biopsy and DSA testing performed 
after halting / completing treatment in order to confirm eligibility per the inclusion 
criteria (see Section 5.2). 
mTOR inhibitors (everolimus, sirolimus) are not allowed within 4 weeks prior to the start 
of Screening or during the study. Subjects may discontinue mTOR inhibitors and switch 
to another suitable immunosuppressant and be treated for at least 4 weeks prior to 
Screening for eligibility. 
Administration of live vaccines (eg, measles, mumps, and rubella; varicella zoster) is 
prohibited within 6 weeks prior to the start of Screening and during the study. During the 
5-month safety follow-up period following the last dose of IP, live vaccines, and any 
additional immunosuppressive therapies should be administered only after careful 
consideration of the risk / benefit profile by the health care provider. 
In addition, the following are prohibited during the study: 
• 
Anti-IL-6 / IL-6R mAbs (approved or investigational). 
• 
Belatacept, unless subject is already taking belatacept at the start of 
Screening. 
• 
Eculizumab. 
• 
Intravenous Immunoglobulin (IVIG) and plasma exchange (PLEX): 
o 
Screening: IVIG and PLEX are prohibited for any reason for the 3-month 
period prior to Screening. 
o 
During the study1: IVIG and PLEX may be administered only to subjects who 
1) have hypogammaglobulinemia at any point during the study, 2) meet the 
40% decline in eGFR (from Baseline) endpoint and who have received 
> 12 months of IP (see Section 7.5.3). 
 
Double-blind medication and IVIG should be administered 2 weeks apart 
due to potential binding of IVIG to clazakizumab. For treatment with IVIG, 
subjects may be called in for unscheduled visits between regularly 
scheduled dosing with IP according to the SOE. 
 
DSA testing, per the SOE, should occur ≥ 2 weeks after administration of 
IVIG. 
 
Pharmacokinetic samples for the assessment of clazakizumab will be 
collected for subjects that receive IVIG as defined in Table 9. 
• 
Proteasome inhibitors (eg, bortezomib). 
• 
Rituximab. 
• 
T cell depleting agents (eg, alemtuzumab, anti-thymocyte globulin [except for 
acute TCMR]). 
• 
Other IPs / treatments. 


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1 In a specific clinical setting only (ie, worsening DSA and / or worsening proteinuria, 
AND pathology showing stable to worsening cg score or other measure[s] of chronic 
pathology on recent / updated biopsy, accompanied by a worsening measure[s] of activity 
[eg, peritubular capillaritis score {ptc}, glomerulitis score {g}, complement component 
4d Banff score {C4d}]), consideration for use of this medication must be discussed with 
the Medical Monitor prior to its use. 
Selection Criteria 
Unless specified otherwise, all eligibility criteria time intervals are assessed with respect 
to the Screening Visit. 
Inclusion Criteria: 
1.A8 
Age 18 to 75 years. 
2. 
Living donor / deceased donor kidney transplant recipients ≥ 6 months from time 
of transplant. 
3.A9 
Diagnosis of CABMR determined by kidney biopsy and the presence of human 
leukocyte antigen (HLA) DSA using single-antigen bead-based assays. For 
eligibility, kidney biopsy must not be older than 12 months and DSA analysis 
must be performed no longer than 6 months prior to the start of Screening. 
NOTE: 
• 
Within 3 months prior to the start of Screening, treatments for ABMR or 
TCMR, with the exception of steroids*, are not allowed (see Exclusion 
Criterion 3). 
• 
If treatment for ABMR (including CABMR) or TCMR (other than steroids*) 
was given between 3 to 12 months of Screening, a repeat kidney biopsy and 
DSA analysis are required at least 6 weeks after the end of treatment to 
confirm continuing CABMR and presence of HLA DSA and to determine 
eligibility. 
* A maximum dose of 2g of methylprednisolone intravenously (or dose 
equivalent of other steroids), followed by a taper to the original maintenance 
steroid dose is allowed. 
The following histopathologic and serologic diagnostic criteria (based on Banff 
2015 criteria [Loupy et al, 2017]) must be met for inclusion: 
a. 
Morphologic evidence of chronic tissue injury, as demonstrated by 
transplant glomerulopathy (TG) (cg>0). Biopsies without evidence of 
chronic tissue injury on light microscopy, but with glomerular basement 
membrane double contours on electron microscopy (cg1a) are eligible. 
b. Evidence of current / recent antibody interaction with vascular endothelium, 
including 1 or more of the following: 


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i. 
Linear complement component 4d (C4d) staining in peritubular 
capillaries or medullary vasa recta (Banff scores C4d2 or C4d3 by 
immunofluorescence on frozen sections, or C4d > 0 by 
immunohistochemistry on paraffin sections). 
ii. 
At least moderate microvascular inflammation (glomerulitis score, 
[g] + peritubular capillaritis score [ptc] ≥ 2) in the absence of recurrent 
or de novo glomerulonephritis, although in the presence of acute 
TCMR, borderline infiltrate, or infection, ptc ≥ 2 alone is not 
sufficient and g must be ≥ 1. 
NOTE: The local pathologist’s diagnosis must be reviewed by a 
central pathologist to confirm eligibility for entry into the study. 
Biopsies with other histopathologic changes (eg, BKV nephropathy or 
recurrent glomerulonephritis) may be eligible if concurrent CABMR 
changes (as detailed above) are present and determined to be the 
predominant cause of renal dysfunction. 
c. 
Serologic evidence of circulating HLA DSA. 
NOTE: The local laboratory DSA results must be reviewed and confirmed 
by the central HLA reviewer during the Screening Period. 
4. 
Written informed consent obtained from the subject (or legally acceptable 
representative) before any trial-related procedures. 
 
Exclusion Criteria: 
1.A8 
Subject is unable or unwilling to comply with study procedures in the opinion of 
the Investigator. 
2.A6 
Multi-organ transplant recipient (except for simultaneous kidney-pancreas or 
previous multiple kidney transplants) or cell transplant (islet, bone marrow, stem 
cell) recipient. 
3. 
Treatment for ABMR (including CABMR) or TCMR within 3 months prior to 
the start of Screening with the exception of steroids. 
4. 
Received T cell depleting agents (eg, alemtuzumab, anti-thymocyte globulin) 
within 3 months prior to the start of Screening. 
5. 
Treatment with mTOR inhibitors within 4 weeks prior to the start of Screening 
(see Section 7.6.1). 
6.A9 
Biopsy indicating predominant cause of renal dysfunction caused by pathology 
other than CABMR, within 12 months prior to the start of Screening. 
7.A8 
Impaired renal function due to disorders in the transplanted allograft (eg, renal 
artery stenosis, significant vascular disease of the donor, hydronephrosis). 
8. 
eGFR < 25 mL/min/1.73 m2 or > 65 mL/min/1.73 m2 (MDRD4). 
9.A8 
Nephrotic range proteinuria defined as spot urine albumin-to-creatinine ratio 
(UACR) ≥ 2200 mg/g (≥ 248.4 mg/mmol). If spot UACR is above the defined 
limits, a single repeat test can be performed on a separate day to confirm 
ineligibility. 


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10.A9 Pregnant, breastfeeding, or unwillingness to practice adequate contraception (eg, 
a highly effective method of contraception) during the study and for 5 months 
after the last dose of IP. 
11.A9 History of anaphylaxis or known hypersensitivity related to clazakizumab or to 
any constituent of the drug product. 
12.A8 Abnormal liver function tests (LFTs [alanine aminotransferase (ALT) or 
aspartate aminotransferase (AST) or bilirubin > 1.5 x upper limit of normal]) or 
other significant liver disease. Subjects with an established diagnosis of 
Gilbert’s syndrome are allowed. 
13.A8 Active tuberculosis (TB) or history of active TB. 
14.A8 History of latent TB (eg, positive QuantiFERON-TB test) without history of 
active TB unless the subject has completed a documented course of prophylactic 
treatment. 
15. 
History of human immunodeficiency virus (HIV) infection or positive for HIV. 
16. 
Seropositive for hepatitis B surface antigen (HBsAg). 
17. 
Hepatitis C virus (HCV) RNA positive. 
18.A8 Known EBV mismatch (at time of transplant): donor seropositive, recipient 
seronegative. Seroconversion to EBV IgG-positive post-transplant is allowed, if 
documented. 
19.A8 History of gastrointestinal (GI) perforation; diverticular disease defined as 
clinically significant diverticulosis (except if disease has been fully excised and 
the subject has recovered from surgery) or diverticulitis (except if disease has 
been fully excised and the subject has recovered from surgery); or inflammatory 
bowel disease (except fully excised ulcerative colitis and the subject has 
recovered from surgery). 
20.A8 Neutropenia (< 1500/mm3) or thrombocytopenia (< 75,000/mm3). 
21. 
Active infections requiring systemic antimicrobial agents and unresolved prior to 
Screening. 
22.A8 History of or current invasive fungal infection or other opportunistic infection, 
including (but not limited to) the following: a nontuberculous mycobacterial 
infection, aspergillosis, pneumocystosis, and toxoplasmosis, etc. 
23.A8 Active viral infections such as BKV, CMV, or EBV based on plasma polymerase 
chain reaction (PCR) testing. Active infection is defined as a test result ≥ lower 
limit of quantification (LLOQ) (see definition in Table 6). 
24. 
Current or recent (within 3 months) participation in an interventional trial. 
25. 
Administration of a live vaccine within 6 weeks prior to the start of Screening, 
including but not limited to the following: 
a. 
Adenovirus. 
b. Measles, mumps, and rubella. 
c. 
Oral polio. 
d. Oral typhoid. 


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e. 
Rotavirus. 
f. 
Varicella zoster. 
g. Yellow fever. 
26.A8 History of alcohol or illicit substance (including marijuana) abuse < 5 years 
before Screening. 
27.A8 Present or previous (within 3 years) malignancy except for basal cell carcinoma, 
fully excised squamous cell carcinoma of the skin; other malignancies or those 
that required significant therapy may require longer duration documented cancer-
free (5 years) such as nonrecurrent cervical carcinoma in-situ or malignancy 
treated with resection and chemotherapy. These cases should be discussed with 
the Medical Monitor and Sponsor on a case-by-case basis. 
28. 
The presence of a condition or abnormality (ie, clinically significant endocrine, 
autoimmune, metabolic, neurological, psychiatric / psychological, renal, GI, 
hepatic, and hematological or any other system abnormalities that are 
uncontrolled with standard treatment) that in the opinion of the Investigator 
would compromise the safety or life expectancy of the subject or the quality of 
the data. 
29.A9 History of intolerance to trimethoprim and / or sulfamethoxazole. This criterion 
does not apply if the subject is already taking another suitable Investigator-
approved alternative therapy for PJP prophylaxis, or if the subject is willing to 
begin taking a suitable Investigator-approved alternative prophylactic therapy 
approximately 1 week prior to the Day 1 Baseline Visit (Visit 2). 
30. 
Prior exposure to clazakizumab, TCZ, or other IL-6 / IL-6R blockers. 
31. 
ABO-incompatible transplant recipient. 
32. 
Severe hypogammaglobulinemia (defined as immunoglobulin G [IgG] 
< 400 mg/dL). 
33. 
Prior (within 2 years prior to the start of Screening) exposure to proteasome 
inhibitors (eg, bortezomib). 
34.A9 Active infection with coronavirus disease 2019 (COVID-19): 
Subjects must have a negative rapid antigen test or PCR test result during the 
Screening Period as near to the Day 1 Baseline Visit (Visit 2) as possible. If the 
subject is unwell with symptoms suggestive of COVID-19 but rapid antigen test 
or PCR test result is negative, other causes for symptoms must be ruled out to 
determine subject eligibility. Subjects must be without symptoms attributable to 
COVID-19 for at least 1 month prior to the start of Screening. 
35.A9 For subjects receiving anti-hypertensive agents (eg, ACEIs or ARBs), the dose of 
the agent has been stable for at least 2 months prior to the start of Screening.  
Duration of Subject 
Participation 
The average study duration for an individual subject will be approximately 5.5 years. 
This includes a Screening Period of up to 42 days, a Treatment Period from Day 1 until 
the subject permanently discontinues treatment with IP, withdraws from the study, 
experiences allograft loss, dies, or reaches the CTED, whichever occurs first 
(approximately 260 weeks on average), and a Follow-up period of 5 months after the last 
dose of IP (completion or early termination). The CTED will be communicated to study 
sites when the target number of primary composite all-cause allograft loss or irreversible 


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loss of allograft function events (221) has been reached to enable study sites to plan their 
subjects’ final visit (common treatment end date visit).  
Pharmacokinetic 
assessments 
Blood samples will be collected for assessment of clazakizumab PK in serum in a subset 
study and in those subjects who receive IVIG.  
Pharmacodynamic 
assessments 
Blood samples will be collected for assessment of PD biomarkers, including but not 
limited to: IL-6 levels (total and free) and / or hsCRP. 
Interim Efficacy 
Endpoint 
A sample size reestimation, Interim Analysis #1 (IA #1), will be conducted when 
approximately 100 subjects have been randomized and completed at least 52 weeks of 
study participation and may result in an increase in the number of subjects included in IA 
#2. 
Interim Efficacy Analysis 2 (IA #2) Surrogate Endpoint: 
• 
Change in mean eGFR (in mL/min/1.73 m2) from Baseline to Week 52. 
An interim efficacy analysis will be performed to support expedited marketing approval 
based on a surrogate endpoint of change in mean eGFR from Baseline to Week 52. 
Baseline eGFR is defined as an average of 2 pre-treatment measurements up to 8 weeks 
apart. 
This analysis is planned for when approximately 200 subjects have been randomized and 
completed at least 52 weeks of study participation.  
Primary Efficacy 
Endpoint: Final 
Analysis 
• 
Time to composite all-cause allograft loss or irreversible loss of allograft 
function, defined as time to first occurrence of any of the following 
components: 
o 
eGFR < 15 mL/min/1.73 m2* 
o 
return to dialysis* 
o 
allograft nephrectomy 
o 
retransplantation 
o 
death from any cause, or 
o 
a sustained (≥ 60 days) 40% decline in eGFR from Baseline. 
*total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days. 
 
If the eGFR < 15 mL/min/1.73 m2 is the only component reached, the value must be 
sustained over at least 60 days and must be confirmed by a repeat measurement after 
≥ 60 days from the first measurement. 
Subjects who reach the endpoint of sustained 40% decline in eGFR from Baseline (but 
did not reach any of the non-fatal endpoint components of allograft failure) will continue 
to receive double-blind medication until they reach any of the other primary endpoints of 
allograft loss. The subject will remain in the study attending all regular clinic visits and 
undergoing all assessments per the SOE. IVIG and PLEX may be administered at the 
discretion of the Investigator to these subjects if they have completed the Week 52 visit. 
Double-blind medication and IVIG should be administered 2 weeks apart due to 
potential binding of IVIG to clazakizumab. For treatment with IVIG, subjects may be 
called in for unscheduled visits between regularly scheduled dosing with IP according to 
the SOE. 


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Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 29 of 185 
Date 10 July 2023 
Confidential 
The primary efficacy endpoint will be analyzed as part of the final analysis when at least 
221 composite all-cause allograft loss or irreversible loss of allograft function events 
have occurred. 
Safety Endpoints 
• 
Treatment-emergent adverse events (TEAEs), serious TEAEs, and adverse 
events of special interest (AESIs). 
• 
Viral infection monitoring for BK virus (BKV), cytomegalovirus (CMV), and 
EBV by plasma PCR. 
• 
Laboratory tests including LFTs, complete blood count (CBC), plasma lipids, 
hsCRP. 
• 
Vital signs, electrocardiograms (ECGs), and physical examination. 
• 
Incidence of antibodies to clazakizumab. 
Secondary Efficacy 
Endpoints 
• 
Time to composite all-cause allograft loss, defined as, time to first occurrence 
of any of the following components: 
o 
eGFR < 15 mL/min/1.73 m2* 
o 
return to dialysis* 
o 
allograft nephrectomy 
o 
retransplantation, or 
o 
death from any cause. 
• 
Incidence and time to irreversible loss of allograft function as defined by a 
40% decline in eGFR from Baseline. 
• 
Incidence of composite all-cause allograft loss or irreversible loss of allograft 
function, defined by occurrence of any of the following components: 
o 
eGFR < 15 mL/min/1.73 m2* 
o 
return to dialysis* 
o 
allograft nephrectomy 
o 
retransplantation 
o 
death from any cause, or 
o 
a sustained (≥ 60 days) 40% decline in eGFR from Baseline. 
• 
Incidence and time to death-censored allograft loss, defined as occurrence of 
any of the following components: 
o eGFR < 15 mL/min/1.73 m2* 
o return to dialysis* 
o allograft nephrectomy, or 
o retransplantation. 
• 
Change in mean eGFR from Baseline to End of Treatment (EOT). 
• 
Change in spot UACR from Baseline to EOT. 
• 
Change in DSA titers and MFI scores from Baseline to EOT. 
• 
Change in Banff lesion grading score (2015 criteria) of pre-treatment to post-
treatment (Week 52) kidney biopsies. 
• 
Incidence of acute rejection episodes (TCMR and ABMR) from Baseline to 
EOT. 
• 
Overall subject survival. 
*total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days. 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 30 of 185 
Date 10 July 2023 
Confidential 
 
If the eGFR < 15 mL/min/1.73 m2 is the only component reached, the value must be 
sustained over at least 60 days and must be confirmed by repeat measurement after 
≥60 days from the date of the first measurement.  
Secondary 
Pharmacokinetic 
Endpoints 
The pharmacokinetic endpoints for a subset of subjects who consent to participate in the 
PK / PD Substudy will include the following: 
• 
maximum concentration (Cmax, steady state Cmax [Cmax ss]). 
• 
trough concentrations (Ctrough, steady state Ctrough [Ctrough ss]). 
• 
area under the concentration-time curve at steady state (AUC0-tau ss). 
• 
time of maximum concentration (Tmax, steady state Tmax [Tmax ss]). 
Exploratory 
Endpoints 
PK / PD Endpoints: 
• 
The pharmacodynamic endpoints for subjects who consent to participate in 
the PK / PD Substudy will include the following: evaluation of IL-6 (total), 
IL-6 (free), and hsCRP. 
o Baseline and change from Baseline of free interleukin 6 (IL-6) in plasma. 
o Baseline and change from Baseline of total interleukin 6 (IL-6) in plasma. 
o Baseline and change from Baseline of hsCRP levels in serum. 
• 
Correlation of hsCRP and IL-6 (total and free) to plasma clazakizumab 
plasma concentration. 
Other Exploratory Endpoints: 
• 
HRQoL associated with the treatment of CABMR to Week 52 as well as to 
EOT. 
• 
Change from Baseline in eGFR at 2 years. 
• 
40% decline in eGFR accompanied by the Investigator’s decision to 
supplement the therapy by additional treatment. 
DSMB and 
Planned Interim 
Analyses  
An independent Data and Safety Monitoring Board (DSMB) will review cumulative 
study data to evaluate safety, study conduct, scientific validity, and data integrity. 
The first formal safety review will occur after approximately 50 subjects per group have 
been randomized and received at least 1 dose of IP. A second safety review will occur 
after approximately 100 subjects per group have been randomized and received at least 
1 dose of IP. Further safety reviews may be conducted at the discretion of the DSMB as 
outlined in the DSMB charter. 
Two formal interim analyses will be conducted: 
IA #1 for sample size reestimation: After approximately 100 subjects (50 per group) have 
been randomized and completed at least 52 weeks of study participation, a formal interim 
analysis will be conducted by an independent statistician (external to the blinded study 
team ) to assess the adequacy of the sample size for the interim efficacy analysis of the 
52-week eGFR endpoint (see IA #2 below). Observed data from subjects not completing 
/ not reaching Week 52 will also be included in the analysis. The DSMB will review and 
approve the recommendation of the independent statistician. IA #1 may result in an 
increase in the number of subjects included in the interim efficacy analysis (see IA #2 
below). 
IA #2: An interim efficacy analysis of the 52-week eGFR endpoint is planned when 
approximately 200 subjects (100 per group) have been randomized and completed at least 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 31 of 185 
Date 10 July 2023 
Confidential 
52 weeks of study participation. The number of subjects included in this interim efficacy 
analysis may be increased by the outcome of IA #1. If IA #2 shows a statistically 
significant (p ≤ 0.05) and clinically meaningful treatment effect on eGFR between the 
clazakizumab and placebo treatment groups, the results will be submitted to regulatory 
authorities for expedited marketing approval. If this analysis does not reach statistical or 
clinical significance, the study will continue until 221 composite all-cause allograft loss 
or irreversible loss of allograft function events have been observed. Any decision to stop 
the study in the event of a non-significant effect on eGFR or to increase the sample size 
for the primary efficacy endpoint (time to composite all-cause allograft loss or 
irreversible loss of allograft function) would be made based on the recommendation of 
the DSMB after review of the totality of the data, ie, observed effect on eGFR, updated 
predicted survival based on the model using data observed in the study, and safety data. 
The DSMB can recommend stopping the study for safety reasons at any time. 
A DSMB charter will be created and finalized after the first DSMB operational meeting 
and before any data review meetings. 
Procedures 
See the SOE for full details of protocol-required procedures and applicable visits and 
timings. 
Screening (Up to 42 days) 
Subjects who provide signed and dated informed consent will be enrolled in the study 
and screened for eligibility (Visit 1). 
Randomization and Study Visits During the Treatment Period 
Subjects who satisfy the inclusion and exclusion criteria will be randomized to treatment 
with either 12.5 mg clazakizumab or placebo administered at clinical sites by SC 
injection Q4W. 
Subjects will return to the clinic for post-randomization visits as detailed in the SOE. 
Throughout the Treatment Period, clazakizumab (or placebo) will be administered Q4W 
as SC injections. Prior to dosing at each applicable visit, review of the most recent LFT 
and CBC analyses and viral monitoring results from a prior visit (scheduled or otherwise) 
will be reviewed for safety considerations. 
Subjects will receive treatment until the subject permanently discontinues treatment with 
IP, withdraws from the study, experiences allograft loss, dies, or reaches the CTED, 
whichever occurs first. 
Baseline assessments will be performed before the first dose of IP at Day 1 (Visit 2). 
Safety monitoring, including eGFR, pregnancy testing (for women of childbearing 
potential), AE, and concomitant medication monitoring will be conducted at dosing 
visits. Additional assessments will occur at Week 1, Q4W between Week 4 and Week 12, 
every 8 to 12 weeks up to Week 52, and then every 8 to 24 weeks until the SFV as 
detailed in the SOE. 
Guidelines for Dose Modification, Withholding or Discontinuation of Investigational 
Product, and / or Modification of Background Immunosuppression 
Abnormal LFTs, Neutropenia, and Thrombocytopenia 
During the study, LFT abnormalities will be monitored and neutropenia and 
thrombocytopenia will be evaluated at Screening and every 4 to 8 weeks in Year 1, and 
every 8 weeks after Year 1 as detailed in the SOE. Depending on Common Toxicity 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
Page 32 of 185 
Date 10 July 2023 
Confidential 
Criteria for Adverse Events (CTCAE) Version 5.0 severity grading, IP dose reduction (to 
6.25 mg SC Q4W), withholding, or discontinuation will be permitted in the event of 
abnormal LFTs (ie, AST / ALT), neutrophil, or platelet counts as per the table of 
Guidelines for Dose Modification, Withholding, or Discontinuation of IP and / or 
Modification of Background Immunosuppression. Investigational Product should be 
temporarily withheld or discontinued for any LFT abnormalities, neutrophil or platelet 
counts that meet CTCAE Grade ≥ 3. Once the adverse event (AE) resolves, IP may be 
restarted (at reduced dose or target dose) if clinically appropriate. The table below 
provides further guidelines for dose adjustment of IP and / or background 
immunosuppression according to CTCAE severity grade. Decisions regarding dose 
modification, withholding, discontinuation, or restarting of IP should be made in 
consultation with the Medical Monitor. 
 
Parameter 
Guidelines for Dose Modification, Withholding or 
Discontinuation of Investigational Product, and / or 
Modification of Background Immunosuppression 
LFTs (AST / ALT) 
> ULN to 3.0 x 
ULN (CTCAE 
Grade 1) 
• 
No change to IP dose. 
> 3.0 to 5.0 x ULN 
(CTCAE Grade 2) 
• 
In addition, if total bilirubin is ≥ 2.0 x ULN (or INR > 1.5), 
withhold or discontinue IP and contact Medical Monitor. 
• 
If total bilirubin is < 2.0 x ULN, reduce dose of IP to 
6.25 mg SC Q4W. Repeat LFT analysis every 2 to 4 weeks 
and consult Medical Monitor. 
• 
Increase dose of IP back up to 12.5 mg SC Q4W if 
circumstances allow or continue at 6.25 mg SC Q4W. 
• 
Perform investigations to exclude other causes of abnormal 
LFTs (eg, other hepatotoxic drugs, alcohol, viral infections, 
autoimmune hepatitis, hemochromatosis, etc.). 
> 5.0 x ULN 
(CTCAE Grade 
≥ 3) 
• 
Withhold or discontinue IP treatment and contact Medical 
Monitor. 
LFTs (Total bilirubin) 
> 3.0 x ULN 
• 
Withhold or discontinue IP and contact Medical Monitor. 
Neutrophil Count (cells per mm3) 
< 2500 to 1500 
(CTCAE Grade 1) 
• 
Reduce dose of MMF / MPA / AZA by 50%. 
• 
No change to IP dose.  
< 1500 to 1000 
(CTCAE Grade 2) 
• 
Reduce dose of MMF / MPA / AZA by 50%. 
• 
Reduce dose of IP to 6.25 mg SC Q4W. Repeat CBC every 
2 to 4 weeks and consult Medical Monitor. 
• 
Increase dose of IP back up to 12.5 mg SC Q4W if 
circumstances allow or continue at 6.25 mg SC Q4W. 
< 1000 (CTCAE 
Grade ≥ 3) 
 
• 
Withhold or discontinue IP and contact Medical Monitor. 
Platelets (cells per mm3) 
< LLN to 75,000 
(CTCAE Grade 1) 
• 
Reduce dose of MMF / MPA / AZA by 50%. 
• 
No change to IP dose. 
< 75,000 to 50,000 
• 
Reduce dose of MMF / MPA / AZA by 50%. 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
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Protocol version: Amendment 9 
 
Page 33 of 185 
Date 10 July 2023 
Confidential 
(CTCAE Grade 2) 
• 
Reduce dose of IP to 6.25 mg SC Q4W. Repeat CBC every 2 
to 4 weeks and consult Medical Monitor. 
• 
Increase dose of IP back up to 12.5 mg SC Q4W if 
circumstances allow or continue at 6.25 mg SC Q4W. 
< 50,000 (CTCAE 
Grade ≥ 3) 
• 
Withhold or discontinue IP and contact Medical Monitor. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; AZA = azathioprine; 
CBC = complete blood count; CTCAE = Common Toxicity Criteria for Adverse Events; INR = 
International Normalized Ratio; IP = investigational product; LFT = liver function test; LLN = 
lower limit of normal; MMF = mycophenolate mofetil; MPA = mycophenolic acid; Q4W = 
once every 4 weeks; SC = subcutaneous; ULN = upper limit of normal. 
In general, in cases where IP is reduced to 6.25 mg SC Q4W, it should be continued at 
the reduced dose for 1 or 2 doses and laboratory test monitoring performed before 
considering increasing IP dose back to 12.5 mg SC Q4W. In the case of neutropenia or 
thrombocytopenia, increasing the IP back to 12.5 mg SC Q4W should be considered 
first before increasing MMF / MPA / AZA. If this is not possible, the subject should 
continue in the study at the reduced dose of IP. 
 
In consultation with the Medical Monitor, the above approach to IP dose modification, 
withholding, discontinuation, or restarting should be followed at the discretion of the 
Investigator for any laboratory abnormality depending on the CTCAE severity (Grade 1 
[mild], Grade 2 [moderate], Grade 3 [severe or medically significant]), and corrective 
actions taken. 
 
Monitoring for BKV, CMV, and EBV Infection 
During the study, monitoring for BKV, CMV, and EBV infection will be performed by 
plasma PCR testing at Screening and every 8 to 24 weeks after Baseline thereafter as 
detailed in the SOE. If the DNA Viral PC test result is positive (ie, exceeds the LLOQ) or 
viral load increases, IP dose reduction (to 6.25 mg SC Q4W), withholding or 
discontinuation will be permitted as summarized in the table below. IP should be 
permanently discontinued for serious BKV, CMV, or EBV infections according to the 
criteria defined. The following table provides further guidelines for dose adjustment / 
withdrawal of IP and / or background immunosuppression according to the viral load as 
detected by the plasma PCR test result. Decisions regarding dose modification, 
withholding, discontinuation, or restarting of IP should be made in consultation with the 
Medical Monitor. 
Parameter 
Guidelines for Dose Modification, Withholding or 
Discontinuation of Investigational Product, and / or 
Modification of Background Immunosuppression 
BKV(a) 
> LLOQ 
to < 320 
IU/mL 
> LLOQ 
to < 2.51  
log IU/mL 
> LLOQ 
to < 1000 
copies/mL 
• 
Reduce dose of MMF / MPA / AZA by 
50% or reduce CNI target trough levels 
(ie, cyclosporine: 25 to 75 ng/mL; 
tacrolimus: 4 to 6 ng/mL). 
• 
No change to IP dose. 
• 
Repeat PCR test every 2 weeks and 
contact Medical Monitor. 
 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
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Protocol version: Amendment 9 
 
Page 34 of 185 
Date 10 July 2023 
Confidential 
≥ 320 to 
< 3200  
IU/mL  
≥ 2.51 to 
< 3.51 
log IU/mL 
≥ 1000 to 
< 10,000  
copies/mL 
• 
Reduce dose of MMF / MPA / AZA by 
50% and / or reduce CNI target trough 
levels (ie, cyclosporine: 25 to 75 ng/mL; 
tacrolimus: 4 to 6 ng/mL). 
• 
Reduce IP to 6.25 mg SC Q4W or 
consider withholding or discontinuing IP 
depending on severity of infection. 
• 
Repeat PCR test every 2 weeks and 
contact Medical Monitor. 
• 
Increase IP dose back up to 12.5 mg SC 
Q4W if circumstances allow or continue 
at 6.25 mg SC Q4W. Or, if IP was 
temporarily withheld, restart at 6.25 mg 
SC Q4W if circumstances allow. Repeat 
PCR at discretion of Investigator. 
Biopsy-proven BKV nephropathy or: 
• 
Discontinue IP and contact Medical 
Monitor. (Adjustment of MMF / MPA / 
AZA dose and CNI levels at Investigator’s 
discretion.) 
≥ 3200  
IU/mL  
≥ 3.51 
log IU/mL 
≥ 10,000 
copies/mL 
CMV(b) 
> LLOQ 
to < 1000 
IU/mL 
> LLOQ 
to < 3.0  
log IU/mL 
> LLOQ 
to < 640  
copies/mL 
• 
No change to IP dose. 
• 
Repeat PCR test weekly and contact 
Medical Monitor. 
≥ 1000 to 
< 5000  
IU/mL 
≥ 3.0 to 
< 3.70 
log IU/mL 
≥ 640 to 
< 3200 
copies/mL 
• 
Treat with oral valganciclovir or IV 
ganciclovir. 
• 
Repeat PCR test weekly and contact 
Medical Monitor. 


CSL Behring LLC 
Study Number:  CSL300_3001 
 
Study Product: 
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Protocol version: Amendment 9 
 
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Date 10 July 2023 
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Parameter 
Guidelines for Dose Modification, Withholding or 
Discontinuation of Investigational Product, and / or 
Modification of Background Immunosuppression 
CMV(b) (Cont’d) 
≥ 5000 
IU/mL 
≥ 3.70 
log IU/mL 
≥ 3200 
copies/mL 
• 
Reduce dose of MMF / MPA / AZA by 
50% and / or reduce CNI target trough 
levels (ie, cyclosporine: 25 to 75 ng/mL; 
tacrolimus: 4 to 6 ng/mL). 
• 
Treat with oral valganciclovir or IV 
ganciclovir. 
• 
Repeat PCR test weekly and contact 
Medical Monitor. 
• 
Reduce IP to 6.25 mg SC Q4W or 
consider withholding or discontinuing IP 
depending on severity of infection. 
• 
Increase IP dose back up to 12.5 mg SC 
Q4W if circumstances allow or continue 
at 6.25 mg SC Q4W. Or, if IP was 
temporarily withheld, restart at 6.25 mg 
SC Q4W if circumstances allow. Repeat 
PCR at discretion of Investigator. 
CMV end-organ disease (eg, hepatitis, 
colitis, pneumonitis, retinitis)  
• 
Discontinue IP and contact Medical 
Monitor. (Adjustment of MMF / MPA / 
AZA dose and CNI levels at Investigator’s 
discretion.) 
EBV(c) 
> LLOQ to 
< 10,200 
IU/mL 
> LLOQ to 
< 4.01 log 
IU/mL 
>LLOQ to 
< 5000 
copies/mL 
• 
No change to IP dose. 
• 
Repeat PCR test every 2 weeks and 
contact Medical Monitor. 
≥ 10,200 to 
< 20,400 
IU/mL 
≥ 4.01 to 
< 4.31 
log IU/mL 
≥ 5000 to 
< 10,000 
copies/mL 
• 
Reduce dose of MMF / MPA / AZA by 
50% and / or reduce CNI target trough 
levels (ie, cyclosporine: 25 to 75 ng/mL; 
tacrolimus: 4 to 6 ng/mL). 
• 
Repeat PCR test every 2 weeks and 
contact Medical Monitor. 
Post-transplant lymphoproliferative 
disorder or primary EBV infection in 
seronegative recipient or: 
• 
Discontinue IP and contact Medical 
Monitor. (Adjustment of MMF / MPA / 
AZA dose and CNI levels at Investigator’s 
discretion.) 
≥ 20,400 
IU/mL 
≥ 4.31 
log IU/mL 
≥ 10,000 
copies/mL  
 
 
 
AZA = azathioprine; BKV = polyoma BK virus; CMV = cytomegalovirus; CNI = calcineurin 
inhibitor; EBV = Epstein-Barr virus; IP = investigational product; IU = International Units; 
IV = intravenous; LLOQ = lower limit of quantification; MMF = mycophenolate mofetil; 
MPA = mycophenolic acid; PCR = polymerase chain reaction; Q4W = once every 4 weeks; 
SC = subcutaneous. 
Notes:  
a.LLOQ for BKV: 50.12 IU/mL (1.70 log IU/mL; 156 copies/mL). 
b LLOQ for CMV: 371.54 IU/mL (2.57 log IU/mL; 238 copies/mL). 
c LLOQ for EBV: 50.12 IU/mL (1.70 log IU/mL; 24.6 copies/mL). 


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Study Number:  CSL300_3001 
 
Study Product: 
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Protocol version: Amendment 9 
 
Page 36 of 185 
Date 10 July 2023 
Confidential 
In general, in cases where IP is reduced to 6.25 mg SC Q4W, it should be continued at 
the reduced dose for 1 or 2 doses and plasma PCR test monitoring performed before 
considering increasing IP dose back to 12.5 mg SC Q4W. Restoring the IP dose back to 
12.5 mg SC Q4W should be considered first before restarting / increasing MMF / MPA / 
AZA or increasing CNI levels. If this is not possible, the subject should continue in the 
study at the reduced dose. Decisions regarding dose modification, discontinuation, 
withholding and / or restarting of IP should be made in consultation with the Medical 
Monitor. 
For any other clinically significant infections, IP should be withheld, discontinued or 
dose reduced to 6.25 mg SC Q4W (the Investigator’s decision in consultation with 
Medical Monitor), and subject should be managed as per clinical practice with respect to 
background immunosuppressants. Once the infection has been treated and resolved, IP 
can be restarted at reduced dose or dose increased back to 12.5 mg SC Q4W at the 
discretion of the Investigator. 
Monitoring for Hypogammaglobulinemia 
During the study, IgG levels will be monitored at Screening and every 12 weeks after 
Baseline in Year 1 and every 16 weeks in Year 2 through SFV as detailed in the SOE. In 
the case of severe hypogammaglobulinemia (IgG < 400 mg/dL), reduction of background 
immunosuppression and treatment with IVIG will be permitted as detailed in the table 
below. Decisions regarding dose modification of IP and treatment with IVIG should be 
made in consultation with the Medical Monitor. 
Parameter 
Guidelines for Modification of Dose of Background Immunosuppression 
and Treatment with IVIG for Severe Hypogammaglobulinemia 
IgG (mg/dL) 
≥ 400 
• 
No change to background immunosuppression. 
• 
No change in dose of IP. 
< 400 
• 
Reduce dose of MMF / MPA by 50%. 
• 
No change in dose of IP. 
• 
After 4 weeks, if IgG < 400 mg/dL, continue with reduced dose of 
MMF / MPA and treat with IVIG, 0.5 g/kg monthly for 6 months, 
administered in between doses of IP (ie, 2 weeks postdose of IP is 
recommended). 
• 
After 6 months of IVIG treatment: 
o 
If IgG ≥ 400 mg/dL, continue with reduced MMF / MPA dose. If IgG 
levels remain ≥ 400 mg/dL after another 6 months post-IVIG 
treatment, MMF / MPA dose may be increased back to original dose. 
o 
If IgG < 400 mg/dL, consider stopping MMF / MPA and consult the 
Medical Monitor. 
IgG = immunoglobulin G; IVIG = intravenous immunoglobulin; MMF = mycophenolate mofetil; 
MPA = mycophenolic acid. 
Notes: 
Clazakizumab should not be administered within 2 weeks of IVIG due to potential binding of 
clazakizumab by IVIG. Subjects are not allowed to receive IVIG for any reason during the 
3-month pre-Screening Period. For treatment with IVIG, subjects may be called in for 
unscheduled visits between regularly scheduled dosing with IP according to the SOE. 


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Study Number:  CSL300_3001 
 
Study Product: 
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Protocol version: Amendment 9 
 
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Date 10 July 2023 
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Discontinuation of Investigational Product 
If IP is withheld for ≥ 3 consecutive doses because of an AE, the Medical Monitor should 
be consulted to consider discontinuing IP permanently. 
Subjects who permanently discontinued treatment with IP for any reason and who have 
not reached an endpoint of composite all-cause allograft loss or irreversible loss of 
allograft function event, defined as either: 
• 
eGFR < 15 mL/min/1.73 m2* 
• 
return to dialysis* 
• 
allograft nephrectomy 
• 
retransplantation 
• 
death from any cause, or 
• 
a sustained (≥ 60 days) 40% decline in eGFR from Baseline, 
will remain in the study and be followed for the occurrence of such events, or until 
subject withdraws from the study, or until the CTED is reached, whichever occurs first.  
 
Subjects who subsequently reach the endpoint of sustained (≥ 60 days) 40% decline in 
eGFR from Baseline will continue to remain in the study and will be followed for all-
cause allograft loss events, or until subject withdraws from the study, or until the CTED 
is reached, whichever occurs first. 
 
(*total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days.) 
 
If possible, the subject will return for an in-clinic EOT / Early withdrawal visit within 
4-weeks of receiving the last dose of IP. Following the EOT/ Early withdrawal visit, all 
subjects will be asked to return for 2 in-clinic Safety Follow-up Visits, 3 and 5 months 
after receiving the last dose of IP. In addition, all subjects will be contacted by telephone 
call (TC) 1, 2, and 4 months after the last dose of IP for monitoring for new AEs, SAEs, 
or pregnancies. Thereafter, the subject will be asked to return in 6-month intervals until 
the CTED is reached to collect renal function and allograft status data. If a subject is  
unable to return for 6-monthly follow-up visits, he / she will be asked to agree to be 
contacted at CTED to collect allograft and survival status.  
 
Subjects who permanently discontinued treatment with IP ≥ 5 months before their EOT 
Visit (and attended regular visits as per SOE) will not require any follow-up telephone 
calls. An in-clinic SFV will be performed after the 5-month Follow-up-period. 
 
Post-treatment Follow-up (5 Months After the Last Dose of Investigational Product) 
After the EOT / Early Withdrawal Visit, the subjects enter the 5-month safety follow-up 
period. All subjects who complete the study (ie, reached any of the composite non-fatal 
all-cause allograft loss endpoints) will be contacted monthly by telephone call for 
monitoring for new AEs, serious AEs, or pregnancies with the final in-clinic SFV 
5 months after the last dose of IP. In addition, live vaccines and any additional 
immunosuppressive therapies should be administered only after careful consideration of 
the risk / benefit profile by the health care provider. An in-clinic SFV will be performed 
after the 5-month Follow-up period. 
 


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Study Number:  CSL300_3001 
 
Study Product: 
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Protocol version: Amendment 9 
 
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Study Withdrawal 
Only if a subject is unable / unwilling to continue in the study will he / she be withdrawn 
from the study. Every effort should be made, before the subject withdraws from the 
study, either voluntarily or at the investigator’s discretion, to undergo the EOT 
assessments and safety follow-up as it is in the best interest of the subject. If possible, the 
subject will return for an in-clinic EOT /Early Withdrawal visit within 4-weeks of the 
subject’s last dose of IP. If the subject agrees to the safety follow-up following the EOT / 
Early withdrawal visit, the subject will be asked to return for 2 additional in-clinic Safety 
Follow-up Visits, 3 and 5 months after receiving the last dose of IP. Subjects may be 
called in for additional clinic visits during the 5-month Follow-up period at the discretion 
of the investigator. 
Subjects may withdraw consent from further participation in the study at any time. No 
further assessments will be performed after the subject has withdrawn consent from study 
participation.  
Statistical Methods: 
Primary Analysis 
Plan 
The analysis of the primary and secondary efficacy endpoints will be an intention-to-treat 
and per-protocol analysis. All statistical testing will be two-sided and will be performed 
using a significance (alpha) level of 0.05. 
Analysis Sets 
The intention-to-treat set will consist of all subjects who received at least 1 dose of IP 
and who completed a Baseline assessment and at least 1 assessment after Baseline. These 
subjects will be analyzed according to their randomization group. 
The Per-Protocol Analysis Set will consist of all subjects who satisfy the intention-to-
treat criteria and have no major protocol deviations that impact the primary efficacy 
endpoint for the final or interim analysis. 
The PK Analysis Set consists of all subjects in the Safety Analysis Set with at least 
1 quantifiable PK concentration of IP after administration. 
The PK / PD Substudy Analysis Set consists of all subjects in the Safety Analysis Set 
who consent to be a part of the PK / PD Substudy, and have at least 1 quantifiable PK 
concentration of IP after administration. 
The Safety Analysis Set will consist of all randomized subjects who have received at 
least 1 dose of IP. Subjects in the Safety Analysis Set will be analyzed according to the 
actual treatment received. 
Randomization 
Approximately 350 subjects will be randomized 1:1 into the 2 treatment arms using a 
stratified block randomization scheme: 175 subjects in the clazakizumab group and 
175 subjects in the placebo group. 
Stratification factors will include Baseline eGFR (25 to 45 mL/min/1.73 m2) 
or > 45 mL/min/1.73 m2; (Baseline eGFR is defined as an average of 2 pre-treatment 
measurements up to 8 weeks apart); Baseline proteinuria (UACR < 300 mg/g 
[< 30 mg/mmol] or UACR ≥ 300 mg/g [≥ 30 mg/mmol]); treatment for early (within 
6 months of transplant) ABMR rejection episodes (yes / no); and treatment for late 
(greater than 6 months post-transplant) ABMR rejection episodes (yes / no). 
 


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Interim Analysis #1 (IA #1) 
IA#1 will be conducted to confirm the sample size required for the IA#2. 
Interim Efficacy Analysis #2 (IA #2) 
The interim efficacy endpoint is the difference between the clazakizumab and placebo 
groups in the change in mean eGFR (in mL/min/1.73 m2) from Baseline to Week 52. 
The interim efficacy endpoint will be analyzed using a mixed model repeated measures 
approach. The model will include terms for treatment, stratification factors, Baseline 
eGFR and other pre-defined covariates. 
Sensitivity analyses will include the following: 
• 
Missing values imputed using the mean of the observed values at that time 
point within the same treatment group. 
• 
The delta adjustment method will be used to estimate the tipping point 
beyond which the active treatment would have an unfavorable effect. 
• 
Nonparametric rank-based method where subjects will first be ranked on the 
time point that they last provided data, and then by the value of eGFR at that 
visit. A Wilcoxon rank sum test will then be applied to compare treatment 
groups using the ranks. 
Primary Efficacy Analyses 
The primary efficacy endpoint is the time to composite all-cause allograft loss or 
irreversible loss of allograft function, defined as time to first occurrence of any of the 
following components: 
• 
eGFR < 15 mL/min/1.73 m2* 
• 
return to dialysis* 
• 
allograft nephrectomy 
• 
retransplantation 
• 
death from any cause, or 
• 
a sustained (≥ 60 days) 40% decline in eGFR from Baseline. 
(*total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days.) 
 
A stratified log rank test will be used to compare the median time-to-event between each 
treatment arm. Incidence rates and hazard ratios will also be presented. 
To assess the robustness of the primary efficacy analysis, the primary efficacy variable 
will be repeated in sensitivity analyses using the Per-Protocol Analysis Set. An additional 
sensitivity analysis will address the nature of composite all-cause allograft loss or 
irreversible loss of allograft function as a recurrent event. 
Secondary Efficacy Analyses 
Secondary efficacy endpoints will be analyzed in a manner analogous to the primary 
efficacy endpoint. For time-to-event analysis, a stratified log rank test will be used to 
estimate the median time-to-event for each treatment arm. Incidence rates will be 
analyzed using nonparametric approaches. 


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Pharmacokinetic Analyses 
Serum PK concentration data will be summarized by nominal timepoint. The PK 
parameters (for those in the PK / PD Substudy) will be derived by noncompartmental 
analysis (NCA) using WinNonLin® version 5.2 (or higher) and will be summarized 
descriptively. 
Exploratory Analyses 
For subjects participating in the PK / PD Substudy, plasma IL-6 (total and free) and 
serum hsCRP will be listed and summarized by nominal timepoint. Exploratory analyses 
will be used to investigate the relationship between serum hsCRP, plasma IL-6 (total and 
free), and serum clazakizumab. 
HRQoL will be evaluated based on the domains and summary measures appropriate for 
the selected instruments included in the protocol by comparing the change from Baseline 
in scores between treatment groups. 
Safety Endpoints 
Safety endpoints will be presented using descriptive statistics. 
Additional details are documented in the Statistical Analysis Plan. Detailed procedures 
for maintaining the integrity of study blinding will be specified in the DSMB charter and 
/ or Data Access Plan.  
Rationale for 
Number of 
Subjects  
Primary Efficacy Analysis 
The primary efficacy endpoint is the time to composite all-cause allograft loss or 
irreversible loss of allograft function, defined as time to first occurrence of any of the 
following components: 
• 
eGFR < 15 mL/min/1.73 m2* 
• 
return to dialysis* 
• 
allograft nephrectomy 
• 
retransplantation 
• 
death from any cause, or 
• 
a sustained (≥60 days) 40% decline in eGFR from Baseline. 
( *total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days.) 
 
Assuming a rate of composite all-cause allograft loss or irreversible loss of allograft 
function survival of 24.7% for the placebo arm over a period of approximately 48 
months, at least 221 composite all-cause allograft loss or irreversible loss of allograft 
function events (expected to accrue in 316 subjects) will be required to provide 80% 
power (two-sided alpha of 0.05) to detect a 31% reduction in the relative risk of allograft 
loss in the clazakizumab group compared to the placebo group, assuming clazakizumab 
can reduce the slope of eGFR decline by 50%. A relative risk reduction of 31% would 
improve the 4-year graft survival rate from 24.7% to 38.3%. Approximately 350 subjects 
will be enrolled to allow 10% for subjects lost to follow-up or withdrawals. 
Interim Analysis for Sample Size Reestimation (IA #1) 
Once approximately 100 subjects (50 per group) have been randomized and completed at 
least 52 weeks of study participation, reestimation (IA #1) of the planned sample size of 
200 subjects will be conducted using the inverse normal method with prespecified 


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Date 10 July 2023 
Confidential 
information rates (0.5556, 1) to control the Type I error rate. Observed data from subjects 
not completing / not reaching Week 52 will also be included in the analysis. The sample 
size reestimation ensures a power of 95.9%, when the assumed difference between 
treatment groups in the 52-week eGFR of 4.515 mL/min/1.73 m2 and a common standard 
deviation of 9.252 mL/min/1.73 m2 (effect size = 4.515/9.252 = 0.488). The average 
sample size under these assumptions is 202 subjects with at least 52 weeks of study 
participation data (corresponding to approximately 224 randomized subjects, assuming 
10% for subjects lost to follow-up or withdrawals). When the assumed eGFR effect size 
is 0.368, then the power is 79.6% and the average sample size is 218 subjects 
(approximately 242 randomized subjects). The sample size for the interim efficacy 
analysis surrogate endpoint (IA #2) will not exceed a total of 250 subjects with at least 
52 weeks of study participation (approximately 280 randomized subjects). 
Interim Efficacy Analysis of Surrogate eGFR Week 52 Endpoint (IA #2) 
A planned sample size of approximately 200 subjects (100 per group) has been 
determined for the IA #2 based on the following assumptions: The interim efficacy 
analysis surrogate endpoint is the change in mean eGFR (in mL/min/1.73 m2) from 
Baseline to Week 52. A fixed sample size of 180 subjects (90 per group) will have 90% 
power (two-sided alpha of 0.05) to detect a minimum difference in the 52-week eGFR of 
4.515 mL/min/1.73 m2 between the treatment groups (assuming eGFR declines at a rate 
of 0.75 mL/min/1.73 m2/month in the placebo treated group and that clazakizumab 
reduces eGFR decline by 50%). The sample size determination for the fixed design is 
based on a two-sided alpha of 0.05 and a common standard deviation of 
9.252 mL/min/1.73 m2 for the mean eGFR change from Baseline to Week 52 (effect size 
= 4.515/9.252 = 0.488). The planned sample size has been increased to a minimum of 
200 subjects to allow 10% for subjects lost to follow-up or withdrawals. 
 


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SCHEMA 
 


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Date: 10 July 2023 
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Schedule of Events 
Table 1 
Schedule of Events for Year 1 (Screening to Week 52 Inclusive) 
Procedures 
Screening(A) 
Treatment Period: Clazakizumab Q4W SC Injection (Until Discontinuation of IP, Withdrawal from Study, Allograft Loss, Death, or Common 
Treatment End Date, whichever occurs first)(A) 
Up to 
-42 Days 
+2 days 
Day 1(A) 
BL 
Wk 1(C) 
±5 days 
Wk 4(A) & 8 
±5 days 
Wk 12(A) 
±5 days 
Wk 16 
±5 days 
Wk 20 
±5 days 
Wk 24(A), 28, 32, 
36, 40, 44, 48(A) 
 ±5 days 
Wk 52(A) 
±5 days 
EOT / Early 
Withdrawal 
Visit(A,B) 
SF 
Visits(B) 
Q6M 
after 
DC of 
IP(B) 
CTED 
Visit(B) 
Visit 1 
Visit 2 
Visit 3 
Visit 4, 5 
Visit 6 
Visit 7 
Visit 8 
Visits 9 to 15 
Visit 16 
Informed consent(D) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Complete physical 
examination and vital 
signs(E) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history(E) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Review historical 
serology for HIV, 
HBsAg, HCV, CMV, 
and EBV; and test for 
HIV and HBsAg if 
seronegative or 
unknown 
X 
 
 
 
 
 
 
 
 
 
 
 
 
TB Screening 
(QuantiFERON-TB 
Gold and CXR)(E) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
HCV; COVID-19(F) 
rapid antigen test or 
PCR test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
Standard urinalysis 
dipstick(G) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / exclusion 
criteria review / 
check  
X 
X 
 
 
 
 
 
 
 
 
 
 
 


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Procedures 
Screening(A) 
Treatment Period: Clazakizumab Q4W SC Injection (Until Discontinuation of IP, Withdrawal from Study, Allograft Loss, Death, or Common 
Treatment End Date, whichever occurs first)(A) 
Up to 
-42 Days 
+2 days 
Day 1(A) 
BL 
Wk 1(C) 
±5 days 
Wk 4(A) & 8 
±5 days 
Wk 12(A) 
±5 days 
Wk 16 
±5 days 
Wk 20 
±5 days 
Wk 24(A), 28, 32, 
36, 40, 44, 48(A) 
 ±5 days 
Wk 52(A) 
±5 days 
EOT / Early 
Withdrawal 
Visit(A,B) 
SF 
Visits(B) 
Q6M 
after 
DC of 
IP(B) 
CTED 
Visit(B) 
Visit 1 
Visit 2 
Visit 3 
Visit 4, 5 
Visit 6 
Visit 7 
Visit 8 
Visits 9 to 15 
Visit 16 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated physical 
examination(H) and 
vital signs 
 
X 
 
X 
X 
 
 
Wks 24, 36 & 48 
only 
(Visits 9, 12 & 
15) 
 
X 
 
 
X 
12-lead ECG 
X 
 
 
 
X 
 
 
Wks 24 & 48 
only 
(Visits 9 & 15) 
 
X 
 
 
X 
Pregnancy test (for 
WOCBP)(I) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Safety laboratory 
tests (clinical 
chemistry, CBC, 
lipids, hsCRP)(J) 
X 
X 
 
X 
X 
 
X 
Wks 28, 36 & 44 
only 
(Visits 10, 12 & 
14) 
X 
X 
X 
X 
(minus 
hs-
CRP) 
X 
BKV, CMV & EBV, 
DNA Viral PCR 
monitoring 
X 
 
 
X 
X 
 
X 
Wks 28, 36 & 44 
only 
(Visits 10, 12 & 
14) 
X 
X 
 
 
X 
IgG monitoring 
X 
 
 
 
X 
 
 
Wks 24, 36 & 48 
only 
(Visits 9, 12 & 
15) 
 
X 
 
 
X 
DSA MFI scores 
X 
Local 
testing(K) 
X 
 
 
 
 
 
Wk 24 only 
(Visit 9) 
X 
X 
X 
X 
(only 
Q12M) 
X 
DSA titers 
 
X 
 
 
 
 
 
 
X 
X 
 
 
 


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Procedures 
Screening(A) 
Treatment Period: Clazakizumab Q4W SC Injection (Until Discontinuation of IP, Withdrawal from Study, Allograft Loss, Death, or Common 
Treatment End Date, whichever occurs first)(A) 
Up to 
-42 Days 
+2 days 
Day 1(A) 
BL 
Wk 1(C) 
±5 days 
Wk 4(A) & 8 
±5 days 
Wk 12(A) 
±5 days 
Wk 16 
±5 days 
Wk 20 
±5 days 
Wk 24(A), 28, 32, 
36, 40, 44, 48(A) 
 ±5 days 
Wk 52(A) 
±5 days 
EOT / Early 
Withdrawal 
Visit(A,B) 
SF 
Visits(B) 
Q6M 
after 
DC of 
IP(B) 
CTED 
Visit(B) 
Visit 1 
Visit 2 
Visit 3 
Visit 4, 5 
Visit 6 
Visit 7 
Visit 8 
Visits 9 to 15 
Visit 16 
Renal biopsy  
X(L) 
 
 
 
 
 
 
 
X(M) 
X(N) 
 
 
 
eGFR(O) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UACR(P) 
X 
 
 
 
X 
 
 
Wks 24 & 48 only 
(Visits 9 & 15) 
 
X 
X 
X 
X 
IL-6 levels (total and 
free)  
 
X 
 
 
X 
 
 
Wks 24 & 48 only 
(Visits 9 & 15) 
 
X 
X 
 
X 
MPA levels(Q) 
 
X 
As clinically indicated per investigator discretion. 
X 
 
 
X 
CNI levels(R) 
 
X 
X 
X 
X 
 
X 
Wks 28, 36 & 44 
only 
(Visits 10, 12 & 
14) 
X 
X 
 
 
X 
Adverse event / 
concomitant 
medication monitoring 
X(S) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
Clazakizumab drug 
levels and anti-
clazakizumab 
antibodies(T) 
 
X 
 
 
X 
 
 
Wks 24 & 48 only 
(Visits 9 & 15) 
 
X 
X 
 
X 
Prophylactic 
antibiotic(U) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
EQ-5D-5L, KDQoL-
36, and FACIT 
Fatigue Scale(V) 
 
X 
 
 
 
 
 
 Wk 24 only (Visit 
9) 
X 
X 
 
X 
X 
Clazakizumab /  
placebo injection(W) 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
 


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Study Number: 
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Page 46 of 185 
Date: 10 July 2023 
Confidential 
AE = adverse event; AKI = acute kidney injury; BKV = polyoma BK virus; BL = Baseline; CBC = complete blood cell count; CMV = cytomegalovirus; CNI = calcineurin inhibitor; CRO = contract 
research organization; CTED = common treatment end date; CTEV = common treatment end visit; CXR = chest X-ray; DSA = donor-specific antibodies; EBV = Epstein-Barr virus; ECG = 
electrocardiogram; eCOA = electronic clinical outcomes assessment; eGFR = estimated glomerular filtration rate; EOT = End of Treatment; EQ-5D-5L = EuroQol-5 Dimensions – 5 Levels; 
FACIT Fatigue Scale = Functional Assessment of Chronic Illness Therapy-Fatigue Scale; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; 
HLA = human leukocyte antigen; hsCRP = high-sensitivity C-reactive protein; HRQoL = health-related quality of life; ICF = informed consent form; IgG = immunoglobulin G; IL-6 = 
interleukin 6; IP = investigational product; KDQoL36 = Kidney Disease Quality of Life Questionnaire 36; MDRD4 = Modification of Diet in Renal Disease 4; MFI = mean fluorescence 
intensity; MMF = mycophenolate mofetil; MPA = mycophenolate / mycophenolic acid; PCR = polymerase chain reaction; PJP = pneumocystis jiroveci pneumonia; Q4W = once every 4 weeks; 
Q6M = every 6 months; Q12M = every 12 months; RNA = ribonucleic acid; SAE = serious adverse event; SF= safety follow-up; SOE = schedule of events; TB = tuberculosis; UACR = urine 
albumin creatinine ratio; Wk = Week; WOCBP = women of childbearing potential. 
Notes: During the Treatment Period, blood and urine samples should be collected prior to IP dosing at the clinic visit. Except where indicated otherwise, all samples will be analyzed by the central 
laboratory. 
 
A. 
At some sites, home / workplace visits may be offered as an option instead of in-clinic visits for certain visits during the Treatment Period. This service may not be available for all subjects at all 
sites. In Year 1 of the study, in-clinic visits are mandatory at Visit 1 (Screening), Visit 2 (Baseline; Day 1), Visit 4 (Wk 4), Visit 6 (Wk 12), Visit 9 (Wk 24), Visit 15 (Wk 48), and Visit 16 
(Wk 52). An in-clinic visit is required at EOT / Early Withdrawal; if a subject meets the primary efficacy endpoint (composite all-cause allograft loss or irreversible loss of allograft function); and, 
at the discretion of the Investigator, if clinically indicated (eg, because of an AE). Other scheduled visits can be home / workplace visits. 
B. 
All early withdrawal subjects and subjects who permanently discontinued IP treatment due to loss of their allograft, will undergo all assessments per the EOT / Early Withdrawal Visit schedule. 
Subjects who permanently discontinued treatment with IP for any reason and who have not reached an endpoint of allograft loss, defined as an eGFR < 15 mL/min/1.73 m2*, return to dialysis*, 
allograft nephrectomy, retransplantation, or death from any cause or subjects with a sustained (≥ 60 days) 40% decline in eGFR from Baseline who discontinued IP for any reason will not be 
withdrawn; they will remain in the study as described in Section 9.2.5.3. *total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days. Following the EOT / 
Early Withdrawal Visit, subjects will be asked to return for 2 in-clinic Safety Follow-up Visits, 3 and 5 months after receiving the last dose of IP. (Note: DSA MFI Scores, UACR, and IL-6 levels 
are not required at the 3-month Safety Follow-up Visit). In addition, all subjects will be contacted by telephone call 1, 2, and 4 months after the last dose of IP for monitoring for new AEs, SAEs, 
or pregnancies. Thereafter, the subject will be asked to return in 6-month intervals until the CTED is reached to collect renal function and allograft status data. If a subject is unable to return for 6-
monthly follow-up visits, he / she will be asked to agree to be contacted at CTED to collect allograft and survival status. The common treatment end visit (CTEV) will be performed within 4 weeks 
after the CTED is reached. 
C. 
This visit is required only if the subject is taking a CNI. 
D. 
Informed consent to be signed before any study-related procedures, including washout of prohibited medications. If consent is signed more than 30 days before Screening, it must be re-signed and 
re-dated at Screening to reaffirm the subject’s continued interest to participate in the study. The Screening Period starts on the date the first Screening assessment is completed after signing the ICF. 
E. 
A complete physical examination, including chest X-ray, and medical history, including historical serology for vital infections should be performed to evaluate exposure to TB and whether 
subjects with a history of latent TB (without active TB) completed a documented course of prophylactic treatment. If a positive result is obtained for the interferon-γ-release assay, the test should 
not be repeated. For an indeterminate result, the assay may be repeated 1 time. If the second test is positive or indeterminate, the result should be considered positive for that subject. A third test 
may not be performed. Note: local QuantiFERON-TB Gold testing is acceptable. 
F. 
Subjects must have a negative rapid antigen test or PCR test result during the Screening Period as near to the Day 1 Baseline Visit (Visit 2) as possible. If the subject is unwell with symptoms 
suggestive of COVID-19 but rapid antigen test or PCR test result is negative, other causes for symptoms must be ruled out to determine subject eligibility. Subjects must be without symptoms 
attributable to COVID-19 for at least 1 month prior to the start of Screening. Additional testing during the trial may be performed at the discretion of the Investigator if clinically indicated. 
G. 
Urinalysis dipstick (chemical profile) with optional microscopic profile if dipstick is abnormal. 
H. 
Height will be included at Visit 1 only. 
I. 
Urinary pregnancy test prior to every dose of IP. For subjects who permanently discontinued treatment with IP, this assessment will be conducted monthly for an additional 5 months following the 
last dose of IP. Positive urine tests will be confirmed by a serum pregnancy test that is analyzed at the central laboratory. 
J. 
Fasting for a minimum of 10 hours is required for determination of fasting glucose and for lipids / triglycerides. If the subject failed to fast, samples should still be collected and processed with 
failure to fast recorded on the laboratory requisition and also recorded as a protocol deviation. Note: glucose and lipids / triglycerides will not be assessed at Visit 1. See Table 8 for details 
regarding the required assessments. 
K. 
If the presence of HLA DSA has been confirmed within 6 months prior to the start of Screening, the test does not need to be repeated for eligibility. Rather, sites will submit the historical, local 
laboratory DSA results for review by the central HLA reviewer to confirm eligibility for entry into the study. If DSA has not been confirmed within 6 months prior to the start of Screening, local 
laboratory DSA testing should be performed, and the results submitted for review by the central HLA reviewer. If the central HLA reviewer disagrees with the local laboratory results, the central 
laboratory may repeat the Screening DSA test once; the repeat results must be reviewed by the central HLA reviewer to confirm DSA eligibility criteria. If local DSA testing is not available, a 
sample should be submitted to the central laboratory for analysis. 


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Study Number: 
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Study Product: 
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Page 47 of 185 
Date: 10 July 2023 
Confidential 
L. 
The local pathologist’s diagnosis must be reviewed by a central pathologist to confirm eligibility for entry into the study. If treatment for ABMR (including CABMR) or TCMR (other than 
steroids*) was given between 3 to 12 months of Screening, a repeat kidney biopsy and DSA analysis are required at least 6 weeks after the end of treatment to confirm continuing CABMR and 
presence of HLA DSA and to determine eligibility. 
M. 
At Wk 52 (Visit 16 [window -2 weeks to +6 weeks]). If clinically indicated, an unscheduled biopsy may be performed at any time. If a for-cause biopsy has been performed within 2 months of 
Wk 52, a repeat biopsy at Wk 52 is not required. Subjects who withdraw from the study on or after Visit 6 (Wk 12) and prior to Visit 16 (Wk 52; and the subject has not had a biopsy within this 
period) should have a biopsy performed as part of the EOT / Early withdrawal assessments. 
N. 
EOT renal biopsy required if the subject withdraws on or after Visit 6 (Wk 12) and prior to Visit 16 (Wk 52), and the subject has not had a biopsy within this period. 
O. 
The MDRD4 equation will be used for determination of eGFR. Baseline eGFR is defined as an average of 2 pre-treatment measurements up to 8 weeks apart. If the eGFR < 15 mL/min/1.73 m2 is 
the only component reached, the value must be sustained over at least 60 days and must be confirmed by a repeat measurement after ≥60 days from the date of the first measurement.The 
confirmatory measurement of eGFR < 15 mL/min/1.73 m2 done at least 60 days from the initial measurement must be processed by the central laboratory. 
P. 
UACR determined using spot urine test. At Screening, if spot UACR is above the defined limits, a single repeat test can be performed on a separate day to confirm ineligibility. 
Q. 
As clinically indicated per investigator discretion; only for subjects taking concomitant MMF / MPA. At relevant visits, treatment with MMF / MPA is to be withheld until after collection of the 
blood sample for determination of MPA levels. 
R. 
Required only for subjects taking a concomitant CNI. CNI trough levels will be monitored at Year 1: Visits 2 (Baseline) through 6, 8, 10, 12, 14, and 16; Year 2 through EOT: every second visit 
(Q8W) starting with Visit 18 through the EOT / Early Withdrawal Visit. CNIs will also be monitored every 2 weeks following a change in CNI dose, withholding, discontinuation, or restarting of 
IP, until target CNI trough levels are achieved. After Year 1, CNI levels may be checked per local practice through local laboratories, including being a part of evaluating any significant changes in 
creatinine. Locally drawn CNI levels may qualify for monitoring if drawn within the specified interval of ± 2 weeks. With prior alignment and permission from CSLB, CNI monitoring may be 
conducted locally during Year 1. If monitored locally during Year 1, CNI monitoring should be conducted at the same laboratory throughout the study, ie beginning from and including the 
Baseline CNI level. Also, if CNI monitoring is conducted locally in Year 1, a sample should be drawn and submitted to the central laboratory each time CNI levels are assessed as per the schedule 
described in the SOE. At relevant visits, CNIs are to be withheld until after collection of the blood sample for determination of CNI trough levels. 
S. 
AEs occurring during the Screening Period are to be recorded as medical history. Any AE that meets the definition of an SAE must also be immediately reported to CSL Behring (or its delegate; 
eg, CRO) within 24 hours of site awareness. 
T. 
Not required if the subject has been permanently discontinued from treatment with IP. For subjects participating in the PK / PD Substudy, additional samples will be collected as per Table 3. All 
PK samples will be drawn prior to administration of IP, except for those specified in the PK / PD Substudy. For subjects that go on to receive IVIG, additional PK samples will be collected (see 
Table 9). 
U. 
All subjects will be required to take prophylactic treatment for PJP; these drugs will be prescribed and supplied by the investigational sites. For the first year of the study (ie, from Screening up to 
and including Wk 52), subjects should take trimethoprim / sulfamethoxazole as a single-strength pill (80 mg as trimethoprim) daily or double-strength pill (160 mg as trimethoprim) 3 times per 
week. It is recommended that treatment with trimethoprim / sulfamethoxazole should be started approximately 1 week before the Day 1 Baseline Visit (Visit 2) or dose should be stable at least 1 
week before Screening if the subject is already taking it. If subject is already receiving a suitable Investigator-approved alternative therapy for PJP prophylaxis, the subject should remain on that 
therapy and not start trimethoprim / sulfamethoxazole. Subjects who are intolerant to trimethoprim / sulfamethoxazole and not already receiving an Investigator-approved alternative therapy should 
be started on atovaquone (mepron), inhaled pentamidine, or oral dapsone for approximately 1 week before the Day 1 Baseline Visit (Visit 2) based on consultation with the Medical Monitor. In the 
event of AKI (eg, interstitial nephritis) considered related to trimethoprim / sulfamethoxazole, prophylactic treatment with this drug should be discontinued, and the subject should be started on 
another antibiotic therapy for PJP prophylaxis (see Section 7.1.3.2). In the event of other serious adverse reactions, the Medical Monitor should be consulted with respect to discontinuing 
prophylactic treatment or switching to another prophylactic treatment. 
V. 
EQ-5D-5L, KDQoL-36, and FACIT Fatigue questionnaires will be completed by subjects using an eCoA solution whether at the study site or during a home visit. Subjects who are randomized 
before the availability of the eCOA solution will not complete HRQoL questionnaires. 
W. Throughout the Treatment Period, subjects will return to the clinic Q4W for investigational treatment with clazakizumab / placebo until the subject permanently discontinues IP, withdraws from 
the study, experiences allograft loss, dies, or reaches the CTED, whichever occurs first. Note: as detailed in Footnote A, home / workplace visits may be offered as an option instead of in-clinic 
visits for certain visits during the treatment phase (at some sites only). 
 


CSL Behring 
Study Number: 
CSL300_3001 
 
Study Product: 
CSL300, clazakizumab  
 
Protocol version: Amendment 9 
 
Page 48 of 185 
Date: 10 July 2023 
Confidential 
Table 2 
Schedule of Events for Year 2 to the Safety Follow-up Visit / Common Treatment End VisitN 
Procedures 
Clazakizumab Q4W SC Injection (Until Discontinuation of IP, Withdrawal from Study, Allograft Loss, Death, or Common Treatment End Date, 
whichever occurs first)(A) 
Year 2 & 
Year 6 
Wk 56, 
264 
±5 days 
(V17, 
V69) 
Wk 60, 
268(A) 
±5 days 
(V18, 
V70) 
Wk 64 
+272 
±5 days 
(V19, 
V71) 
Wk 68 
+ 276 
±5 days 
(V20, 
V72) 
Wk 
72(A) + 
280 
±5 days 
(V21, 
V73) 
Wk 76(A) 
+ 284 
±5 days 
(V22, 
V74) 
Wk 80 
+ 288 
±5 days 
(V23, 
V75) 
Wk 84 
+ 292(A) 
±5 days 
(V24, 
V76) 
Wk 88 
+ 296 
±5 days 
(V25, 
V77) 
Wk 92 
+ 300,  
±5 days 
(V26, 
V78) 
Wk 96 + 
304  
±5 days 
(V27, 
V79) 
Wk 100(A) 
+ 308  
±5 days 
(V28, 
V80) 
Wk 104 
+ 312 
±5 days 
(V29, 
V81) 
 
 
EOT /  
Early 
With- 
drawal 
Visit 
(A,B) 
SF 
Visits 
(B) 
Q6M 
after 
DC(B) 
CTED 
Visit(B) 
Year 3 & 
Year 7 
 
Wk 
108, 
316(A) 
±5 days 
(V30, 
V82) 
Wk 112 
+ 320 
±5 days 
(V31, 
V83) 
Wk 116 
+ 324 
±5 days 
(V32, 
V84) 
Wk 120 
+ 328 
±5 days 
(V33, 
V85) 
Wk 
124(A)+ 
332 
±5 days 
(V34, 
V86) 
Wk 128 
+ 336 
±5 days 
(V35, 
V87) 
Wk 132 
+ 340(A) 
±5 days 
(V36, 
V88) 
Wk 136 
+ 344 
±5 days 
(V37, 
V89) 
Wk 140 
+ 348 
 ±5 days 
(V38, 
V90) 
Wk 144 
+ 352 
 ±5 days 
(V39, 
V91) 
Wk 148(A) 
+ 356  
±5 days 
(V40, 
V92) 
Wk 152 
+360 
±5 days 
(V41, 
V93) 
Wk 156 
+ 364(A) 
±5 days 
(V42, 
V94) 
Year 4 
 
Wk 160 
±5 days 
(V43) 
Wk 164 
±5 days 
(V44) 
Wk 168 
±5 days 
(V45) 
Wk 
172(A) 
±5 days 
(V46) 
Wk 176 
±5 days 
(V47) 
Wk 180 
±5 days 
(V48) 
Wk 184 
±5 days 
(V49) 
Wk 188 
±5 days 
(V50) 
Wk 192 
±5 days 
(V51) 
Wk 196(A) 
±5 days 
(V52) 
Wk 200 
±5 days 
(V53) 
Wk 204 
±5 days 
(V54) 
Wk 208 
±5 days 
(V55) 
Year 5 
 
Wk 212 
±5 days 
(V56) 
Wk 216 
±5 days 
(V57) 
Wk 
220(A) 
±5 days 
(V58) 
Wk 224 
±5 days 
(V59) 
Wk 228 
±5 days 
(V60) 
Wk 232 
±5 days 
(V61) 
Wk 236 
±5 days 
(V62) 
Wk 240 
±5 days 
(V63) 
Wk 244(A) 
±5 days 
(64) 
Wk 248 
±5 days 
(V65) 
Wk 252 
±5 days 
(V66) 
Wk 256 
±5 days 
(V67) 
Wk 260 
±5 days 
(V68) ( N) 
Clazakizumab / 
placebo 
injection(C) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Abbreviated 
physical 
examination(D) 
and vital signs 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
 
 
X 
12-lead ECG 
 
 
 
 
 
 
 
 
 
 
 
Wk 100 
(V28) 
Wk 308 
(V80) 
 
Wk 156 
(V42) 
Wk 204 
(V54) 
Wk 364 
(V94) 
 
X 
X 
 
 
X 
Pregnancy test 
(for 
WOCBP)(E) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 


CSL Behring 
Study Number: 
CSL300_3001 
 
Study Product: 
CSL300, clazakizumab  
 
Protocol version: Amendment 9 
 
Page 49 of 185 
Date: 10 July 2023 
Confidential 
Procedures 
Clazakizumab Q4W SC Injection (Until Discontinuation of IP, Withdrawal from Study, Allograft Loss, Death, or Common Treatment End Date, 
whichever occurs first)(A) 
Year 2 & 
Year 6 
Wk 56, 
264 
±5 days 
(V17, 
V69) 
Wk 60, 
268(A) 
±5 days 
(V18, 
V70) 
Wk 64 
+272 
±5 days 
(V19, 
V71) 
Wk 68 
+ 276 
±5 days 
(V20, 
V72) 
Wk 
72(A) + 
280 
±5 days 
(V21, 
V73) 
Wk 76(A) 
+ 284 
±5 days 
(V22, 
V74) 
Wk 80 
+ 288 
±5 days 
(V23, 
V75) 
Wk 84 
+ 292(A) 
±5 days 
(V24, 
V76) 
Wk 88 
+ 296 
±5 days 
(V25, 
V77) 
Wk 92 
+ 300,  
±5 days 
(V26, 
V78) 
Wk 96 + 
304  
±5 days 
(V27, 
V79) 
Wk 100(A) 
+ 308  
±5 days 
(V28, 
V80) 
Wk 104 
+ 312 
±5 days 
(V29, 
V81) 
 
 
EOT /  
Early 
With- 
drawal 
Visit 
(A,B) 
SF 
Visits 
(B) 
Q6M 
after 
DC(B) 
CTED 
Visit(B) 
Year 3 & 
Year 7 
 
Wk 
108, 
316(A) 
±5 days 
(V30, 
V82) 
Wk 112 
+ 320 
±5 days 
(V31, 
V83) 
Wk 116 
+ 324 
±5 days 
(V32, 
V84) 
Wk 120 
+ 328 
±5 days 
(V33, 
V85) 
Wk 
124(A)+ 
332 
±5 days 
(V34, 
V86) 
Wk 128 
+ 336 
±5 days 
(V35, 
V87) 
Wk 132 
+ 340(A) 
±5 days 
(V36, 
V88) 
Wk 136 
+ 344 
±5 days 
(V37, 
V89) 
Wk 140 
+ 348 
 ±5 days 
(V38, 
V90) 
Wk 144 
+ 352 
 ±5 days 
(V39, 
V91) 
Wk 148(A) 
+ 356  
±5 days 
(V40, 
V92) 
Wk 152 
+360 
±5 days 
(V41, 
V93) 
Wk 156 
+ 364(A) 
±5 days 
(V42, 
V94) 
Year 4 
 
Wk 160 
±5 days 
(V43) 
Wk 164 
±5 days 
(V44) 
Wk 168 
±5 days 
(V45) 
Wk 
172(A) 
±5 days 
(V46) 
Wk 176 
±5 days 
(V47) 
Wk 180 
±5 days 
(V48) 
Wk 184 
±5 days 
(V49) 
Wk 188 
±5 days 
(V50) 
Wk 192 
±5 days 
(V51) 
Wk 196(A) 
±5 days 
(V52) 
Wk 200 
±5 days 
(V53) 
Wk 204 
±5 days 
(V54) 
Wk 208 
±5 days 
(V55) 
Year 5 
 
Wk 212 
±5 days 
(V56) 
Wk 216 
±5 days 
(V57) 
Wk 
220(A) 
±5 days 
(V58) 
Wk 224 
±5 days 
(V59) 
Wk 228 
±5 days 
(V60) 
Wk 232 
±5 days 
(V61) 
Wk 236 
±5 days 
(V62) 
Wk 240 
±5 days 
(V63) 
Wk 244(A) 
±5 days 
(64) 
Wk 248 
±5 days 
(V65) 
Wk 252 
±5 days 
(V66) 
Wk 256 
±5 days 
(V67) 
Wk 260 
±5 days 
(V68) ( N) 
 
 
Safety 
laboratory 
tests (clinical 
chemistry, 
CBC, lipids, 
hsCRP)(F) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
(minus 
hs-
CRP) 
X 
BKV, CMV & 
EBV, DNA 
Viral PCR 
monitoring 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
IgG 
monitoring 
 
X 
 
 
 
X 
 
 
 
X  
 
 
 
X 
 
 
X 
 
 
X 
DSA MFI 
scores  
 
 
 
 
 
 
 
 
 
 
 
Wk 100 
(V28), 
Wk 308 
(V80) 
 
Wks 156, 
204, & 
364 (V42, 
54, & 94) 
 
X 
X 
X 
X (only 
Q12M) 
X 


CSL Behring 
Study Number: 
CSL300_3001 
 
Study Product: 
CSL300, clazakizumab  
 
Protocol version: Amendment 9 
 
Page 50 of 185 
Date: 10 July 2023 
Confidential 
Procedures 
Clazakizumab Q4W SC Injection (Until Discontinuation of IP, Withdrawal from Study, Allograft Loss, Death, or Common Treatment End Date, 
whichever occurs first)(A) 
Year 2 & 
Year 6 
Wk 56, 
264 
±5 days 
(V17, 
V69) 
Wk 60, 
268(A) 
±5 days 
(V18, 
V70) 
Wk 64 
+272 
±5 days 
(V19, 
V71) 
Wk 68 
+ 276 
±5 days 
(V20, 
V72) 
Wk 
72(A) + 
280 
±5 days 
(V21, 
V73) 
Wk 76(A) 
+ 284 
±5 days 
(V22, 
V74) 
Wk 80 
+ 288 
±5 days 
(V23, 
V75) 
Wk 84 
+ 292(A) 
±5 days 
(V24, 
V76) 
Wk 88 
+ 296 
±5 days 
(V25, 
V77) 
Wk 92 
+ 300,  
±5 days 
(V26, 
V78) 
Wk 96 + 
304  
±5 days 
(V27, 
V79) 
Wk 100(A) 
+ 308  
±5 days 
(V28, 
V80) 
Wk 104 
+ 312 
±5 days 
(V29, 
V81) 
 
 
EOT /  
Early 
With- 
drawal 
Visit 
(A,B) 
SF 
Visits 
(B) 
Q6M 
after 
DC(B) 
CTED 
Visit(B) 
Year 3 & 
Year 7 
 
Wk 
108, 
316(A) 
±5 days 
(V30, 
V82) 
Wk 112 
+ 320 
±5 days 
(V31, 
V83) 
Wk 116 
+ 324 
±5 days 
(V32, 
V84) 
Wk 120 
+ 328 
±5 days 
(V33, 
V85) 
Wk 
124(A)+ 
332 
±5 days 
(V34, 
V86) 
Wk 128 
+ 336 
±5 days 
(V35, 
V87) 
Wk 132 
+ 340(A) 
±5 days 
(V36, 
V88) 
Wk 136 
+ 344 
±5 days 
(V37, 
V89) 
Wk 140 
+ 348 
 ±5 days 
(V38, 
V90) 
Wk 144 
+ 352 
 ±5 days 
(V39, 
V91) 
Wk 148(A) 
+ 356  
±5 days 
(V40, 
V92) 
Wk 152 
+360 
±5 days 
(V41, 
V93) 
Wk 156 
+ 364(A) 
±5 days 
(V42, 
V94) 
Year 4 
 
Wk 160 
±5 days 
(V43) 
Wk 164 
±5 days 
(V44) 
Wk 168 
±5 days 
(V45) 
Wk 
172(A) 
±5 days 
(V46) 
Wk 176 
±5 days 
(V47) 
Wk 180 
±5 days 
(V48) 
Wk 184 
±5 days 
(V49) 
Wk 188 
±5 days 
(V50) 
Wk 192 
±5 days 
(V51) 
Wk 196(A) 
±5 days 
(V52) 
Wk 200 
±5 days 
(V53) 
Wk 204 
±5 days 
(V54) 
Wk 208 
±5 days 
(V55) 
Year 5 
 
Wk 212 
±5 days 
(V56) 
Wk 216 
±5 days 
(V57) 
Wk 
220(A) 
±5 days 
(V58) 
Wk 224 
±5 days 
(V59) 
Wk 228 
±5 days 
(V60) 
Wk 232 
±5 days 
(V61) 
Wk 236 
±5 days 
(V62) 
Wk 240 
±5 days 
(V63) 
Wk 244(A) 
±5 days 
(64) 
Wk 248 
±5 days 
(V65) 
Wk 252 
±5 days 
(V66) 
Wk 256 
±5 days 
(V67) 
Wk 260 
±5 days 
(V68) ( N) 
eGFR(G) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
UACR(H) 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
IL-6 levels 
(total and free) 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
MPA levels(I) 
As clinically indicated as per investigator discretion. 
X 
 
 
X 
CNI levels(J) 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
 
X 
Adverse event 
/ concomitant 
medication 
monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 


CSL Behring 
Study Number: 
CSL300_3001 
 
Study Product: 
CSL300, clazakizumab  
 
Protocol version: Amendment 9 
 
Page 51 of 185 
Date: 10 July 2023 
Confidential 
Procedures 
Clazakizumab Q4W SC Injection (Until Discontinuation of IP, Withdrawal from Study, Allograft Loss, Death, or Common Treatment End Date, 
whichever occurs first)(A) 
Year 2 & 
Year 6 
Wk 56, 
264 
±5 days 
(V17, 
V69) 
Wk 60, 
268(A) 
±5 days 
(V18, 
V70) 
Wk 64 
+272 
±5 days 
(V19, 
V71) 
Wk 68 
+ 276 
±5 days 
(V20, 
V72) 
Wk 
72(A) + 
280 
±5 days 
(V21, 
V73) 
Wk 76(A) 
+ 284 
±5 days 
(V22, 
V74) 
Wk 80 
+ 288 
±5 days 
(V23, 
V75) 
Wk 84 
+ 292(A) 
±5 days 
(V24, 
V76) 
Wk 88 
+ 296 
±5 days 
(V25, 
V77) 
Wk 92 
+ 300,  
±5 days 
(V26, 
V78) 
Wk 96 + 
304  
±5 days 
(V27, 
V79) 
Wk 100(A) 
+ 308  
±5 days 
(V28, 
V80) 
Wk 104 
+ 312 
±5 days 
(V29, 
V81) 
 
 
EOT /  
Early 
With- 
drawal 
Visit 
(A,B) 
SF 
Visits 
(B) 
Q6M 
after 
DC(B) 
CTED 
Visit(B) 
Year 3 & 
Year 7 
 
Wk 
108, 
316(A) 
±5 days 
(V30, 
V82) 
Wk 112 
+ 320 
±5 days 
(V31, 
V83) 
Wk 116 
+ 324 
±5 days 
(V32, 
V84) 
Wk 120 
+ 328 
±5 days 
(V33, 
V85) 
Wk 
124(A)+ 
332 
±5 days 
(V34, 
V86) 
Wk 128 
+ 336 
±5 days 
(V35, 
V87) 
Wk 132 
+ 340(A) 
±5 days 
(V36, 
V88) 
Wk 136 
+ 344 
±5 days 
(V37, 
V89) 
Wk 140 
+ 348 
 ±5 days 
(V38, 
V90) 
Wk 144 
+ 352 
 ±5 days 
(V39, 
V91) 
Wk 148(A) 
+ 356  
±5 days 
(V40, 
V92) 
Wk 152 
+360 
±5 days 
(V41, 
V93) 
Wk 156 
+ 364(A) 
±5 days 
(V42, 
V94) 
Year 4 
 
Wk 160 
±5 days 
(V43) 
Wk 164 
±5 days 
(V44) 
Wk 168 
±5 days 
(V45) 
Wk 
172(A) 
±5 days 
(V46) 
Wk 176 
±5 days 
(V47) 
Wk 180 
±5 days 
(V48) 
Wk 184 
±5 days 
(V49) 
Wk 188 
±5 days 
(V50) 
Wk 192 
±5 days 
(V51) 
Wk 196(A) 
±5 days 
(V52) 
Wk 200 
±5 days 
(V53) 
Wk 204 
±5 days 
(V54) 
Wk 208 
±5 days 
(V55) 
Year 5 
 
Wk 212 
±5 days 
(V56) 
Wk 216 
±5 days 
(V57) 
Wk 
220(A) 
±5 days 
(V58) 
Wk 224 
±5 days 
(V59) 
Wk 228 
±5 days 
(V60) 
Wk 232 
±5 days 
(V61) 
Wk 236 
±5 days 
(V62) 
Wk 240 
±5 days 
(V63) 
Wk 244(A) 
±5 days 
(64) 
Wk 248 
±5 days 
(V65) 
Wk 252 
±5 days 
(V66) 
Wk 256 
±5 days 
(V67) 
Wk 260 
±5 days 
(V68) ( N) 
Clazakizumab 
drug levels and 
anti-
clazakizumab 
antibodies(K) 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
X 
 
X 
Prophylactic 
antibiotic(L) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
EQ-5D-5L, 
KDQoL-36, 
and FACIT 
Fatigue Scale 
(M) 
 
 
 
 
 
 
Wk 80 
only 
(V23) 
 
 
 
 
 
Wk 104 
(V29) + 
Wk 312 
(V81) 
Wk 156 
(V42) + 
Wk 364 
(V94) 
Wk 208 
(V55) 
X 
X 
 
X 
X 


CSL Behring 
Study Number: 
CSL300_3001 
 
Study Product: 
CSL300, clazakizumab  
 
Protocol version: Amendment 9 
 
Page 52 of 185 
Date: 10 July 2023 
Confidential 
AE = adverse event; BKV = polyoma BK virus; CBC = complete blood cell count; CMV = cytomegalovirus; CNI= calcineurin inhibitor;CTED = common treatment end date; CTEV = common 
treatment end visit; DNA = deoxyribonucleic acid; DSA = donor-specific antibodies; EBV = Epstein-Barr virus; ECG = electrocardiogram; eCOA = electronic clinical outcomes assessment; eCRF 
= electronic case report form; eGFR = estimated glomerular filtration rate; EOT = End of Treatment; EQ-5D-5L = EuroQol-5 Dimensions – 5 Levels; FACIT Fatigue = Functional Assessment of 
Chronic Illness Therapy-Fatigue Scale; hsCRP = high-sensitivity C-reactive protein; HRQoL = health-related quality of life; IgG = Immunoglobulin G; IL6 = Interleukin 6; IP = investigational 
product; KDQoL36 = Kidney Disease Quality of Life Questionnaire 36; MDRD4=Modification of Diet in Renal Disease 4; MFI = Mean fluorescence intensity; MMF = Mycophenolate mofetilt; 
MPA = mycophenolate / mycophenolic acid; PCR = polymerase chain reaction; PJP = pneumocystis jiroveci pneumonia; Q4W = once every 4 weeks; Q6M = every 6 months; Q12M = every 12 
months; SAE = serious adverse event; SF= safety follow-up; SFV = safety follow-up visit; SOE = schedule of events; UACR = urine albumin creatinine ratio; V = visit; Wk = Week; WOCBP = 
women of childbearing potential. 
Notes: During the Treatment Period, blood and urine samples should be collected prior to dosing at the clinic visit. Unscheduled visits may be performed during the course of the study for safety 
reasons. 
A. At some sites, home / workplace visits may be offered as an option instead of in-clinic visits for certain visits during the Treatment Period. This service may not be available for all subjects at all 
sites. In Year 2 to SFV, in-clinic visits are required approximately every 6 months (ie, at Visit 22 [Wk 76], Visit 28 [Week 100], Visit 34 [Week 124], Visit 40 [Week 148], Visit 46 [Week 172], 
Visit 52 [Week 196], Visit 58 [Week 220], Visit 64 [Week 244], Visit 70 [Week 268], Visit 76 [Week 292], Visit 82 [Week 316], Visit 88 [Week 340], and Visit 94 (Week 364]). An in-clinic visit is 
required at EOT / Early Withdrawal; if a subject meets the primary efficacy endpoint (composite all-cause allograft loss or irreversible loss of allograft function); and, at the discretion of the 
Investigator, if clinically indicated (eg, because of an AE). Other scheduled visits can be home / workplace visits. 
B. All early withdrawal subjects and subjects who permanently discontinued IP treatment due to loss of their allograft, will undergo all assessments per the EOT / Early Withdrawal Visit schedule. 
Subjects who permanently discontinued treatment with IP for any reason and who have not reached an endpoint of allograft loss, defined as an eGFR < 15 mL/min/1.73 m2*, return to dialysis*, 
allograft nephrectomy, retransplantation, or death from any cause or subjects with a sustained (≥ 60 days) 40% decline in eGFR from Baseline who discontinue IP for any reason, will not be 
withdrawn; they will remain in the study as described in Section 9.2.5.3. *total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days. Following the EOT / 
Early Withdrawal Visit, subjects will be asked to return for 2 in-clinic Safety Follow-up Visits, 3 and 5 months after receiving the last dose of IP. (Note: DSA MFI Scores, UACR, and IL-6 levels 
are not required at the 3-month Safety Follow-up Visit). In addition, all subjects will be contacted by telephone call (TC) 1, 2, and 4 months after the last dose of IP for monitoring for new AEs, 
SAEs, or pregnancies. Thereafter, the subject will be asked to return in 6-month intervals until the CTED is reached to collect renal function and allograft status data. If a subject is unable to return 
for 6-monthly follow-up visits, he / she will be asked to agree to be contacted at CTED to collect allograft and survival status. The CTEV will be performed within 4 weeks after the CTED is 
reached. 
C. Throughout the Treatment Period, subjects will return to the clinic Q4W for treatment with IP until the subject discontinues IP, withdraws from the study, experiences allograft loss, dies, or the 
reached CTED, whichever occurs first. Note: as detailed in Footnote A, home / workplace visits may be offered as an option instead of in-clinic visits for certain visits during the treatment phase (at 
some sites only). 
D. Height will be included at Visit 1 only. 
E. Urinary pregnancy test prior to every dose of IP. For subjects who permanently discontinued investigational treatment with clazakizumab / placebo, this assessment will be conducted monthly for an 
additional 5 months following the last dose of IP. Positive urine tests will be confirmed by a serum pregnancy test that is analyzed at the central laboratory. 
F. Fasting for a minimum of 10 hours is required for the determination of fasting glucose and for lipids / triglycerides. If the subject failed to fast, samples should still be collected and processed with 
failure to fast recorded on the laboratory requisition and also recorded as a protocol deviation. See Table 8 for details regarding the required assessments. 
G. The MDRD4 equation will be used for determination of eGFR. Baseline eGFR is defined as an average of 2 pre-treatment measurements up to 8 weeks apart. If the eGFR < 15 mL/min/1.73 m2 is 
the only component reached, the value must be sustained over at least 60 days and must be confirmed by a repeat measurement after ≥60 days from the date of the first measurement. The 
confirmatory measurement of eGFR < 15 mL/min/1.73 m2 done at least 60 days from the initial measurement must be processed by the central laboratory. 
H. UACR determined using spot urine test. 
I 
As clinically indicated per investigator discretion; only for subjects taking concomitant MMF / MPA. At relevant visits, treatment with MMF / MPA is to be withheld until after collection of the 
blood sample for determination of MPA levels. 
J. 
Required only for subjects taking a concomitant CNI. CNI trough levels will be monitored at Year 1: Visits 2 (Baseline) through 6, 8, 10, 12, 14, and 16; Year 2 through EOT: every second visit 
(Q8W) starting with Visit 18 through the EOT / Early Withdrawal Visit. CNIs will also be monitored every 2 weeks following a change in CNI dose, withholding, discontinuation, or restarting of 
IP, until target CNI trough levels are achieved. With prior alignment and permission from CSLB, CNI monitoring may be conducted locally during Year 1. If monitored locally during Year 1, CNI 
monitoring should be conducted at the same laboratory throughout the study, ie beginning from and including the Baseline CNI level. Also, if CNI monitoring is conducted locally in Year 1, a 
sample should be drawn and submitted to the central laboratory each time CNI levels are assessed as per the schedule described in the SOE. After Year 1, CNI levels may be checked per local 
practice through local laboratories, including being a part of evaluating any significant changes in creatinine. Locally drawn CNI levels may qualify for monitoring if drawn within the specified 
interval of ± 2 weeks. At relevant visits, CNIs are to be withheld until after collection of the blood sample for determination of CNI trough levels. 
K. Not required if the subject has been permanently discontinued from treatment with IP. For subjects that go on to receive IVIG, additional PK samples will be collected (see Table 9). 


CSL Behring 
Study Number: 
CSL300_3001 
 
Study Product: 
CSL300, clazakizumab  
 
Protocol version: Amendment 9 
 
Page 53 of 185 
Date: 10 July 2023 
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L. PJP prophylaxis should be continued at the discretion of the Investigator. 
M. EQ-5D-5L, KDQoL-36, and FACIT Fatigue questionnaires will be completed by subjects using an eCoA solution whether at the study site or during a home visit. Subjects who are randomized 
before the availability of the eCOA solution will not complete HRQoL questionnaires. 
N. For those subjects who complete the SOE (through Year 5) and remain on study, the SOE schedule for Year 2 through 5 will repeat ie, Year 6 follows the Year 2 SOE, Year 7 follows the Year 3 
SOE, etc. The first visit in Year 6 is Visit 69 (Week 264). 


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Study Number: 
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Study Product: 
CSL300, clazakizumab  
 
Protocol version: Amendment 9 
 
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Table 3 
Pharmacokinetic / Pharmacodynamic Substudy Schedule of Sample CollectionA,B 
Activity 
Analyte 
Sampling Timepoint 
Timepoint Window 
Week 1 (Day 8) 
Blood Draw 
hsCRP, IL-6, Clazakizumab 
168 hours  
± 24 hours 
Week 4 / Visit 4 (± 1 day) 
Blood Draw 
hsCRPC, IL-6, Clazakizumab 
Predose 
-30 minutes 
SC Administration of Clazakizumab 
 
0 minutes 
NA 
Week 24 / Visit 9 (± 5 days) 
Blood Draw 
hsCRP 
Predose 
-30 minutes 
 
SC Administration of Clazakizumab 
 
0 minutes 
NA 
Blood Draw 
hsCRP, IL-6, Clazakizumab 
72 hours (3 days) after dosing 
± 12 hours 
Blood Draw 
hsCRP, IL-6, Clazakizumab 
120 hours (5 days) after 
dosing 
± 12 hours 
Week 25 
Blood Draw  
hsCRP, IL-6, Clazakizumab 
168 hours (7 days) after 
dosing 
± 24 hours 
Week 26  
Blood Draw 
hsCRP, IL-6, Clazakizumab 
336 hours (14 days) after 
dosing 
± 2 days 
Week 27  
Blood Draw 
hsCRP, IL-6, Clazakizumab 
504 hours (21 days) after 
dosing 
± 2 days 
hsCRP = High-sensitivity C-reactive protein; IL-6 = Interleukin 6; SC = subcutaneous. 
A. 
Participation in the PK / PD Substudy is optional. Subjects participating in the PK / PD Substudy will have these blood samples drawn, in addition to the blood samples drawn 
in the main study. Refer to the Laboratory Manual for additional details on the PK / PD Substudy. 
B. 
Not required if a subject has been permanently discontinued from treatment with IP. 
C. 
hsCRP is included in the safety laboratory tests in Week 4 as described in Table 1.


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Study Number: 
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Table of Contents 
Protocol Synopsis .................................................................................................................... 19 
Schema ..................................................................................................................................... 42 
Schedule of Events................................................................................................................... 43 
Table of Contents ..................................................................................................................... 55 
List of Tables............................................................................................................................ 61 
List of Appendices ................................................................................................................... 62 
List of Abbreviations ............................................................................................................... 63 
1. 
Introduction and Background ........................................................................................ 67 
1.1 
IL-6 and Antibody-mediated Rejection in Kidney Transplant Recipients ................ 67 
1.2 
Clazakizumab – Properties and Mechanism of Action ............................................. 70 
1.3 
Clazakizumab Development Program – Overview .................................................. 70 
1.3.1 
Nonclinical Studies ............................................................................................. 70 
1.3.2 
Clinical Studies ................................................................................................... 71 
2. 
Rationale........................................................................................................................ 73 
3. 
Objectives ...................................................................................................................... 77 
3.1 
Primary Objectives ................................................................................................... 77 
3.2 
Secondary Objectives ............................................................................................... 77 
3.3 
Exploratory Objectives ............................................................................................. 77 
4. 
Investigational Plan ....................................................................................................... 79 
4.1 
Overall Study Design ................................................................................................ 79 
4.1.1 
PK / PD Substudy ............................................................................................... 82 
4.2 
Dose Selection .......................................................................................................... 82 
4.3 
Duration of Subject Participation and Study ............................................................ 84 
4.4 
Access to Study Product After the End of Study ...................................................... 84 
5. 
Selection and Withdrawal of Subjects ........................................................................... 85 
5.1 
Number of Subjects .................................................................................................. 85 
5.2 
Inclusion Criteria ...................................................................................................... 85 
5.3 
Exclusion Criteria ..................................................................................................... 86 
5.4 
Adequate Contraception ........................................................................................... 89 
5.5 
Withdrawal from Study ............................................................................................. 90 
5.6 
Withholding or Permanent Discontinuation of Investigational Product ................... 91 


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5.6.1 
Withholding or Discontinuation of Investigational Product Due to an Adverse 
Event ................................................................................................................... 92 
5.6.2 
Withholding or Discontinuation of Investigational Product Due to Abnormal 
LFTs .................................................................................................................... 92 
5.6.3 
Withholding or Discontinuation of Investigational Product Due to Neutropenia 
and / or Thrombocytopenia ................................................................................. 93 
5.6.4 
Discontinuation of Investigational Product Due to BKV, CMV, or EBV Viral 
Infection .............................................................................................................. 93 
6. 
Randomization, Blinding and Unblinding Procedures .................................................. 93 
6.1 
Randomization .......................................................................................................... 93 
6.2 
Blinding .................................................................................................................... 94 
6.3 
Unblinding ................................................................................................................ 94 
7. 
Study Treatments ........................................................................................................... 95 
7.1 
Dosage Forms / Formulation .................................................................................... 95 
7.1.1 
Clazakizumab – Investigational Treatment......................................................... 95 
7.1.2 
Placebo Control................................................................................................... 95 
7.1.3 
Pneumocystis Jiroveci Pneumonia Prophylaxis ................................................. 95 
7.1.3.1 
Trimethoprim / Sulfamethoxazole .................................................................. 96 
7.1.3.2 
Other Antibiotics for Pneumocystis Jiroveci Pneumonia Prophylaxis ........... 96 
7.2 
Dosage and Administration of Investigational Product – Clazakizumab or Placebo97 
7.3 
Packaging and Labeling ............................................................................................ 97 
7.4 
Site Supply, Storage, and Accountability .................................................................. 97 
7.4.1 
Site Supply .......................................................................................................... 97 
7.4.2 
Storage ................................................................................................................ 98 
7.4.3 
Accountability ..................................................................................................... 98 
7.4.4 
Destruction of Investigational Product ............................................................... 98 
7.5 
Guidelines for Dose Modification, Withholding or Discontinuation of 
Investigational Product and / or Modification of Background Immunosuppression 99 
7.5.1 
Guidelines for Dose Modification, Withholding or Discontinuation of 
Investigational Product and / or Modification of Background 
Immunosuppression Based on Abnormal LFTs, Neutropenia, or 
Thrombocytopenia ............................................................................................ 100 
7.5.2 
Guidelines for Dose Modification, Withholding, or Discontinuation of 
Investigational Product and / or Modification of Background 
Immunosuppression Based on Results of Monitoring for BKV, CMV, and EBV 
Infection ............................................................................................................ 102 
7.5.3 
Guidelines for Modification of Dose of Background Immunosuppression Based 
on Results of Monitoring for Hypogammaglobulinemia .................................. 105 


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7.6 
Prohibited Therapy and Concomitant Treatments / Interventions .......................... 106 
7.6.1 
Prohibited Therapy and Medications ................................................................ 106 
7.6.2 
Allowed Concomitant Medications / Interventions .......................................... 108 
7.6.3 
Required Background (Prophylactic) Therapy ................................................. 110 
8. 
Risks / Precautions ...................................................................................................... 111 
8.1 
Identified Risks ....................................................................................................... 111 
8.1.1 
Infections .......................................................................................................... 111 
8.1.1.1 
Viral Monitoring for BKV, CMV, and EBV Infection ................................. 112 
8.1.1.2 
Viral Monitoring for COVID-19 Infection ................................................... 112 
8.1.2 
Liver Function Test Abnormalities ................................................................... 112 
8.1.3 
Hematology Parameters .................................................................................... 113 
8.1.4 
Dyslipidemia ..................................................................................................... 113 
8.1.5 
Gastrointestinal Perforation .............................................................................. 114 
8.1.6 
Injection Site Reactions .................................................................................... 114 
8.2 
Potential Risks ........................................................................................................ 114 
8.2.1 
Demyelination ................................................................................................... 114 
8.2.2 
Malignancies ..................................................................................................... 114 
8.2.3 
Immunogenicity ................................................................................................ 115 
8.2.4 
Infusion Related (Allergic) Reactions .............................................................. 115 
8.3 
Additional Warnings and Precautions ..................................................................... 115 
8.3.1 
Drug Interactions .............................................................................................. 115 
8.3.2 
Overdose ........................................................................................................... 116 
8.3.3 
Women of Childbearing Potential ..................................................................... 116 
9. 
Study Procedures ......................................................................................................... 118 
9.1 
Description of Study Assessments .......................................................................... 118 
9.1.1 
Clinical Laboratory Assessments ...................................................................... 118 
9.1.1.1 
Viral Monitoring (Plasma PCR) ................................................................... 120 
9.1.1.2 
Monitoring for Hypogammaglobulinemia (IgG) ......................................... 121 
9.1.1.3 
eGFR ............................................................................................................ 121 
9.1.1.4 
DSA Titers and MFI Scores ......................................................................... 122 
9.1.1.5 
Plasma hsCRP .............................................................................................. 122 
9.1.1.6 
Plasma IL-6 .................................................................................................. 123 
9.1.1.7 
Serum Clazakizumab .................................................................................... 123 
9.1.1.8 
Immunogenicity ........................................................................................... 124 
9.1.1.9 
MPA Levels .................................................................................................. 125 
9.1.1.10 
CNI Levels ................................................................................................... 125 


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9.1.1.11 
Biomarkers and Pharmacogenomics Research ............................................ 126 
9.1.2 
Physical Examinations ...................................................................................... 126 
9.1.3 
Vital Signs ......................................................................................................... 126 
9.1.4 
Standard 12-lead Electrocardiogram ................................................................ 127 
9.1.5 
Tuberculosis Screening ..................................................................................... 127 
9.1.6 
Renal Biopsy ..................................................................................................... 128 
9.1.7 
Health-Related Quality of Life ......................................................................... 128 
9.1.7.1 
EQ-5D-5L ..................................................................................................... 128 
9.1.7.2 
Kidney Disease Quality of Life Questionnaire – 36 .................................... 129 
9.1.7.3 
Functional Assessment of Chronic Illness Therapy – Fatigue Scale ........... 129 
9.2 
Schedule of Events.................................................................................................. 129 
9.2.1 
Screening Visit (Assessment Visit 1) ................................................................ 129 
9.2.2 
Treatment Procedures ....................................................................................... 131 
9.2.2.1 
Optional Home Health Visits ....................................................................... 132 
9.2.3 
Modifications to the Visit Schedule Due to Extraordinary Circumstances ...... 135 
9.2.4 
End of Treatment (or Early Treatment Withdrawal) Procedures ...................... 136 
9.2.5 
Study Procedures Based Upon Subject Disposition ......................................... 137 
9.2.5.1 
Subjects Who Reach the Endpoint of “Sustained 40% Decline in eGFR from 
Baseline” ...................................................................................................... 138 
9.2.5.2 
Subjects Who Met Any of the Other Composite Non-fatal All-cause Allograft 
Loss Endpoints ............................................................................................. 138 
9.2.5.3 
Subjects Who Permanently Discontinued Investigational Product .............. 138 
9.2.5.4 
Subjects Who Withdraw from the Study (ie, Withdrawal of Consent from 
Further Participation in the Study, Including any Contact by Study Site 
Personnel) ..................................................................................................... 139 
9.2.5.5 
Subjects Who are Still on Study When the Common Treatment End Date is 
Reached ........................................................................................................ 140 
9.2.6 
Unscheduled Visits ........................................................................................... 141 
10. 
Evaluation, Recording and Reporting of Adverse Events, Serious Adverse Events, and 
Special Situations ........................................................................................................ 141 
10.1 
Definitions .............................................................................................................. 141 
10.1.1 
Definition of Adverse Event ............................................................................. 141 
10.1.2 
Definition of Adverse Drug Reaction ............................................................... 142 
10.1.3 
Definition of Serious Adverse Event ................................................................ 142 
10.1.4 
Definition of Adverse Events of Special Interest.............................................. 143 
10.1.4.1 
Liver Function Test Abnormalities, Neutropenia, Thrombocytopenia, and 
Hyperlipidemia ............................................................................................. 143 
10.1.4.2 
Gastrointestinal Perforation .......................................................................... 144 


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10.1.4.3 
Hypersensitivity and Anaphylaxis ................................................................ 144 
10.1.4.4 
Malignancy ................................................................................................... 144 
10.1.4.5 
Opportunistic Infections ............................................................................... 145 
10.2 
Classification of Adverse Events ............................................................................ 146 
10.2.1 
Severity Classification ...................................................................................... 146 
10.2.2 
Relationship to Investigational Product ............................................................ 147 
10.2.3 
Outcome Categorization ................................................................................... 147 
10.2.4 
Preexisting and Worsening of Medical Condition ............................................ 147 
10.2.5 
Symptoms of the Disease Under Study ............................................................ 148 
10.2.6 
Clinical Laboratory Evaluations ....................................................................... 148 
10.2.7 
Physical Examinations and Vital Signs............................................................. 148 
10.2.8 
Special Situations .............................................................................................. 148 
10.3 
Reporting Procedures for Adverse Events, Serious Adverse Events and Pregnancy
 ................................................................................................................................ 148 
10.3.1 
Reporting of Adverse Events ............................................................................ 148 
10.3.2 
Reporting of Serious Adverse Events ............................................................... 150 
10.3.3 
Reporting of Pregnancy .................................................................................... 151 
11. 
Data and Safety Monitoring Board Procedures........................................................... 153 
12. 
Statistical Analysis ...................................................................................................... 154 
12.1 
Statistical Methods .................................................................................................. 154 
12.2 
Sample Size and Power Calculations...................................................................... 154 
12.3 
Pharmacokinetic Analyses ...................................................................................... 156 
12.4 
Pharmacodynamic Analyses ................................................................................... 157 
12.5 
Analysis Sets ........................................................................................................... 157 
12.5.1 
Intention-to-Treat Set ........................................................................................ 157 
12.5.2 
Per-Protocol Set ................................................................................................ 158 
12.5.3 
Safety Analysis Set ........................................................................................... 158 
12.5.4 
Pharmacokinetic Analysis Set ........................................................................... 158 
12.5.5 
Pharmacokinetic / Pharmacodynamic Substudy Analysis Set .......................... 158 
12.6 
Baseline and Demographic Characteristics ............................................................ 158 
12.7 
Investigational Product ........................................................................................... 159 
12.8 
Concomitant Therapy ............................................................................................. 159 
12.9 
Efficacy Evaluations ............................................................................................... 159 
12.9.1 
Secondary Efficacy Endpoints .......................................................................... 160 
12.9.2 
Pharmacokinetic / Pharmacodynamic Endpoints ............................................. 162 


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Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
 
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12.9.3 
Exploratory Analyses ........................................................................................ 162 
12.9.4 
Additional Analyses .......................................................................................... 163 
12.10 
Safety Evaluations .................................................................................................. 163 
12.11 
Safety Reviews and Interim Analyses .................................................................... 164 
13. 
Study Ethical Considerations ...................................................................................... 166 
13.1 
Ethical Conduct of the Study .................................................................................. 166 
13.2 
Informed Consent ................................................................................................... 166 
13.3 
Institutional Review Board ..................................................................................... 167 
14. 
Quality Control and Quality Assurance ...................................................................... 169 
15. 
Administrative Procedures .......................................................................................... 170 
15.1 
Sponsor’s Responsibilities ...................................................................................... 170 
15.1.1 
Study Supplies .................................................................................................. 170 
15.1.2 
Insurance ........................................................................................................... 170 
15.1.3 
Financial Disclosure and Obligations ............................................................... 170 
15.1.4 
Investigator Training ......................................................................................... 170 
15.1.5 
Study Monitoring .............................................................................................. 171 
15.1.6 
Medical Monitoring .......................................................................................... 171 
15.2 
Investigator’s Responsibilities ................................................................................ 172 
15.2.1 
Reporting and Recording of Data ..................................................................... 172 
15.2.2 
Study Records ................................................................................................... 173 
15.2.3 
Record Retention .............................................................................................. 173 
15.2.4 
Protocol Violations and Deviations .................................................................. 174 
16. 
Procedure for Modification of Protocol or Premature Termination of the Study ....... 175 
16.1 
Protocol Waivers, Deviations and Violations ......................................................... 175 
16.2 
Protocol Amendments ............................................................................................. 175 
16.3 
Study Termination ................................................................................................... 175 
17. 
Policy for Publication and Presentation of Data ......................................................... 175 
17.1 
Disclosure of Data .................................................................................................. 176 
18. 
References ................................................................................................................... 177 
19. 
Appendices .................................................................................................................. 182 
 


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CSL300, clazakizumab 
 
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List of Tables 
Table 1 
Schedule of Events for Year 1 (Screening to Week 52 Inclusive) ................... 43 
Table 2 
Schedule of Events for Year 2 to the Safety Follow-up Visit / Common 
Treatment End VisitN ....................................................................................... 48 
Table 3 
Pharmacokinetic / Pharmacodynamic Substudy Schedule of Sample 
CollectionA,B .................................................................................................... 54 
Table 4 
Summary of Number of Patients Included in Analysis, Allograft Loss Rates 
and Median Times to Allograft Loss: Primary Analysis Set ............................ 74 
Table 5 
Guidelines for Dose Modification, Withholding or Discontinuation of 
Investigational Product and / or Modification of Background 
Immunosuppression Based on Abnormal LFTs, Neutropenia, or 
Thrombocytopenia ......................................................................................... 101 
Table 6 
Guidelines for Dose Modification, Withholding or Discontinuation of 
Investigational Product and / or Modification of Background 
Immunosuppression Based on Results of Monitoring for BKV, CMV, and 
EBV Infection ................................................................................................ 103 
Table 7 
Guidelines for Modification of Dose of Background Immunosuppression 
Based on Low IgG Levels ............................................................................. 106 
Table 8 
Summary of Laboratory Assessments............................................................ 118 
Table 9 
Pharmacokinetic Sample Collection for Subjects Receiving IVIG ............... 124 
Table 10 
Schedule of Mandatory In-Clinic Visits ........................................................ 134 
Table 11 
Schedule of “Mandatory In-clinic” Visits that may be Completed as Remote 
Visits During Extraordinary Circumstances .................................................. 135 
Table 12 
Adverse Event Severity Grading ................................................................... 146 
Table 13 
Adverse Event Relationship to Investigational Product ................................ 147 
Table 14 
Sample Size Estimates for Composite All-cause Allograft Loss or Irreversible 
Loss of Allograft Function Based on eGFR Data Restricted to 52 Weeks Post-
Diagnosis of Active ABMR ........................................................................... 155 
Table 15 
Sample Size Estimates for Change in eGFR (mL/min/1.73 m2) at 52 Weeks 
After Diagnosis of Active ABMR .................................................................. 156 
 


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CSL300, clazakizumab 
 
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LIST OF APPENDICES 
Appendix 1 
Signatures 
Appendix 2 
Summary Table of All Scheduled Study Visits 
Appendix 3 
IL-6 and Antibody-mediated Rejection in Kidney Transplant Recipients 
Appendix 4 
Dose Selection Rationale 


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List of Abbreviations 
Abbreviation 
Term 
ABMR 
Antibody-mediated rejection 
ACEI 
Angiotensin-converting enzyme inhibitor 
ADA 
Anti-drug antibody 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AESI 
Adverse event of special interest 
AKI 
Acute kidney injury 
ALT 
Alanine aminotransferase 
ARB 
Angiotensin II receptor blocker 
AST 
Aspartate aminotransferase 
AZA 
Azathioprine 
BKV 
Polyoma BK virus 
C4d 
Complement component 4d 
CABMR 
Chronic active antibody-mediated rejection 
CBC 
Complete blood count 
CFR 
Code of Federal Regulations 
CTFG 
Clinical Trial Facilitation Group 
cg 
Chronic glomerulopathy  
CMV 
Cytomegalovirus 
CNI 
Calcineurin inhibitor 
COVID-19 
Coronavirus disease 2019 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CSLB 
CSL Behring 
CTCAE 
Common Toxicity Criteria for Adverse Events 
CTED 
Common treatment end date 
CTEV 
Common treatment end visit 
CYP 
Cytochrome P450  
DMARD 
Disease-modifying antirheumatic drug 
DSA 
Donor-specific antibodies 
DSMB 
Data and Safety Monitoring Board 
EBV 
Epstein-Barr virus 


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EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCOA 
Electronic clinical outcomes assessment 
eCRF 
Electronic case report form 
eGFR 
Estimated glomerular filtration rate 
EOT 
End of Treatment 
EQ-5D-5L 
EuroQoL-5 Dimensions-5 Levels 
FACIT Fatigue  
Functional Assessment of Chronic Illness Therapy – Fatigue Scale 
FDA 
Food and Drug Administration 
FSH 
Follicle stimulating hormone 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GVHD 
Graft-versus-host disease 
HbsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV  
Human immunodeficiency virus 
HLA 
Human leukocyte antigen 
HRQoL 
Health-related quality of life 
hsCRP 
High-sensitivity C-reactive protein 
IA #1 
Interim analysis #1 
IA #2 
Interim analysis #2 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgG1 
Immunoglobulin G1 
IIT 
Investigator-initiated trial 
IL-6 
Interleukin 6 
IL-6R 
Interleukin 6 receptor 
INR 
International normalized ratio  
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
Intention-to-treat 
IU 
International units 


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IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
KDIGO 
Kidney Disease: Improving Global Outcomes 
KDQoL-36 
Kidney Disease Quality of Life Questionnaire – 36 
LC-MS / MS 
Liquid chromatography-tandem mass spectrometry 
LFT 
Liver function test 
LLOQ 
Lower limit of quantification 
mAb 
Monoclonal antibody 
MDRD4 
Modification of Diet in Renal Disease 4  
MedDRA 
Medical Dictionary for Regulatory Activities 
MFI 
Mean fluorescence intensity 
MMF 
Mycophenolate mofetil 
MPA 
Mycophenolic acid 
mRNA 
Messenger ribonucleic acid 
mTOR 
Mechanistic target of rapamycin 
MTX 
Methotrexate  
PCR 
Polymerase chain reaction 
PD 
Pharmacodynamic 
PJP 
Pneumocystis jiroveci pneumonia  
PK 
Pharmacokinetic  
PLEX 
Plasma exchange 
PP 
Per-protocol 
PsA 
Psoriatic arthritis 
PT 
Preferred Term 
Q2W 
Once every 2 weeks 
Q4W 
Once every 4 weeks 
QIU 
Qualified Investigator Undertaking 
QW 
Once a week 
RA 
Rheumatoid arthritis 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SC 
Subcutaneous  
SFV 
Safety Follow-up Visit 
SOC 
System Organ Class 
SOE 
Schedule of Events 


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STAT3 
Signal transducer and activator of transcription 3  
t1/2 
Terminal or elimination half-life 
TB 
Tuberculosis 
TC 
Telephone call 
TCMR 
T cell-mediated rejection 
TCZ 
Tocilizumab 
TEAE 
Treatment-emergent adverse event 
TG 
Transplant glomerulopathy 
Th 
T helper (cell) 
Treg 
Regulatory T (cell) 
UACR 
Urine albumin creatinine ratio 
ULN 
Upper limit of normal  
WOCBP 
Women of childbearing potential 
 


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1. 
Introduction and Background 
1.1 
IL-6 and Antibody-mediated Rejection in Kidney Transplant 
Recipients 
A detailed discussion of the role of interleukin 6 (IL-6) in the pathogenesis of 
antibody-mediated rejection (ABMR) and preliminary evidence that blocking the activity of 
this cytokine may benefit patients with active antibody-mediated rejection (ABMR) is 
provided in Appendix 3. The clinical setting and unmet medical need are also discussed. 
IL-6 is a pleiotropic cytokine that regulates the immune response, inflammation, 
hematopoiesis, and bone metabolism [Keller et al, 1996]. IL-6 also has a range of effects on 
the adaptive immune response. It stimulates B cell differentiation and secretion of antibodies 
and prevents apoptosis of activated B cells [Hirano et al, 1985; Muraguchi et al, 1988; 
Kawano et al, 1995]. IL-6 also activates and induces proliferation of T cells and, in the 
presence of interleukin 2, induces differentiation of mature and immature T cells into 
cytotoxic T cells [Lotz et al, 1988; Okada et al, 1988]. 
IL-6 appears to be a critical cytokine involved in the humoral rejection of kidney allografts 
(ie, ABMR). IL-6 promotes the development and maturation of B cells to plasma cells that 
produce donor-specific antibodies (DSA) targeting the allograft. These donor-specific 
antibodies (DSA) damage the allograft via complement and non-complement mediated 
pathways and induce graft endothelial cells to produce inflammatory (eg, p-selectin, vascular 
cell adhesion molecule [VCAM-1]) and pro-thrombotic (eg, von Willebrand factor) 
molecules [Gaston et al, 2010; Thomas et al, 2015; Jordan et al, 2017]. Furthermore, IL-6 
shapes the T cell immune response resulting in promotion of long-lived pro-inflammatory 
T helper (Th) cells (eg, follicular Th cells, Th17, Th1, and Th2 cells) and inhibition of 
immune regulatory T (Treg) cells that promote allograft tolerance. 
Active ABMR, especially chronic active antibody-mediated rejection (CABMR), is now 
recognized as the most common cause of allograft failure after a successful kidney transplant. 
Active ABMR and CABMR are part of a continuum of injury which, left untreated, results in 
the loss of the transplanted allograft. The continuum of injury produced by active ABMR is 
triggered by inflammation following interaction between complement-activating recipient 
DSA and donor human leukocyte antigen (HLA) expressed on the surface of the transplant 
vascular endothelium. Active ABMR is the pathological expression of a repetitive pattern of 
cellular injury and repair. Regardless of how the process is initiated, this ongoing injury 
eventually manifests as CABMR with its hallmark chronic tissue injury pathology (ie, 


CSL Behring 
Study Number: 
CSL300_3001 
Study Product: 
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transplant glomerulopathy [TG]) and loss of functional renal mass that leads to a decline in 
renal function. 
In kidney transplant recipients with CABMR, a progressive decline in renal function is, by 
definition, on the pathway to graft loss. Numerous studies in kidney transplant recipients, and 
specifically in post-transplant patients with ABMR, have shown that progressive renal 
function decline (as measured by estimated glomerular filtration rate [eGFR]) is significantly 
correlated with graft loss and patient survival [Hariharan et al, 2002; Kasiske et al, 2011; 
Wiebe et al, 2012; Eskandary et al, 2014; Wiebe et al, 2015; Clayton et al, 2016]. Indeed, 
measures of renal function (eg, serum creatinine or eGFR) are commonly used in clinical 
practice to make decisions on the need and timing of re-initiating dialysis in kidney transplant 
recipients with imminent graft loss. 
Although effective treatment of acute cellular rejections has led to high short-term survival of 
kidney allografts (ie, > 95% in the first year post-transplant), long-term graft survival has not 
improved. Death-censored graft failure rates beyond the first year have remained relatively 
unchanged since the late 1980s, and by 10 years, 20% to 30% of all kidney allografts will 
have failed [Stegall et al, 2014]. Current standard of care antirejection treatments target 
cellular-mediated (ie, T cell-mediated rejection [TCMR]) processes and do not affect this 
antibody-mediated process. 
Currently, there are no approved or effective treatments for active ABMR, including 
CABMR. The Kidney Disease: Improving Global Outcomes (KDIGO) 2009 guideline 
[Kidney Disease: Improving Global Outcomes, 2009] recognizes the lack of good quality 
data and suggests the use of one or more of the following alternatives, with or without 
corticosteroids, to treat acute humoral rejections due to DSA: PLEX; intravenous 
immunoglobulin (IVIG); anti-CD20 antibody; and lymphocyte-depleting antibody. Recent 
systematic reviews of treatments for ABMR have shown that the situation remains 
unchanged, even with novel agents targeting B cells, plasma cells and the complement 
system [Roberts et al, 2012; Wan et al, 2018]. In the RITUX ERAH study, there was not early 
or late (up to 5 years) benefit with rituximab (an anti-CD20 monoclonal antibody [mAb]) 
administered with IVIG, PLEX and corticosteroids in kidney transplant recipients with early 
acute ABMR [Sautenet et al, 2016; Bailly et al, 2017]. More specifically, no evidence of 
efficacy was seen in studies in CABMR with eculizumab (a complement inhibitor), 
bortezomib (a proteasome inhibitor), IVIG, rituximab and PLEX [Kulkarni et al, 2017; 
Piñeiro et al, 2017; Eskandary et al, 2018; Moreso et al, 2018]. 


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Blocking the activity of IL-6 in kidney transplant recipients with ABMR has been 
investigated in a number of small uncontrolled clinical trials with promising results. In a 
study in 36 HLA-sensitized kidney transplant recipients with CABMR and TG who had 
failed treatment with IVIG plus rituximab with / without PLEX, Choi et al. showed that 
treatment with tocilizumab (TCZ) 8 mg/kg intravenous (IV) administered monthly, was able 
to significantly reduce immunodominant DSA levels and stabilize long-term renal function 
(eGFR) in these patients [Choi et al, 2017a]. Improvements in microvascular inflammation 
and complement component 4d (C4d) staining scores were also seen in the allograft biopsies. 
Promising graft survival (80%) and patient survival (91%) rates were observed over 6 years. 
Extended experience with a larger cohort of 65 kidney transplant recipients with CABMR 
and TG, treated monthly with TCZ 4 to 8 mg/kg, demonstrated similar promising results 
[Choi et al, 2017b]. Puliyanda et al. showed that the administration of TCZ 4 to 8 mg/kg 
monthly for 4 to 12 doses in 6 pediatric kidney transplant recipients with severe CABMR 
refractory to B cell immunotherapy was able to stabilize the progression of ABMR, resulting 
in no graft loss and no decline in renal function [Puliyanda et al, 2017]. In a small cohort of 
highly sensitized kidney transplant recipients with acute ABMR, Venkatachalam et al. 
showed that the addition of TCZ 8 mg/kg IV monthly for 3 to 6 months appeared to be 
effective, resulting in improved renal function and reduced DSAs [Venkatachalam et al, 
2017]. In a small randomized controlled study in kidney transplant recipients with biopsy 
evidence of subclinical inflammation within Year 1 of their transplant, Chandran et al. 
showed that treatment with TCZ 8 mg/kg IV monthly for 6 months was well tolerated and 
was associated with a significant increase in circulating Treg cells, a significant decrease in 
CD4+ T cell cytokine (interleukin 17) production, and a trend towards decreased graft 
inflammation [Chandran et al, 2017]. In a group of kidney transplant recipients with CABMR 
refractory to other treatments, Patel et al. showed that the addition of TCZ 8 mg/kg IV 
monthly to a regimen of tacrolimus, mycophenolate and prednisone stabilized eGFR, despite 
persistent DSA and with few infectious complications [Patel et al, 2017]. Finally, in a study 
by Vo et al., mean wait time to renal transplant in highly HLA-sensitized patients (resistant to 
desensitization standard of care [ie, IVIG + rituximab +/- PLEX]) was shortened following 
treatment with TCZ (+ IVIG) 8 mg/kg IV administered on Day 15, then monthly for 
6 months [Vo et al, 2015]. Significant reductions in immunodominant DSAs were seen in all 
transplanted patients with no biopsy evidence of ABMR at 6 months. In all these trials, the 
safety profile of TCZ was acceptable. 
In summary, the current treatments commonly being used for the treatment of CABMR are 
not evidenced-based. Considering the cost and potential for serious toxicity with the current 
treatments, this highlights the need for well-designed randomized controlled studies to 


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investigate the safety and efficacy of any new drugs for the treatment of CABMR – a serious 
and rare condition with an unmet clinical need. Promising signals of efficacy have been seen 
with an anti-IL-6 approach. 
1.2 
Clazakizumab – Properties and Mechanism of Action 
Clazakizumab is a genetically engineered humanized immunoglobulin G1 (IgG1) mAb that 
binds to human IL-6. Using multiple assays for signaling and cellular functions in response to 
IL-6 alone (to measure classical signaling) and a combination of IL-6 and soluble IL-6 
receptor (IL-6R) (to measure trans-signaling), it was demonstrated that clazakizumab is a 
potent and full antagonist of IL-6-induced signaling as measured by phosphorylation of 
signal transducer and activator of transcription 3 (STAT3), as well as cellular functions such 
as cell proliferation, differentiation, activation, B cell production of immunoglobulins, and 
hepatocyte production of acute phase proteins (C-reactive protein [CRP] and fibrinogen). In 
addition, clazakizumab is shown to be a competitive antagonist of IL-6-induced cell 
proliferation. This in vitro pharmacological profile supports the potential of clazakizumab to 
impact multiple immune and non-immune cellular processes that are central to the 
pathogenesis of ABMR in kidney transplant recipients. 
1.3 
Clazakizumab Development Program – Overview 
The clazakizumab development program includes a comprehensive nonclinical development 
program and clinical studies (conducted by previous Sponsors of the drug) in healthy subjects 
and in subjects with rheumatoid arthritis (RA), psoriatic arthritis (PsA), Crohn’s disease, 
graft-versus-host disease (GVHD), and oncology. To date, no studies with clazakizumab have 
been completed in kidney transplant recipients, although supporting safety data are available 
from the previous clinical studies. Preliminary safety data are also available from 
3 Investigator-initiated trials (IITs) in the kidney transplant setting. 
1.3.1 
Nonclinical Studies 
A comprehensive nonclinical development program has been completed (see the CSL300 
Investigator’s Brochure for details). Clazakizumab was shown to be a potent inhibitor of 
IL-6-induced acute phase proteins. In pharmacokinetic (PK) / pharmacodynamic (PD) 
studies, a single dose of clazakizumab resulted in full inhibition of IL-6 activity as measured 
by the inhibition of IL-6-induced phosphorylated STAT3 activity in whole blood treated 
ex vivo with IL-6. The results of this functional PD assay correlated with drug exposures 
where full inhibition of phosphorylated STAT3 activity was observed when drug levels 
exceeded 50 ng/mL (approximately 0.3 nM). In a tissue cross-reactivity study, tissue binding 


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of clazakizumab was observed in multiple tissues in both human and cynomolgus monkey, 
was generally cytoplasmic in nature, and was consistent with the known expression of IL-6 
by cells and tissues. Results from both single- and repeat-dose nonclinical toxicology studies 
of up to 6 months in cynomolgus monkeys demonstrated an acceptable safety profile for 
clazakizumab. In a preliminary enhanced pre- and post-natal development study conducted in 
cynomolgus monkeys, an increase in the number of monkeys with retention of the placenta at 
parturition was observed at clazakizumab doses of 3 mg/kg (n=2) and 30 mg/kg (n=3), 
corresponding to doses 34 and 340 times the planned human dose of 12.5 mg once every 
4 weeks (Q4W) in the current study. There were no other safety findings of clinical concern. 
For further details regarding the nonclinical studies with clazakizumab, please consult the 
CSL300 Investigator’s Brochure. 
1.3.2 
Clinical Studies 
Clinical studies have been conducted in healthy subjects and in the following patient 
populations: RA, PsA, Crohn’s disease, GVHD, and oncology. These completed clinical 
studies include a total of 1223 subjects, of which 1056 subjects were exposed to 
clazakizumab for up to 175 weeks (including open-label, long-term extension phases) with 
doses ranging from 1 to 640 mg, given by either IV or subcutaneous (SC) injection. 
Preliminary safety data from ongoing IITs are discussed in Appendix 4. 
Clinical Pharmacology 
Following the administration of clazakizumab as a 1-hour IV infusion, the PK of 
clazakizumab were linear over the dose ranges of 30 to 640 mg in healthy subjects and 80 to 
320 mg in subjects with RA, as indicated by consistent clearance at these dose levels. The 
terminal elimination half-life (t1/2) of clazakizumab at all doses was very similar in healthy 
male subjects and in subjects with RA and was consistent with that expected for a humanized 
IgG1 antibody. Across the doses studied, the mean t1/2 of clazakizumab ranged from 19.5 to 
31.0 days in healthy male subjects and from 26.4 to 30.9 days in subjects with RA. The t1/2 of 
clazakizumab after SC administration in healthy male subjects was comparable to the IV 
administration. In a phase 1 study comparing IV and SC dosing in healthy male subjects, the 
mean t1/2 of clazakizumab was 30.7 days after a single IV dose and 31.1 to 33.6 days after SC 
administration. The bioavailability of clazakizumab after SC administration was 60% of the 
IV formulation. As expected, the maximum observed concentration was lower and time to 
maximum observed concentration was longer for the SC administration relative to IV 
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Clinical Efficacy and Safety Studies 
Efficacy and safety data for clazakizumab are available from clinical studies conducted in 
healthy subjects, and in subjects with RA, PsA, and oncology. Studies conducted in GVHD 
and Crohn’s disease were prematurely terminated due to safety concerns and therefore no 
efficacy conclusions are available for these studies. 
In phase 2 studies in RA and PsA, doses from 5 mg SC Q4W up to 320 mg IV once every 
8 weeks were significantly effective with clinical response evident as early as 2 weeks post-
treatment. One study in RA also demonstrated that the efficacy of clazakizumab is 
comparable or may be better than the standard of care treatment in RA (ie, adalimumab + 
methotrexate [MTX]). 
Efficacy with clazakizumab was not shown in the 2 phase 2 studies in oncology (head and 
neck cancer and non-small cell lung cancer). 
Two studies were terminated prematurely due to safety concerns. A phase 2 study in Crohn’s 
disease was terminated early because of gastrointestinal (GI) perforation in 3 subjects who 
had received clazakizumab, and this indication is no longer being studied. Although these 
subjects had multiple confounding medical issues, and the disease itself has an inherent risk 
of mucosal perforation, GI perforations were also observed during the clinical studies with 
TCZ in patients with RA. Gastrointestinal perforation is a recognized risk of anti-IL-6 mAbs. 
After only 3 subjects were enrolled, a study in subjects with GVHD was also prematurely 
terminated due to 2 subjects experiencing similar serious adverse events (SAEs) (ie, acute 
renal failure) which led to death. Both subjects had severe GVHD disease at the time of 
death. 
Overall, the safety findings from the completed clinical studies conducted with clazakizumab 
to date are consistent with the known effects of blocking the IL-6 pathway [Actemra® 
Prescribing Information (USA), 2017; Actemra® Product Monograph (Canada), 2018; 
RoActemra® Summary of Product Characteristics (EU), 2018]. Identified risks associated 
with clazakizumab administration include the following: infections, liver function test (LFT) 
abnormalities, changes in hematology parameters (ie, neutropenia and thrombocytopenia), 
dyslipidemia (ie, hypercholesterolemia and hypertriglyceridemia), GI perforations, and 
injection site reactions (see Section 8.1). 
For further details regarding clinical studies with clazakizumab, please consult the CSL300 
Investigator’s Brochure. 


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2. 
Rationale 
A detailed discussion of the role of IL-6 in the pathogenesis of ABMR and preliminary 
evidence that blocking the activity of this cytokine may benefit patients with ABMR is 
provided in Appendix 3. 
This multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase 3 trial 
investigates whether clazakizumab (an anti-IL-6 mAb) may be beneficial for the treatment of 
CABMR in kidney transplant recipients by inhibiting the production of DSA and re-shaping 
T cell alloimmune responses. Subjects will be administered clazakizumab at a target dose of 
12.5 mg (or placebo) by SC injection, Q4W until the subject permanently discontinues IP, 
withdraws from the study, experiences allograft loss, dies, or reaches the common treatment 
end date (CTED), whichever occurs first. This “event-driven” trial has been designed to 
evaluate the benefits of clazakizumab in prolonging the time to composite all-cause allograft 
loss or irreversible loss of allograft function (primary efficacy endpoint) in subjects with 
CABMR. A total of 221 composite all-cause allograft loss or irreversible loss of allograft 
function events (expected to accrue in 316 kidney transplant recipients with CABMR) is 
estimated to be required to show a relative risk reduction of 31%, which would improve the 
4-year graft survival rate from 24.7% to 38.3% (see Section 12.2). An interim efficacy 
analysis (Interim Analysis #2 [IA #2]) will be conducted to evaluate the benefits of 
clazakizumab in reducing the slope of decline in eGFR when an initial cohort of 
approximately 200 subjects have completed at least 52 weeks of study participation. If this 
interim analysis shows a significant positive effect of clazakizumab on eGFR decline, a 
submission for expedited regulatory approval will be sought while the study continues to its 
final allograft loss endpoint. If this interim endpoint does not reach statistical significance, 
the study will continue as planned until its final allograft loss endpoint is completed. 
Relationship Between Change in eGFR and Risk of Allograft Failure 
To inform the study design and demonstrate the suitability of the Week 52 eGFR as a 
surrogate endpoint reasonably likely to predict clinical benefit, a data modeling exercise was 
conducted to evaluate the functional relationship between rate of eGFR decline following 
diagnosis of acute / active ABMR or CABMR and risk of allograft failure (death-censored 
composite all-cause allograft loss), to enable quantification of a clinically meaningful change 
in eGFR as it relates to a clinically meaningful change in allograft survival. Results of the 
modeling exercise were also used for sample size estimation (see Section 12.2). 
The data modeling exercise was a non-interventional historical, prospective cohort study that 
evaluated the relationship between change in eGFR (estimated using the Modification of Diet 


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in Renal Disease 4 [MDRD4] equation) and risk of allograft failure in patients diagnosed 
with acute / active ABMR or CABMR following kidney transplantation. The primary 
analysis set of the study used existing data from 91 patients with biopsy-proven active 
ABMR (according to the Banff 2015 criteria [Loupy et al, 2017]), anti-HLA DSA, Baseline 
eGFR ≥ 25 mL/min/1.73 m2 (at time of diagnosis of ABMR), and a minimum of 3 years 
follow-up data. The primary outcome variable was death-censored allograft failure / loss 
(defined as the need for permanent dialysis, allograft nephrectomy, retransplantation, or 
eGFR < 15 mL/min/1.73 m2) occurring at any time over the course of subject follow-up post-
diagnosis of active ABMR. All-cause allograft failure / loss was examined as the key 
secondary outcome variable (defined as the need for permanent dialysis, allograft 
nephrectomy, retransplantation, eGFR < 15 mL/min/1.73 m2, or death from any cause). 
Results involving the primary and key secondary outcome variables of death-censored and 
all-cause- allograft failure, respectively, are summarized in Table 4. As expected, both death-
censored and all-cause allograft loss event rates were high (59.3% and 68.1%, respectively) 
over the 60-month observation period. For both endpoints, most allograft loss events were 
defined by eGFR falling below 15 mL/min/1.73 m2 while the remaining subjects met one or 
more of the other criteria for allograft loss (need for permanent dialysis, allograft 
nephrectomy, or retransplantation) or death (for all-cause allograft failure). The median time 
to reach the composite endpoint of death-censored allograft failure and all-cause allograft 
failure was 46.2 months and 40.7 months, respectively. 
Table 4 
Summary of Number of Patients Included in Analysis, Allograft 
Loss Rates and Median Times to Allograft Loss: Primary Analysis 
Set 
Primary Outcome Variables 
Category 
or Statistic 
Death-Censored 
Allograft Loss Primary 
Endpoint 
All-Cause Allograft 
Loss Key Secondary 
Endpoint 
Pooled Data 
(N=91) 
Pooled Data 
(N=91) 
Allograft failure / loss composite endpoint 
n (%) 
54 (59.3%) 
62 (68.1%) 
Need for permanent dialysis, allograft 
nephrectomy, or retransplantation 
n (%) 
18 (19.8%) 
18 (19.8%) 
eGFR < 15 mL/min/1.73 m2 
n (%) 
36 (39.6%) 
36 (39.6%) 
Death 
n (%) 
N/A 
8 (8.8%) 
Time to allograft loss composite endpoint 
(months) 
Median 
(25th–75th) 
46.2 
(20.6–109.4) 
40.7 
(18.0–109.4) 
Allograft survival post-diagnosis of ABMR(a): 
12 months 
Estimate 
[95% CI] 
88.9% 
[80.4–93.9%] 
87.9% 
[79.2–93.1] 
24 months 
Estimate 
[95% CI] 
66.0% 
[55.0–74.8%] 
62.6% 
[51.9–71.7] 


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Primary Outcome Variables 
Category 
or Statistic 
Death-Censored 
Allograft Loss Primary 
Endpoint 
All-Cause Allograft 
Loss Key Secondary 
Endpoint 
Pooled Data 
(N=91) 
Pooled Data 
(N=91) 
36 months 
Estimate 
[95% CI] 
58.9% 
[47.9–68.4%] 
53.8% 
[43.1–63.4] 
48 months 
Estimate 
[95% CI] 
47.5% 
[36.5–57.7%] 
42.4%  
[32.1–52.3] 
60 months 
Estimate 
[95% CI] 
36.4% 
[25.3–47.6%] 
30.7% 
[20.7–41.3] 
Follow-up (months)(b) 
Median 
(25–75th) 
61.7 
(47.7–91.8) 
67.9 
(49.1-95.7) 
ABMR = antibody-mediated rejection; CI = confidence interval; eGFR = estimated glomerular filtration rate; N / A = not 
applicable. 
Notes:  
a Kaplan-Meier method. 
b Reverse Kaplan-Meier method. 
Source: Modeling Report, Section 10, Table 4. 
To address the objective of the modeling exercise, both a linear mixed effects model to 
describe eGFR decline and a joint model involving longitudinal eGFR and time-to-event data 
were constructed. The joint model predicted that the Baseline eGFR and its rate of decline 
(slope change per month) following active ABMR diagnosis significantly predicts the risk of 
death-censored allograft failure and all-cause allograft failure, especially in patients with 
CABMR. As expected, a lower Baseline eGFR and a higher rate of decline of eGFR were 
significantly associated with a greater risk of allograft loss. Increasing donor age was 
consistently associated with a lower Baseline eGFR. 
Using the modeling results for all-cause allograft loss, the mean eGFR declined from 
Baseline (ABMR diagnosis) to Month 12 post ABMR diagnosis (timing of IA #2, see 
Section 12.11) by 19.8% (-0.75 mL/min/1.73 m2 per month change) and was associated with 
predicted event-free survival rates of 80.0%, 58.7%, 44.4%, and 23.3% at 2, 3, 4, and 5 years 
after ABMR diagnosis, respectively. 
In this study, a 50% reduction in the rate of eGFR decline with clazakizumab (compared to 
placebo) is considered a reasonable and realistic assumption considering that treatment with 
TCZ (an anti-IL-6R mAb) was able to stabilize eGFR decline in kidney transplant recipients 
with CABMR [Choi et al, 2017a; Choi et al, 2017b; Patel et al, 2017; Puliyanda et al, 2017; 
Venkatachalam et al, 2017]. Furthermore, conducting the interim efficacy analysis on the 
52-week eGFR surrogate endpoint is considered appropriate given the relatively rapid rate of 
decline in eGFR that would be expected in the placebo-control group, as reflected in the 
mean rate of eGFR decline seen in the modeling exercise (-0.75 mL/min/1.73 m2/month). As 
summarized in Section 12.2, using data from the modeling exercise, sample sizes based on 


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eGFR data collected for a period of up to 52 weeks after diagnosis of ABMR, and assuming a 
50% reduction in the rate of eGFR decline, were estimated for the risk of composite all-cause 
allograft loss, and “working backwards”, for the interim analysis of the surrogate 52-week 
eGFR endpoint. 
In summary, the results of this data modeling exercise support the clinical trial design. The 
joint modeling of the clinical data meets statistical and clinical expectations: it predicted the 
Baseline eGFR, and its rate of decline (slope change per month) following active ABMR 
diagnosis significantly predicted risk of all-cause allograft failure. The exercise provided 
good evidence that the surrogate 52-week eGFR endpoint to be used in the interim efficacy 
analysis (IA #2), if positive, is reasonably likely to predict clinical benefit based on the final 
clinical endpoint of composite all-cause allograft loss. 


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3. 
Objectives 
3.1 
Primary Objectives 
1. To evaluate the efficacy of clazakizumab in preventing all-cause allograft loss 
(including death) or irreversible loss of allograft function due to CABMR. 
2. To evaluate the efficacy of clazakizumab in slowing / preventing the progressive 
loss of kidney function (as measured by eGFR using the MDRD4 equation [IA #2]). 
3. To evaluate the safety of clazakizumab. 
3.2 
Secondary Objectives 
1. 
To evaluate the efficacy of clazakizumab in preventing all-cause allograft loss 
(including death) due to CABMR. 
2. 
To evaluate the effects of clazakizumab on loss of allograft function (defined as a 
40% decline in eGFR from Baseline that is sustained for at least 60 days). 
3. 
To evaluate the effects of clazakizumab on death-censored allograft loss. 
4. 
To evaluate the effects of clazakizumab on albuminuria. 
5. 
To evaluate the effects of clazakizumab on DSA titers and mean fluorescence 
intensity (MFI) scores. 
6. 
To evaluate the effects of clazakizumab on the histology of kidney biopsies 
according to the Banff 2015 [Loupy et al, 2017] lesion grading scores. 
7. 
To evaluate the effects of clazakizumab on incidence of acute rejection episodes 
(TCMR and ABMR). 
8. 
To evaluate the effects of clazakizumab on overall subject survival. 
9. 
To evaluate the PK of clazakizumab following SC injection in kidney transplant 
recipients with CABMR (for those subjects in the PK / PD Substudy only). 
10. To evaluate the immunogenicity of clazakizumab in kidney transplant recipients 
with CABMR. 
3.3 
Exploratory Objectives 
1. 
To evaluate the PD of clazakizumab (serum IL-6 (total and free) and / or high-
sensitivity C-reactive protein [hsCRP]) following SC injection in kidney transplant 
recipients with CABMR (for those in the PK / PD Substudy only). 
2. 
To explore the relationship between clazakizumab PK and PD parameters (serum 
IL-6 [total and free] and / or hsCRP [for those in the PK / PD Substudy only]). 
3. 
To evaluate the effects of clazakizumab on health-related quality of life (HRQoL) 
associated with the treatment of antibody-mediated rejection to Week 52 as well as 
to the Safety Follow-up Visit (SFV). 


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4. 
To evaluate the efficacy of clazakizumab in slowing / preventing the progressive 
loss of kidney function up to the EOT (as measured by eGFR using the MDRD4 
equation). 


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4. 
Investigational Plan 
4.1 Overall Study Design 
This is a multicenter, randomized, double-blind, parallel-group, placebo-controlled, phase 3 
trial in which subjects receive treatment with either 12.5 mg clazakizumab (n = 175) or 
placebo (n = 175) by SC injection Q4W until the subject permanently discontinues IP, 
withdraws from the study, experiences allograft loss, dies, or reaches the CTED, whichever 
occurs first. The CTED is the date when the primary efficacy endpoint (composite all-cause 
allograft loss or irreversible loss of allograft function) is achieved, ie, the date the target 
number of primary composite all-cause allograft loss or irreversible loss of allograft function 
events (221) has been reached. The primary efficacy endpoint of this “event-driven” study is 
the time to composite all-cause allograft loss or irreversible loss of allograft function, defined 
as the occurrence of any of the following components: 
• eGFR < 15 mL/min/1.73 m2* 
• return to dialysis* 
• allograft nephrectomy 
• retransplantation 
• death from any cause, or 
• a sustained (≥ 60 days) 40% decline in eGFR from Baseline. 
(*total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days.) 
If the eGFR < 15 mL/min/1.73 m2 is the only component reached, the value must be 
sustained over at least 60 days and must be confirmed by a repeat measurement after 
≥ 60 days from the date of the first measurement. The confirmatory measurement of 
eGFR < 15 mL/min/1.73 m2  done at least 60 days from the initial measurement must be 
processed by the central laboratory. 
Subjects who reach the endpoint of sustained 40% decline in eGFR from Baseline (but did 
not reach any of the non-fatal endpoint components of allograft failure) will continue to 
receive double-blind medication until they reach any of the other primary endpoints of 
allograft loss. The subject will remain in the study attending all regular clinic visits and 
undergoing all assessments per the SOE. IVIG and PLEX may be administered at the 
discretion of the PI to these subjects if they have completed the Week 52 visit. Double-blind 
medication and IVIG should be administered 2 weeks apart due to potential binding of IVIG 


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to clazakizumab. For treatment with IVIG, subjects may be called in for unscheduled visits 
between regularly scheduled dosing with IP according to the SOE. 
The CTED will be communicated to study sites when the target number of primary composite 
all-cause allograft loss or irreversible loss of allograft function events (221) has been reached 
to enable study sites to plan their subjects’ final visit(s) (CTEV). Further details on 
procedures for subject follow-up can be found in Section 9.2.5. 
An interim efficacy analysis (IA #2), using a surrogate endpoint (change in mean eGFR from 
Baseline to Week 52) will be conducted to evaluate the benefits of clazakizumab in slowing 
the decline in eGFR when an initial cohort of approximately 200 subjects (100 per group) 
have completed at least 52 weeks of study participation. The adequacy of the planned sample 
size for this analysis will be reevaluated once approximately 100 subjects have been 
randomized and have completed at least 52 weeks of study participation (Interim Analysis #1 
[IA #1]). If the interim analysis of the 52-week eGFR surrogate endpoint shows a statistically 
significant (p ≤ 0.05) positive effect of clazakizumab on eGFR decline, CSL Behring (CSLB) 
will seek expedited approval, where applicable. In the meantime, the trial will continue as 
planned until its final composite allograft loss endpoint is completed. The composite allograft 
loss endpoint data will be used to convert the expedited approval to regular approval. An 
overview of the study design is depicted in the Study Schema. A Schedule of Events (SOE) is 
provided in Table 1 (Year 1) and Table 2 (Year 2 to SFV / CTEV). An overall summary table 
of all scheduled study visits is provided in Appendix 2. 
A Screening Visit (Visit 1) will be conducted up to 42 days before Day 1 (Baseline, Visit 2). 
Subjects who satisfy the inclusion and exclusion criteria will be randomized using an 
Interactive Response Technology (IRT) to treatment with either clazakizumab or placebo 
until the subject permanently discontinues IP, withdraws from the study, experiences allograft 
loss, dies, or reaches the CTED, whichever occurs first. Baseline assessments will be 
performed before the first dose of IP at Visit 2. Subjects will return Q4W for administration 
of IP. Safety monitoring, including eGFR, concomitant medication monitoring, and 
pregnancy testing (for women of childbearing potential [WOCBP]), will be conducted at 
dosing visits. eGFR will be assessed every other visit. Additional assessments of efficacy and 
safety will occur at Week 1, Q4W between Week 4 and Week 12, every 8 to 12 weeks up to 
Week 52, and then every 8 to 24 weeks until the EOT as detailed in Table 1 and Table 2. 
Prior to dosing at each visit, the most recent LFT and complete blood count (CBC) analyses 
and viral monitoring results (for polyoma BK virus [BKV], cytomegalovirus [CMV], and 
Epstein-Barr virus [EBV]) from a prior visit (scheduled or otherwise) will be reviewed for 


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safety considerations. At a minimum, these safety assessments will be performed per the SOE 
in Table 1 and Table 2. Based on the results of these safety assessments, the dose of IP may 
be reduced to 6.25 mg SC Q4W, temporarily withheld, or permanently discontinued as 
detailed in Section 7.5. A modification of the dose of background immunosuppression may 
also be recommended. 
All subjects, completed (ie, subjects who met any of the composite non-fatal all-cause 
allograft loss endpoints), or discontinued treatment with the intent to withdraw will complete 
an in-clinic visit for EOT assessments at the time of completion as described in the SOE. 
After the EOT Visit, subjects will be monitored for safety with monthly follow-up TCs for 
5 months after their last dose of IP if not withdrawn. During the 5-month safety follow-up 
period, subjects may be called in for a clinic visit at the discretion of the Investigator. An in-
clinic SFV is to be completed after the last of the 5-month TCs. Further details on SFV 
procedures for subjects who have completed or withdrew from the study can be found in 
Section 9.2.5.2 and 9.2.5.4, respectively. 
Subjects who permanently discontinued treatment with IP for any reason and who have not 
reached an endpoint of allograft loss or death, will continue in the study as described in 
Section 9.2.5.3. Following the in-clinic EOT / Early Withdrawal Visit within 4 weeks of 
receiving the last dose of IP, all subjects will be asked to return for 2 in-clinic Safety Follow-
up Visits, 3 and 5 months after receiving the last dose of IP. In addition, all subjects will be 
contacted by telephone call 1, 2, and 4 months after the last dose of IP for monitoring for new 
AEs, SAEs, or pregnancies. Thereafter, the subject will be asked to return in 6-month 
intervals until the CTED is reached to collect renal function and allograft status data. If a 
subject is unable to return for 6-monthly follow-up visits, he / she will be asked to agree to be 
contacted at CTED to collect allograft and survival status. 
Depending on the timing of early treatment discontinuation, this follow-up may consist of 
assessments conducted at regularly scheduled visits per-protocol and / or monthly follow-up 
TCs as needed and the in-clinic SFV to complete 5 months of safety monitoring following 
their last dose of IP. Subjects who permanently discontinued treatment with IP ≥ 5 months 
before their EOT Visit (and complete the remainder of the study visits) will not require any 
follow-up TCs. Further details on SFV procedures for subjects who permanently discontinued 
IP can be found in Section 9.2.5.3. 
Subjects who are receiving IP treatment at the time the target number or primary composite 
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(ie, the CTED) will return for a CTEV. Further details on CTEV procedures for subjects 
receiving IP at the time the CTED is reached can be found in Section 9.2.5.5. 
4.1.1 
PK / PD Substudy 
A subset of 44 subjects (out of the 350 enrolled in the main study) will have the option to 
participate in a PK / PD Substudy. The purpose of the PK / PD Substudy is to characterize the 
PK profile of clazakizumab in CABMR subjects and explore the relationship between 
clazakizumab concentration with IL-6 or hsCRP. Subjects enrolled in the PK / PD Substudy 
will provide consent for additional blood samples for the purpose of PK / PD analyses. 
4.2 
Dose Selection 
A full discussion for the dose selection rationale is provided in Appendix 4. 
CSLB has selected 12.5 mg SC injection Q4W as the target dose to be investigated in this 
pivotal trial. However, if required to manage any AEs that may be related to IP, the dose may 
be reduced to 6.25 mg SC Q4W. This dosing regimen is based on a rational dose justification 
considering the results of the clazakizumab nonclinical program and the safety and efficacy 
data from completed clinical trials where repeat dosing was studied, as well as comparison 
with the reported experience with TCZ (an anti-IL-6R mAb approved for use in RA and other 
indications) used in studies for the treatment of patients with ABMR and highly 
HLA-sensitized patients awaiting kidney transplant. Preliminary safety data from 
1 completed and 2 ongoing IITs in the kidney transplant setting were also considered. 
An extensive nonclinical program has been completed with clazakizumab. Further details of 
the nonclinical toxicology and safety pharmacology studies are provided in the CSL300 
Investigator’s Brochure. Results from both single- and repeat-dose SC (up to 4 weeks once a 
week [QW]) or 6 months once every 2 weeks (Q2W) or IV (up to 3 months QW) toxicology 
studies of clazakizumab in cynomolgus monkeys have demonstrated an acceptable safety 
profile, supporting its planned clinical use at 12.5 mg SC injection, Q4W. Results from an 
enhanced pre- and post-natal development study conducted in cynomolgus monkeys 
(DN13073) showed an increase in the number of monkeys with retention of the placenta at 
parturition at clazakizumab doses of 3 mg/kg Q2W (n = 2) and 30 mg/kg Q2W (n = 3), 
corresponding to doses 34 and 340 times a human dose of 12.5 mg Q4W (based on a 70 kg 
adult). These doses are expected to generate exposures approximately 48 and 480 times 
higher, respectively, than a human dose of 12.5 mg SC injection, Q4W. Regular pregnancy 
testing will be undertaken in WOCBP prior to every dose during the trial, and if positive, the 


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subject will discontinue treatment with IP and continue in the trial per-protocol (see 
Section 10.3.3). 
The completed clinical trials with clazakizumab provide an extensive safety database and 
drug exposure experience to define its safety profile, which is primarily associated with its 
IL-6 blocking effects. The AEs observed with clazakizumab have been described with other 
mAbs that block IL-6 signaling, such as TCZ and sarilumab. Clazakizumab has been studied 
in clinical trials in multiple subject populations including healthy subjects, patients with RA, 
PsA, advanced cancer, GVHD, and Crohn’s disease. These trials include 1056 subjects who 
received at least a single dose of clazakizumab with doses ranging from 1 mg to 640 mg, 
given by either IV or SC injection for up to 175 weeks (including long-term extension 
phases), corresponding to a maximum duration of exposure of 196 weeks. A detailed 
description of these trials is given in the CSL300 Investigator’s Brochure. 
In addition, preliminary safety data from 1 completed and 2 ongoing IITs in the kidney 
transplant setting are provided in the CSL300 Investigator’s Brochure. 
Selection of the proposed clazakizumab doses also takes into consideration the comparability 
of doses of clazakizumab and TCZ used in RA. Levels of CRP suppression seen with 
clazakizumab 5 mg and 25 mg SC injection Q4W are comparable to levels seen with TCZ 
8 mg/kg IV injection Q4W [Tocilizumab Arthritis Advisory Report, 2008]. Doses of 
clazakizumab 5 mg and 25 mg SC injection Q4W showed comparable efficacy to TCZ 
(4 mg/kg and 8 mg/kg IV injection Q4W) with respect to the American College of 
Rheumatology response rates and the Disease Activity Scores 28 (DAS-28) based on CRP 
[Tocilizumab Arthritis Advisory Report, 2008]. The comparability of the clazakizumab 5 mg 
and 25 mg SC doses to TCZ 4 mg/kg and 8 mg/kg IV doses, is consistent with the 3 to 
120 times higher potency of clazakizumab versus TCZ demonstrated in in vitro IL-6 
signaling assays [Zhao et al, 2013]. 
As summarized in Section 1.1, TCZ has also been used in several small, uncontrolled clinical 
trials for the treatment of kidney transplant recipients with ABMR [Chandran et al, 2017; 
Choi et al, 2017a; Choi et al, 2017b; Patel et al, 2017; Puliyanda et al, 2017; 
Venkatachalam et al, 2017] and in highly HLA-sensitized patients awaiting kidney transplant 
[Vo et al, 2015]. These trials mainly used the approved TCZ dose of 8 mg/kg IV monthly. 
Promising signals of efficacy with acceptable safety were seen in these trials. 
In conclusion, the proposed clazakizumab dose regimen balances the need to ensure subject 
safety and the potential for demonstrating a meaningful positive clinical response. 


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Nonclinical and clinical studies have shown clazakizumab to be a potent and full antagonist 
of IL-6 with similar pharmacological properties and clinical effects to TCZ. The target dose 
of clazakizumab 12.5 mg SC Q4W is comparable to the dose of TCZ that has been used in 
clinical trials in kidney transplant recipients with ABMR and in highly HLA-sensitized 
patients awaiting kidney transplant. Given that a dose of clazakizumab as low as 5 mg SC 
Q4W showed comparable CRP suppression and clinical efficacy to TCZ 8 mg IV Q4W and 
considering the AEs / SAEs reported in the ongoing IITs with the higher clazakizumab dose 
(25 mg SC Q4W), 12.5 mg SC Q4W was chosen as the target dose for Study VKTX01. A 
higher rate of reported SAEs with TCZ 8 mg/kg (versus 4 mg/kg) IV Q4W was also 
considered [Actemra® Product Monograph (Canada), 2018]. The protocol has been designed 
to exclude subjects with known and potential risk factors to anti-IL-6 blockade and will 
include safety monitoring procedures during the trial to minimize these risks. 
4.3 
Duration of Subject Participation and Study 
The average study duration for an individual subject will be approximately 5.5 years. This 
includes a Screening Period of up to 42 days, a Treatment Period from Day 1 until the subject 
permanently discontinues IP, withdraws from the study, experiences allograft loss, dies, or 
reaches the CTED, whichever occurs first (approximately 260 weeks on average), and a 
Follow-up period of 5 months after the last dose of IP (completion or early termination). The 
CTED will be communicated to study sites when the target number of primary composite all-
cause allograft loss or irreversible loss of allograft function events (221) has been reached to 
enable study sites to plan their subjects’final visit (CTEV). 
4.4 
Access to Study Product After the End of Study 
After completion of the study, clazakizumab will, at the discretion of the treating physician, 
be offered to subjects as agreed upon in their respective country and provided via country-
specific access program(s). Subjects who withdraw from the study and / or permanently 
discontinued treatment before the CTED are not eligible. 


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5. 
Selection and Withdrawal of Subjects 
5.1 
Number of Subjects 
Approximately 350 subjects will be randomized 1:1 into 2 treatment arms using a stratified 
block randomization scheme: 175 subjects in the clazakizumab group and 175 subjects in the 
placebo group. Subjects will be enrolled at approximately 155 study sites worldwide. 
5.2 
Inclusion Criteria 
Unless specified otherwise, all inclusion criteria time intervals are assessed with respect to 
the Screening Visit. In order to be eligible to participate in the trial, a subject must meet all of 
the following inclusion criteria: 
1.A8  Age 18 to 75 years. 
2. 
Living donor / deceased donor kidney transplant recipients ≥ 6 months from time of 
transplant. 
3.A9 Diagnosis of CABMR determined by kidney biopsy and the presence of HLA DSA 
using single-antigen bead-based assays. For eligibility, kidney biopsy must not be 
older than 12 months and DSA analysis must be performed no longer than 6 months 
prior to the start of Screening. 
NOTE: 
• Within 3 months prior to the start of Screening, treatments for ABMR or 
TCMR, with the exception of steroids*, are not allowed (see Exclusion 
Criterion 3). 
• If treatment for ABMR (including CABMR) or TCMR (other than steroids*) 
was given between 3 to 12 months of Screening, a repeat kidney biopsy and 
DSA analysis are required at least 6 weeks after the end of treatment to 
confirm continuing CABMR and presence of HLA DSA and to determine 
eligibility. 
* A maximum dose of 2g of methylprednisolone intravenously (or dose equivalent of 
other steroids), followed by a taper to the original maintenance steroid dose is 
allowed. 


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The following histopathologic and serologic diagnostic criteria (based on Banff 2015 
criteria [Loupy et al, 2017]) must be met for inclusion: 
a. 
Morphologic evidence of chronic tissue injury, as demonstrated by TG 
(chronic glomerulopathy [cg] > 0). Biopsies without evidence of chronic tissue injury 
on light microscopy, but with glomerular basement membrane double contours on 
electron microscopy (cg1a) are eligible. 
b. 
Evidence of current / recent antibody interaction with vascular endothelium, 
including 1 or more of the following: 
i. 
Linear C4d staining in peritubular capillaries or medullary vasa recta (Banff 
scores C4d2 or C4d3 by immunofluorescence on frozen sections, or C4d > 0 
by immunohistochemistry on paraffin sections). 
ii. 
At least moderate microvascular inflammation ([glomerulitis score, g + 
peritubular capillaritis score, ptc] ≥ 2) in the absence of recurrent or de novo 
glomerulonephritis, although in the presence of acute TCMR, borderline 
infiltrate, or infection, ptc ≥ 2 alone is not sufficient and g must be ≥ 1. 
NOTE: The local pathologist’s diagnosis must be reviewed by a central 
pathologist to confirm eligibility for entry into the study. Biopsies with other 
histopathologic changes (eg, BKV nephropathy or recurrent 
glomerulonephritis) may be eligible if concurrent CABMR changes (as 
detailed above) are present and determined to be the predominant cause of 
renal dysfunction. 
c. 
Serologic evidence of circulating HLA DSA. 
NOTE: The local laboratory DSA results must be reviewed and confirmed by the 
central HLA reviewer during the Screening Period. 
4. 
Written informed consent obtained from the subject (or legally acceptable 
representative) before any trial-related procedures. 
 
5.3 
Exclusion Criteria 
Unless specified otherwise, all exclusion criteria time intervals are assessed with respect to 
the Screening Visit. 
1.A8 
Subject is unable or unwilling to comply with study procedures in the opinion of the 
Investigator. 


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2.A6 
Multi-organ transplant recipient (except for simultaneous kidney-pancreas or previous 
multiple kidney transplants) or cell transplant (islet, bone marrow, stem cell) recipient. 
3. 
Treatment for ABMR (including CABMR) or TCMR within 3 months prior to the 
start of Screening with the exception of steroids. 
4. 
Received T cell depleting agents (eg, alemtuzumab, anti-thymocyte globulin) within 
3 months prior to the start of Screening. 
5. 
Treatment with mechanistic target of rapamycin (mTOR) inhibitors within 4 weeks 
prior to the start of Screening (see Section 7.6.1). 
6.A9 
Biopsy indicating predominant cause of renal dysfunction caused by pathology other 
than CABMR, within 12 months prior to the start of Screening. 
7.A8 
Impaired renal function due to disorders in the transplanted allograft (eg, renal artery 
stenosis, significant vascular disease of the donor, hydronephrosis). 
8. 
eGFR < 25 mL/min/1.73 m2 or > 65 mL/min/1.73 m2 (MDRD4). 
9.A8 
Nephrotic range proteinuria defined as spot UACR ≥ 2200 mg/g (≥ 248.4 mg/mmol). 
If spot UACR is above the defined limits, a single repeat test can be performed on a 
separate day to confirm ineligibility. 
10.A9 
Pregnant, breastfeeding, or unwillingness to practice adequate contraception (eg, a 
highly effective method of contraception) during the study and for 5 months after the 
last dose of IP. 
11.A9 
History of anaphylaxis or known hypersensitivity related to clazakizumab or to any 
constituent of the drug product. 
12.A8 
Abnormal LFTs (alanine aminotransferase [ALT] or aspartate aminotransferase 
[AST] or bilirubin > 1.5 x upper limit of normal [ULN]) or other significant liver 
disease. Subjects with an established diagnosis of Gilbert’s syndrome are allowed. 
13.A8 
Active tuberculosis (TB) or history of active TB. 
14.A8 
History of latent TB (eg, positive QuantiFERON-TB test) without history of active 
TB unless the subject has completed a documented course of prophylactic treatment. 
15. 
History of HIV infection or positive for HIV. 
16. 
Seropositive for hepatitis B surface antigen (HBsAg). 
17. 
HCV RNA positive. 
18.A8 
Known EBV mismatch (at time of transplant): donor seropositive, recipient 
seronegative. Seroconversion to EBV IgG-positive post-transplant is allowed, if 
documented. 


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19.A8 
History of GI perforation; diverticular disease defined as clinically significant 
diverticulosis (except if disease has been fully excised and the subject has recovered 
from surgery) or diverticulitis (except if disease has been fully excised and the 
subject has recovered from surgery); or inflammatory bowel disease (except fully 
excised ulcerative colitis and the subject has recovered from surgery). 
20.A8 
Neutropenia (< 1500/mm3) or thrombocytopenia (< 75,000/mm3). 
21. 
Active infections requiring systemic antimicrobial agents and unresolved prior to 
Screening. 
22.A8 
History of or current invasive fungal infection or other opportunistic infection, 
including (but not limited to) the following: a nontuberculous mycobacterial 
infection, aspergillosis, pneumocystosis, and toxoplasmosis, etc. 
23.A8 
Active viral infections such as BKV, CMV, or EBV based on plasma PCR testing. 
Active infection is defined as a test result ≥ LLOQ – see definition in Table 6. 
24. 
Current or recent (within 3 months) participation in an interventional trial. 
25. 
Administration of a live vaccine within 6 weeks prior to the start of Screening, 
including but not limited to the following: 
a. Adenovirus. 
b. Measles, mumps, and rubella. 
c. Oral polio. 
d. Oral typhoid. 
e. Rotavirus. 
f. Varicella zoster. 
g. Yellow fever. 
26.A8 History of alcohol or illicit substance (including marijuana) abuse < 5 years before 
Screening. 
27.A8 Present or previous (within 3 years) malignancy except for basal cell carcinoma, 
fully excised squamous cell carcinoma of the skin; other malignancies or those that 
required significant therapy may require longer duration documented cancer-free 
(5 years) such as non-recurrent cervical carcinoma in-situ or malignancy treated with 
resection and chemotherapy. These cases should be discussed with the Medical 
Monitor and Sponsor on a case-by-case basis. 


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28. 
The presence of a condition or abnormality (ie, clinically significant endocrine, 
autoimmune, metabolic, neurological, psychiatric / psychological, renal, GI, 
hepatic, and hematological or any other system abnormalities that are uncontrolled 
with standard treatment) that in the opinion of the Investigator would compromise 
the safety or life expectancy of the subject or the quality of the data. 
29.A9 
History of intolerance to trimethoprim and / or sulfamethoxazole. This criterion 
does not apply if the subject is already taking another suitable Investigator-approved 
alternative therapy for Pneumocystis jiroveci pneumonia (PJP) prophylaxis, or if the 
subject is willing to begin taking a suitable Investigator-approved alternative 
prophylactic therapy approximately 1 week prior to the Day 1 Baseline Visit 
(Visit 2). 
30. 
Prior exposure to clazakizumab, TCZ, or other IL-6 / IL-6R blockers. 
31. 
ABO-incompatible transplant recipient. 
32. 
Severe hypogammaglobulinemia (defined as immunoglobulin G [IgG] 
< 400 mg/dL). 
33. 
Prior (within 2 years prior to the start of Screening) exposure to proteasome 
inhibitors (eg, bortezomib). 
34.A9 
Active infection with coronavirus disease 2019 (COVID-19). Subjects must have a 
negative rapid antigen test or PCR test result during the Screening Period as near to 
the Day 1 Baseline Visit (Visit 2) as possible. If the subject is unwell with 
symptoms suggestive of COVID-19 but rapid antigen test or PCR test result is 
negative, other causes for symptoms must be ruled out to determine subject 
eligibility. Subjects must be without symptoms attributable to COVID-19 for at 
least 1 month prior to the start of Screening. 
35.A9 
For subjects receiving anti-hypertensive agents (eg, Angiotensin-converting enzyme 
inhibitor [ACEIs] or angiotensin II receptor blockers [ARBs]), the dose of the agent 
has been stable for at least 2 months prior to the start of Screening. 
5.4 
Adequate Contraception 
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP 
on the importance of pregnancy prevention and the implications of an unexpected pregnancy. 
Investigators shall advise these subjects on the use of adequate methods of contraception and 
will check for adherence during study visits. 


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The Clinical Trials Facilitation and Coordination Group (CTFG) provides recommendations 
related to contraception and pregnancy testing in clinical trials. The following methods of 
contraception are considered adequate for this study: 
Highly effective methods of contraception: Highly effective methods of contraception have a 
failure rate of < 1% per year when used consistently and correctly. The following methods are 
considered highly effective: 
• Hormonal methods of contraception including combined oral contraceptive pills, vaginal 
ring, injectables, implants, and intrauterine devices such as Mirena® by female subject or 
male subject’s female partner. Administration of clazakizumab may decrease the efficacy 
of hormonal contraceptive methods. A WOCBP subject using a hormonal contraceptive 
method must also supplement with a barrier method of contraception (preferably male 
condom). 
• Nonhormonal intrauterine devices, such as ParaGard®. 
• Tubal ligation. 
• Vasectomy. 
• Complete abstinence: Complete abstinence is defined as complete avoidance of 
heterosexual intercourse and is a highly effective method form of contraception for all 
IPs. However, WOCBP must continue to have pregnancy tests. 
Subjects must agree to use adequate contraception during the study and for 5 months after the 
last dose of IP. 
5.5 
Withdrawal from Study 
It is the subject’s right to withdraw consent from study participation at any time without 
having to provide a reason. In this case, the source documents and the eCRF should 
document the reason for discontinuation as “withdrawal of consent.” Withdrawn subjects will 
not be replaced. No further assessments will be performed after withdrawal of consent. 
Subjects may also be withdrawn at the Investigator’s discretion if it is in the subject’s best 
interest. 
Every effort should be made before the subject withdraws from the study, either voluntarily 
or at the Investigator’s discretion, to undergo EOT assessments and safety follow-up as it is 
in the best interest of the subject. If possible, the subject will return for an in-clinic EOT / 
Early withdrawal visit within 4-weeks of the subject’s last dose of IP. If the subject agrees to 


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the safety follow-up following the EOT/ Early withdrawal visit, all subjects will be asked to 
return for 2 in-clinic Safety Follow-up Visits, 3 and 5 months after receiving the last dose of 
IP. In addition, all subjects will be contacted by TC 1, 2, and 4 months after the last dose of IP 
for monitoring for new AEs, SAEs, or pregnancies. 
If a subject refuses the EOT / Early withdrawal visit, safety follow-up TCs, and / or SFV(s), 
the reason for refusal should be fully documented in the subject’s source document and 
recorded in the electronic case report form (eCRF). 
5.6 
Withholding or Permanent Discontinuation of Investigational 
Product 
Subjects considered for withholding or discontinuation of IP should be discussed with the 
Medical Monitor where possible. If IP is withheld or discontinued, an explanation of this 
clinical decision will be documented on the eCRF and the subject may be called into the 
clinic for an unscheduled visit, at the discretion of the Investigator. If the reason for 
withholding or discontinuing IP is an AE or an abnormal laboratory test result, the specific 
event or test will be recorded as an AE in the eCRF. 
Withholding of Investigational Product 
While IP is withheld, subjects will continue in the study, attend all regular clinic visits and 
undergoing all study assessments per Table 1 and Table 2, and comply with all aspects of the 
protocol. If IP is withheld for ≥ 3 consecutive doses because of an AE, the Investigator should 
consult with the Sponsor to consider discontinuing IP permanently. 
Discontinuation of Investigational Product 
Subjects who permanently discontinued treatment with IP for any reason and who have not 
reached an endpoint of composite all-cause allograft loss or irreversible loss of allograft 
function, defined as: 
•
eGFR < 15 mL/min/1.73 m2*
•
return to dialysis*
•
allograft nephrectomy
•
retransplantation
•
death from any cause, or
•
a sustained (≥ 60 days) 40% decline in eGFR from Baseline,
will continue in the study as described in Section 9.2.5.3.
(*total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days.) 


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If the eGFR < 15 mL/min/1.73 m2 is the only component reached, the value must be 
sustained over at least 60 days and must be confirmed by a repeat measurement after 
≥60 days from the date of the first measurement. The confirmatory measurement of 
eGFR < 15 mL/min/1.73 m2 done at least 60 days from the initial measurement must be 
processed by the central laboratory. 
If possible, the subject will return for an in-clinic EOT / Early withdrawal visit within 4-
weeks of the last dose of IP. Following the EOT / Early withdrawal visit, subjects will be 
asked to return for 2 in-clinic Safety Follow-up Visits, 3 and 5 months after receiving the last 
dose of IP. In addition, all subjects will be contacted by TC 1, 2, and 4 months after the last 
dose of IP for monitoring for new AEs, SAEs, or pregnancies. Thereafter, the subject will be 
asked to return in 6-month intervals until the CTED is reached to collect renal function and 
allograft status data. 
Subjects who are pregnant will permanently discontinue treatment with IP and continue in the 
study as described in Section 9.2.5.3. Monitoring and reporting of pregnancies is described in 
Section 10.3.3. 
5.6.1 
Withholding or Discontinuation of Investigational Product Due to 
an Adverse Event 
Subjects may have IP withheld or permanently discontinued due to the occurrence of an AE. 
If a subject is discontinued from receiving double-blind medication due to an AE, the event 
should be followed by the Investigator through regular contact with the subject until 
resolution or stabilization has occurred or the subject is lost to follow-up. Every effort must 
be made to perform protocol specified safety follow-up procedures (see Section 10.3). 
Subjects who permanently discontinued IP treatment due to an AE, and who have not reached 
an endpoint of composite all-cause allograft loss or death will continue in the study as 
described in Section 9.2.5.3. 
5.6.2 
Withholding or Discontinuation of Investigational Product Due to 
Abnormal LFTs 
The guidelines for dose modification, withholding, or discontinuing IP due to abnormal LFTs 
are described in Table 5. 
Subjects who permanently discontinued IP treatment due to abnormal LFTs, and who have 
not reached a composite endpoint of all-cause allograft loss or death will continue in the 
study as described in Section 9.2.5.3. 


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5.6.3 
Withholding or Discontinuation of Investigational Product Due to 
Neutropenia and / or Thrombocytopenia 
The guidelines for dose modification, withholding, or discontinuing IP due to neutropenia 
and / or thrombocytopenia are described in Table 5. 
Subjects who permanently discontinued IP treatment due to neutropenia and / or 
thrombocytopenia, and who have not reached a composite endpoint of all-cause allograft loss 
or death will continue in the study as described in Section 9.2.5.3. 
5.6.4 Discontinuation of Investigational Product Due to BKV, CMV, or 
EBV Viral Infection 
The guidelines for dose modification, withholding, or discontinuing IP due to BKV, CMV, or 
EBV viral infection are described in Table 6. Subjects who are discontinued from IP will be 
treated as deemed appropriate by the Investigator. 
Subjects who permanently discontinued IP treatment due to BKV, CMV, or EBV viral 
infection, and who have not reached a composite endpoint of all-cause allograft loss or death 
will continue in the study as described in Section 9.2.5.3. 
6. 
Randomization, Blinding and Unblinding Procedures 
6.1 
Randomization 
All enrolled subjects will be assigned a unique subject number, and the Investigator will 
maintain a list of subject numbers and subject names. 
Approximately 350 subjects will be randomized (via an IRT) 1:1 into the 2 treatment arms 
using a stratified block randomization scheme: 175 subjects in the clazakizumab group and 
175 subjects in the placebo group. Instructions for the IRT will be provided in a separate 
manual. 
Stratification factors will include Baseline eGFR (25 to 45 mL/min/1.73 m2 or 
> 45 mL/min/1.73 m2; Baseline eGFR is defined as an average of 2 pre-treatment 
measurements up to 8 weeks apart); Baseline proteinuria (UACR < 300 mg/g 
[< 30 mg/mmol] or UACR ≥ 300 mg/g [≥ 30 mg/mmol]); treatment for early (within 6 
months of transplant) ABMR rejection episodes (yes / no); and treatment for late (greater 
than 6 months post-transplant) ABMR rejection episodes (yes / no). 


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6.2 
Blinding 
This study is double-blind and therefore neither the Investigator, the subject, the Sponsor and 
its representatives (eg, Contract Research Organization [CRO], health care provider), nor 
other designated study site personnel involved in running of the study will be aware of the 
identification of the IP administered to each subject. To maintain blinding, interim analyses 
(see Section 12.11) will be conducted by the DSMB. Detailed procedures for maintaining the 
blind are specified in the DSMB charter and / or Data Access Plan. 
Given that clazakizumab and placebo are packaged differently, IP will be prepared and 
dispensed by an unblinded pharmacist / qualified personnel at each investigational site. To 
maintain blinding during the study, the pharmacist / designated staff will dispense either 
clazakizumab or placebo into identical syringes, according to each subject’s randomized 
treatment allocation, and all subjects will receive each dose of IP (clazakizumab or placebo) 
as a SC injection (see Section 7.2 and the IMP Manual). 
The pharmacist / designated staff will ensure that blinded personnel will not have access to 
drug supply records. 
6.3 
Unblinding 
In the event that an AE occurs for which knowledge of the identity of the IP administered is 
necessary to manage the subject’s condition and / or for regulatory reporting of a suspected 
unexpected serious adverse reaction (SUSAR), the blinding code for that subject may be 
broken by the Sponsor’s Global Clinical Safety and Pharmacovigilance (GCSP) personnel 
not directly involved with the study. The blinding code is obtained via IRT and is provided to 
the Investigator by the GCSP personnel not directly involved with the study. The GCSP 
physician and other personnel involved in the study remain blinded. 
Emergency unblinding should only be considered if the safety of the subject is at risk and 
planned interventions depend on the knowledge of the administered drug (clazakizumab or 
placebo). If the safety of the subject is not at risk and unblinding is deemed necessary by the 
Investigator, the Investigator should make a reasonable attempt to contact the Medical 
Monitor to discuss a potential unblinding. Only after a reasonable, but unsuccessful attempt 
has been made to consult with the Medical Monitor, the Investigator can unblind the subject’s 
treatment allocation using the IRT. The Investigator must note the date, time, and reason for 
unblinding. The subject’s treatment allocation should not be recorded in the subject’s source 
documents. The Investigator should also subsequently inform the Medical Monitor that the 
subject was unblinded. However, the subject’s treatment allocation should not under any 


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circumstances be revealed to the study team (Sponsor and their representatives). Details of 
unblinded treatment assignments should also not be shared with the Study Monitor, site 
personnel, or Sponsor team or their representatives (CRO) unless necessary for emergency 
care. 
7. 
Study Treatments 
7.1 
Dosage Forms / Formulation 
All IPs used in this study have been manufactured in accordance with current Good 
Manufacturing Practice. 
7.1.1 
Clazakizumab – Investigational Treatment 
Clazakizumab will be provided to study sites by CSLB. 
Generic name:  
Clazakizumab 
Active ingredient: Genetically engineered humanized anti-IL-6 mAb 
Strength: 
12.5 mg/mL 
Excipients: 
L-histidine, L-histidine monohydrochloride, sorbitol, polysorbate-80, 
and water for injection 
Dosage form: 
Single-dose vials (12.5 mg/mL) for injection 
Drug Product: 
Clear to slightly opalescent, colorless to yellow colored solution 
(12.5 mg/mL vial) 
Manufacturer: 
Patheon, Greenville, NC 
 
Storage: Clazakizumab must be stored according to the labeled conditions. 
7.1.2 
Placebo Control 
The placebo will be sourced locally at each study center from commercially available saline. 
Generic name:  
NaCl (normal saline) 
Active ingredient: NaCl 
Strength: 
0.9% w/v NaCl as a sterile solution 
Excipients: 
None 
Storage: 
Per product labeling 
7.1.3 
Pneumocystis Jiroveci Pneumonia Prophylaxis 
All subjects will be required to take prophylactic treatment for PJP; these drugs will be 
prescribed and supplied by the investigational sites. For the first year of the study (ie, from 


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Screening up to and including Week 52), PJP prophylaxis should be administered per the 
dosing guidelines in Section 7.1.3.1 and Section 7.1.3.2. For the remainder of the study (ie, 
after Week 52), PJP prophylaxis should be continued at the discretion of the Investigator. 
7.1.3.1 
Trimethoprim / Sulfamethoxazole 
Year 1 (Screening to Week 52 Inclusive) 
Oral trimethoprim / sulfamethoxazole: 
Single-strength pill (80 mg as trimethoprim) daily, or 
Double-strength pill (160 mg as trimethoprim) 3 times per week. 
It is recommended that treatment with trimethoprim / sulfamethoxazole should be started 
approximately 1 week before the Day 1 Baseline Visit (Visit 2) (for subjects not already 
taking trimethoprim / sulfamethoxazole or other suitable Investigator-approved PJP 
prophylactic therapy prior to entry in the study) or 1 week before Screening if already taking 
it. 
In the event of acute kidney injury (AKI)(eg, interstitial nephritis) considered related to 
trimethoprim / sulfamethoxazole, prophylactic treatment with this drug should be 
discontinued, and the subject should be started on another antibiotic therapy for PJP 
prophylaxis (see Section 7.1.3.2). In the event of other serious adverse reactions, the Medical 
Monitor should be consulted with respect to discontinuing prophylactic treatment or 
switching to another prophylactic treatment. 
Year 2 to the Safety Follow-up Visit 
For the remainder of the study (ie, after Week 52), PJP prophylaxis should be continued at the 
discretion of the Investigator. 
7.1.3.2 
Other Antibiotics for Pneumocystis Jiroveci Pneumonia 
Prophylaxis 
Year 1 (Screening to Week 52 Inclusive) 
Subjects who are already receiving PJP prophylactic therapy (other than trimethoprim / 
sulfamethoxazole) at Screening, may remain on their current therapy at the discretion of the 
Investigator and not start trimethoprim / sulfamethoxazole. If the Investigator does not 
consider a subject’s current prophylactic therapy to be appropriate, trimethoprim / 
sulfamethoxazole should be started approximately 1 week before the Day 1 Baseline Visit 
(Visit 2) (see dosing guidelines in Section 7.1.3.1). Subjects who are intolerant to 


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trimethoprim / sulfamethoxazole and not already receiving a suitable Investigator-approved 
alternative therapy should be started on atovaquone (mepron), inhaled pentamidine, or oral 
dapsone, for approximately 1 week before the Day 1 Baseline Visit (Visit 2) based on 
consultation with the Medical Monitor. 
Year 2 to the Safety Follow-up Visit 
For the remainder of the study (ie, after Week 52), PJP prophylaxis should be continued at the 
discretion of the Investigator. 
7.2 
Dosage and Administration of Investigational Product – 
Clazakizumab or Placebo 
All IP administration will be performed by trained, qualified staff. Clazakizumab will be 
administered at a target dose of 12.5 mg Q4W by SC injection with the possibility of a 
reduced dose of 6.25 mg Q4W by SC injection to support potential dose reductions directed 
by protocol-defined safety parameters (see Section 7.5). 
Clazakizumab or placebo will be administered Q4W by SC injection. Each 12.5 mg dose will 
be administered as a 1 mL injection of clazakizumab (12.5 mg/mL) or placebo by blinded 
qualified study personnel at each site. Each 6.25 mg dose will be administered as a 0.5 mL 
injection of clazakizumab (12.5 mg/mL) or placebo by blinded qualified study personnel at 
each site. All IP administrations will be documented in the subject’s source documents and in 
the eCRF. 
For additional information on the preparation and dispensation of IP, please refer to the IMP 
Manual. 
7.3 
Packaging and Labeling 
Clazakizumab will be supplied as single-dose vials. Vials are 2 mL flint glass, containing 
clazakizumab (12.5 mg/mL) to deliver 1 mL (12.5 mg). Vials of clazakizumab will be labeled 
with an Annex 13 compliant label. 
7.4 
Site Supply, Storage, and Accountability 
7.4.1 
Site Supply 
Once a subject is screened, the site will be supplied with an initial stock of clazakizumab. 
Placebo (normal saline) will be sourced as described in the Pharmacy / IMP Manual. An 
unblinded pharmacist / qualified personnel will prepare and dispense IP in filled, identical 


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syringes for injection (see Section 7.2). IP will be administered at the clinic by the 
Investigator / designee. 
The need for drug resupply will be assessed on a regular basis considering the number of 
subjects enrolled and the number of subjects in Screening at the site. Resupply is triggered 
automatically by an IRT system based on site /subject needs. 
7.4.2 
Storage 
Clazakizumab (and placebo) should be stored at conditions specified in the product labeling. 
For storage of filled syringes, see the IMP Manual. 
7.4.3 
Accountability 
The Investigator at each site is ultimately responsible for accountability of IP supplies 
(including prophylactic antibiotics where applicable). The Investigator / designee will ensure 
that an accurate and current accounting of the dispensing of IP for each subject is maintained 
on an ongoing basis by the study site unblinded pharmacist / designee (see Section 7.4.1). All 
data regarding the IP (eg, vial numbers) must be recorded on the eCRF by the unblinded 
pharmacist / designee and on any other relevant forms provided. The Investigator is 
ultimately responsible for ensuring that only study subject receive IP. 
Further details regarding IP accountability and the drug accountability log will be provided in 
the Pharmacy / IMP Manual. 
7.4.4 
Destruction of Investigational Product 
For this study, IP such as partially used IP vials and syringes may be destroyed on-site. 
Any unused IP vials can only be destroyed only after being inspected and reconciled by the 
responsible unblinded Study Monitor, after approval by the Sponsor. 
On-site destruction is allowed. If conditions for destruction cannot be met, the responsible 
Study Monitor will make arrangements for return of IP. 
It is the Investigator’s responsibility to arrange for disposal of all empty containers, provided 
that procedures for proper disposal have been established according to applicable federal, 
state, local, and institutional guidelines and procedures, and provided that appropriate records 
of disposal are maintained. 


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Further details describing the procedures for destruction of unused materials will be provided 
in the Pharmacy Manual. 
7.5 
Guidelines for Dose Modification, Withholding or Discontinuation of 
Investigational Product and / or Modification of Background 
Immunosuppression 
During the study, subjects will be monitored for abnormal LFTs, neutrophil and platelet 
counts, and viral infection with BKV, CMV and EBV as detailed in the SOE. Based on the 
results of these assessments, the dose of IP may be reduced to 6.25 mg SC Q4W (temporarily 
or permanently), temporarily withheld, or permanently discontinued as detailed in 
Sections 7.5.1 and 7.5.2. Once the AE has resolved, IP may be restarted at the reduced dose 
or at the target dose. Decisions regarding dose modification, withholding, discontinuation, or 
restarting of IP should be made in consultation with the Medical Monitor (as per the dose 
modification guidance provided below). Background immunosuppression may also be 
reduced. 
During the study, subjects will also be monitored for hypogammaglobulinemia (IgG 
< 400 mg/dL). Based on IgG levels, background immunosuppression may be reduced or 
discontinued, and subjects may be treated with IVIG (see Section 7.5.3). Decisions regarding 
dose modification / treatment should be made in consultation with the Medical Monitor. 
In general, the approach to IP dose modification, withholding, discontinuation, or restarting 
described for abnormal LFTs (Table 5) should be followed at the discretion of the 
Investigator for any laboratory abnormality depending on the CTCAE severity (CTCAE 
Grade 1 [mild], Grade 2 [moderate], Grade 3 [severe or medically significant]) and corrective 
actions taken. In the case of neutropenia or thrombocytopenia, guidelines for modification of 
mycophenolate mofetil (MMF) / mycophenolic acid (MPA) / azathioprine (AZA) are also 
provided in Table 5. 
Similarly, the approach to IP dose modification, discontinuation, withholding or restarting 
described for BKV, CMV, and EBV infection (Table 6) should be followed for any other 
clinically significant infection. IP should be withheld, or dose reduced to 6.25 mg SC Q4W, 
and the subject should be managed as per clinical practice with respect to background 
immunosuppressants. Once the infection has been treated and resolved, IP can be restarted at 
the reduced dose or dose increased back to 12.5 mg SC Q4W at the discretion of the 
Investigator. Guidelines for modification of background immunosuppression are also 
provided in Table 6. 


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If IP is withheld for 3 consecutive doses because of an AE, the Investigator should consult 
with the Medical Monitor to consider discontinuing IP permanently. 
Subjects who permanently discontinued treatment with IP because of an AE, and who have 
not reached a non-fatal composite endpoint of all-cause allograft loss or irreversible loss of 
allograft function will continue in the study and undergo EOT assessments within 4 weeks of 
receiving the last dose of IP. Subjects will be asked to return for 2 in-clinic Safety Follow-up 
Visits, 3 and 5 months after receiving the last dose of IP. In addition, all subjects will be 
contacted by telephone call 1, 2, and 4 months after last dose of IP for monitoring for new 
AEs, SAEs, or pregnancies. Thereafter, the subject will be asked to return in 6-month 
intervals until the CTED is reached to collect renal function and allograft status data 
(Section 9.2.5.3). 
Subjects who permanently discontinued IP treatment due to loss of their allograft will 
undergo EOT / Early Withdrawal assessments and be contacted monthly for post-treatment 
follow-up for 5 months after their last dose of IP. An in-clinic SFV will be performed after the 
5-month safety follow-up period (see Section 9.2.5.2). 
7.5.1 Guidelines for Dose Modification, Withholding or Discontinuation of 
Investigational Product and / or Modification of Background 
Immunosuppression Based on Abnormal LFTs, Neutropenia, or 
Thrombocytopenia 
During the study, LFT abnormalities will be monitored and neutropenia and 
thrombocytopenia will be evaluated at Screening and every 4 to 8 weeks in Year 1, and Q8W 
weeks after Year 1 as detailed in the SOE. Depending on CTCAE Version 5.0 severity 
grading, IP dose reduction (to 6.25 mg SC Q4W), withholding or discontinuation will be 
permitted in the event of abnormal LFTs (ie, AST / ALT), neutrophil, or platelet counts as per 
Table 5. IP should be temporarily withheld or discontinued for any LFT abnormalities, 
neutrophil or platelet counts that meet CTCAE Grade ≥ 3 (see also Sections 5.6.2 and 5.6.3, 
respectively). Once the AE resolves, IP may be restarted (at reduced dose or target dose) if 
clinically appropriate. Table 5 provides further guidelines for dose adjustment of IP and / or 
background immunosuppression according to CTCAE severity grade. Decisions regarding 
dose modification, withholding, discontinuation, or restarting of IP should be made in 
consultation with the Medical Monitor. 


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Table 5 Guidelines for Dose Modification, Withholding or Discontinuation of 
Investigational Product and / or Modification of Background 
Immunosuppression Based on Abnormal LFTs, Neutropenia, or 
Thrombocytopenia 
Parameter 
Guidelines for Modification of Dose of Investigational Product and / or 
Background Immunosuppression 
LFTs (AST / ALT) 
> ULN to 3.0 x ULN 
(CTCAE Grade 1) 
• 
No change to IP dose. 
> 3.0 to 5.0 x ULN 
(CTCAE Grade 2) 
• 
In addition, if total bilirubin is ≥ 2.0 x ULN (or INR > 1.5), withhold or 
discontinue IP and contact Medical Monitor. 
• 
If total bilirubin is < 2.0 x ULN, reduce dose of IP to 6.25 mg SC Q4W. 
Repeat LFT analysis every 2 to 4 weeks and consult Medical Monitor. 
• 
Increase dose of IP back up to 12.5 mg SC Q4W if circumstances allow 
or continue at 6.25 mg SC Q4W. 
• 
Perform investigations to exclude other causes of abnormal LFTs (eg, 
other hepatotoxic drugs, alcohol, viral infections, autoimmune hepatitis, 
hemochromatosis, etc). 
> 5.0 x ULN 
(CTCAE Grade ≥ 3) 
• 
Withhold or discontinue IP and contact Medical Monitor. 
LFTs (Total bilirubin) 
> 3.0 x ULN 
• 
Withhold or discontinue IP and contact Medical Monitor. 
Neutrophils (cells per mm3) 
< 2500 to 1500 
(CTCAE Grade 1) 
• 
Reduce dose of MMF / MPA / AZA by 50%. 
• 
No change to IP dose.  
< 1500 to 1000 
(CTCAE Grade 2) 
• 
Reduce dose of MMF / MPA / AZA by 50%. 
• 
Reduce dose of IP to 6.25 mg SC Q4W. Repeat CBC every 2 to 4 weeks 
and consult Medical Monitor. 
• 
Increase dose of IP back up to 12.5 mg SC Q4W if circumstances allow 
or continue at 6.25 mg SC Q4W. 
< 1000 
(CTCAE Grade ≥ 3) 
• 
Withhold or discontinue IP and contact Medical Monitor. 
Platelets (cells per mm3) 
< LLN to 75,000 
(CTCAE Grade 1) 
• 
Reduce dose of MMF / MPA / AZA by 50%. 
• 
No change to IP dose. 


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Parameter 
Guidelines for Modification of Dose of Investigational Product and / or 
Background Immunosuppression 
< 75,000 to 50,000 
(CTCAE Grade 2) 
• 
Reduce dose of MMF / MPA / AZA by 50%. 
• 
Reduce dose of IP to 6.25 mg SC Q4W. Repeat CBC every 2 to 4 weeks 
and consult Medical Monitor. 
• 
Increase dose of IP back up to 12.5 mg SC Q4W if circumstances allow 
or continue at 6.25 mg SC Q4W. 
< 50,000 
(CTCAE Grade ≥ 3) 
• 
Withhold or discontinue IP and contact Medical Monitor. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; AZA = azathioprine; CBC = complete blood count; 
CTCAE = Common Toxicity Criteria for Adverse Events; INR = International Normalized Ratio; IP = investigational 
product; LFT = liver function test; LLN = lower limit of normal; MMF = mycophenolate mofetil; MPA = mycophenolic 
acid; Q4W = once every 4 weeks; SC = subcutaneous; ULN = upper limit of normal. 
Source: CTCAE, Version 5.0 [NCI, 2017]. 
In general, in cases where IP is reduced to 6.25 mg SC Q4W, it should be continued at the 
reduced dose for 1 or 2 doses and laboratory test monitoring performed before considering 
increasing IP dose back to 12.5 mg SC Q4W. In the case of resolved neutropenia or 
thrombocytopenia, increasing the IP dose back to 12.5 mg SC Q4W should be considered 
first before increasing MMF / MPA / AZA. If this is not possible, the subject should continue 
in the study at the reduced dose of IP. 
Note: Given the potential for drug-drug interactions between clazakizumab and calcineurin 
inhibitors (CNIs) (see Section 8.3.1) routine monitoring of CNI levels will be conducted 
throughout the study per the SOE (see Table 1 and Table 2 [for subjects taking a concomitant 
CNI]). 
7.5.2 
Guidelines for Dose Modification, Withholding, or Discontinuation 
of Investigational Product and / or Modification of Background 
Immunosuppression Based on Results of Monitoring for BKV, 
CMV, and EBV Infection 
During the study, monitoring for BKV, CMV, and EBV infection will be performed by 
plasma PCR test at Screening and every 4 to 24 weeks after Baseline as detailed in the SOE. 
If the DNA Viral PCR test result is positive (ie, exceeds the LLOQ) or viral load increases, IP 
dose reduction (to 6.25 mg SC Q4W), withholding, or discontinuation will be permitted as 
summarized in Table 6. IP should be permanently discontinued for serious BKV, CMV, or 
EBV infections according to the criteria defined in Table 6 and Section 5.6.4. Table 6 
provides further guidelines for dose adjustment / withdrawal of IP and / or background 
immunosuppression according to the viral load as detected by the plasma PCR test. Decisions 


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regarding discontinuation or withholding of IP should be made in consultation with the 
Medical Monitor. 
Table 6 
Guidelines for Dose Modification, Withholding or Discontinuation 
of Investigational Product and / or Modification of Background 
Immunosuppression Based on Results of Monitoring for BKV, 
CMV, and EBV Infection 
Parameter 
Modification of Dose of Investigational Product and / or Background 
Immunosuppression 
BKV(a) 
> 
LLOQ 
to < 
320 
IU/mL 
> 
LLOQ 
to < 
2.51  
log 
IU/mL 
> 
LLOQ 
to < 
1000 
copies/
mL 
• 
Reduce dose of MMF / MPA / AZA by 50% or reduce CNI target 
trough levels (ie, cyclosporine: 25 to 75 ng/mL;  
tacrolimus: 4 to 6 ng/mL). 
• 
No change to IP dose. 
• 
Repeat PCR test every 2 weeks and contact Medical Monitor. 
≥ 320 
to 
< 320
0  
IU/mL  
≥ 2.51 
to 
< 3.51 
log 
IU/mL 
≥ 1000 
to < 
10,000  
copies/
mL 
• 
Reduce dose of MMF / MPA / AZA by 50% and / or reduce CNI 
target trough levels (ie, cyclosporine: 25 to 75 ng/mL;  
tacrolimus: 4 to 6 ng/mL). 
• 
Reduce IP to 6.25 mg SC Q4W or consider withholding or 
discontinuing IP depending on severity of infection. 
• 
Repeat PCR test every 2 weeks and contact Medical Monitor. 
• 
Increase IP dose back up to 12.5 mg SC Q4W if circumstances allow 
or continue at 6.25 mg SC Q4W. Or, if IP was temporarily withheld, 
restart at 6.25 mg SC Q4W if circumstances allow. Repeat PCR at 
discretion of Investigator. 
Biopsy-proven BKV 
nephropathy or: 
• 
Discontinue IP and contact Medical Monitor. (Adjustment of MMF / 
MPA / AZA dose and CNI levels at Investigator’s discretion.) 
≥ 3200  
IU/mL  
≥ 3.51 
log 
IU/mL 
≥ 10,000 
copies/mL 
CMV(b) 
> 
LLOQ 
to < 
1000 
IU/mL 
> 
LLOQ 
to < 
3.0  
log 
IU/mL 
> 
LLOQ 
to < 640  
copies/
mL 
• 
No change to IP dose. 
• 
Repeat PCR test weekly and contact Medical Monitor. 


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Parameter 
Modification of Dose of Investigational Product and / or Background 
Immunosuppression 
≥ 1000 
to < 
5000  
IU/mL 
≥ 3.0 
to 
< 3.70 
log 
IU/mL 
≥ 640 to 
< 3200 
copies/
mL 
• 
Treat with oral valganciclovir or IV ganciclovir. 
• 
Repeat PCR test weekly and contact Medical Monitor. 
≥ 5000 
IU/mL 
≥ 3.70 
log 
IU/mL 
≥ 3200 
copies/
mL 
• 
Reduce dose of MMF / MPA / AZA by 50% and / or reduce CNI 
target trough levels (ie, cyclosporine: 25 to 75 ng/mL;  
tacrolimus: 4 to 6 ng/mL). 
• 
Treat with oral valganciclovir or IV ganciclovir. 
• 
Repeat PCR test weekly and contact Medical Monitor. 
• 
Reduce IP to 6.25 mg SC Q4W or consider withholding or 
discontinuing IP depending on severity of infection. 
• 
Increase IP dose back up to 12.5 mg SC Q4W if circumstances allow, 
or continue at 6.25 mg SC Q4W. Or, if IP was temporarily withheld, 
restart at 6.25 mg SC Q4W if circumstances allow. Repeat PCR at 
discretion of Investigator. 
CMV end-organ disease (eg, 
hepatitis, colitis, 
pneumonitis, retinitis)  
• 
Discontinue IP and contact Medical Monitor. (Adjustment of MMF / 
MPA / AZA dose and CNI levels at Investigator’s discretion.) 
EBV(c) 
> 
LLOQ 
to 
< 10,2
00 
IU/mL 
> 
LLOQ 
to < 
4.01 
log 
IU/mL 
> 
LLOQ 
to < 
5000 
copies/
mL 
• 
No change to IP dose. 
• 
Repeat PCR test every 2 weeks and contact Medical Monitor. 
≥ 
10,200 
to 
< 20,4
00 
IU/mL 
≥ 4.01 
to 
< 4.31 
log 
IU/mL 
≥ 5000 
to < 
10,000 
copies/
mL 
• 
Reduce dose of MMF / MPA / AZA by 50% and / or reduce CNI 
target trough levels (ie, cyclosporine: 25 to 75 ng/mL;  
tacrolimus: 4 to 6 ng/mL). 
• 
Repeat PCR test every 2 weeks and contact Medical Monitor. 


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Parameter 
Modification of Dose of Investigational Product and / or Background 
Immunosuppression 
Post-transplant 
lymphoproliferative 
disorder or primary EBV 
infection in seronegative 
recipient or: 
• 
Discontinue IP and contact Medical Monitor. (Adjustment of MMF / 
MPA / AZA dose and CNI levels at Investigator’s discretion.) 
≥ 
20,400 
IU/mL 
≥ 4.31 
log 
IU/mL 
≥ 
10,000 
copies/
mL  
AZA = azathioprine; BKV = polyoma BK virus; CMV = cytomegalovirus; CNI = calcineurin inhibitor; EBV = Epstein-Barr virus; IP = 
investigational product; IU = International Units; IV = intravenous; LLOQ = lower limit of quantification; MMF = mycophenolate mofetil; 
MPA = mycophenolic acid; PCR = polymerase chain reaction; Q4W = once every 4 weeks; SC = subcutaneous 
Notes: 
 
a LLOQ for BKV: 50.12 IU/mL (1.70 log IU/mL; 156 copies/mL) 
b LLOQ for CMV: 371.54 IU/mL (2.57 log IU/mL; 238 copies/mL) 
c LLOQ for EBV: 50.12 IU/mL (1.70 log IU/mL; 24.6 copies/mL) 
In general, in cases where IP is reduced to 6.25 mg SC Q4W, it should be continued at the 
reduced dose for 1 or 2 doses and plasma PCR test monitoring performed before considering 
increasing IP dose back to 12.5 mg SC Q4W. Restoring the investigational dose back to 
12.5 mg SC Q4W should be considered first before restarting / increasing MMF / MPA / AZA 
or increasing CNI levels. If this is not possible, the subject should continue in the study at the 
reduced dose. 
Note: Given the potential for drug-drug interactions between clazakizumab and CNIs (see 
Section 8.3.1), routine monitoring of CNI levels will be conducted throughout the study per 
the SOE (see Table 1 and Table 2 [for subjects taking a concomitant CNI]). 
7.5.3 
Guidelines for Modification of Dose of Background 
Immunosuppression Based on Results of Monitoring for 
Hypogammaglobulinemia 
During the study, IgG levels will be monitored at Screening and every 12 weeks after 
Baseline in Year 1 and every 16 weeks in Year 2 through SFV as detailed in the SOE. In the 
case of severe hypogammaglobulinemia (IgG < 400 mg/dL), reduction of background 
immunosuppression and treatment with IVIG will be permitted as detailed in Table 7. 
Pharmacokinetic samples for the assessment of clazakizumab will be collected for subjects 
that receive IVIG as defined in Table 9. Decisions regarding treatment with IVIG should be 
made in consultation with the Medical Monitor. 


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Table 7 
Guidelines for Modification of Dose of Background 
Immunosuppression Based on Low IgG Levels 
Parameter 
Modification of Dose of Background Immunosuppression 
IgG (mg/dL) 
≥ 400 
• 
No change to background immunosuppression. 
• 
No change in dose of IP. 
< 400 
• 
Reduce dose of MMF / MPA by 50%. 
• 
No change in dose of IP. 
• 
After 4 weeks, if IgG < 400 mg/dL, continue with reduced dose of MMF / 
MPA and treat with IVIG, 0.5 g/kg monthly for 6 months, administered in 
between doses of IP (ie, 2 weeks postdose of IP is recommended). 
 
 
• 
After 6 months of IVIG treatment: 
o 
If IgG ≥ 400 mg/dL, continue with reduced MMF / MPA dose. If IgG levels 
remain ≥ 400 mg/dL after another 6 months post-IVIG treatment, MMF / 
MPA dose may be increased back to original dose. 
o 
If IgG < 400 mg/dL, consider stopping MMF / MPA and consult the Medical 
Monitor. 
IgG = immunoglobulin G; IP = investigational product; IVIG = intravenous immunoglobulin; MMF = mycophenolate mofetil; MPA = 
mycophenolic acid 
Note: Clazakizumab should be administered 2 weeks after IVIG due to potential binding of 
clazakizumab by IVIG. Subjects are not allowed to receive IVIG for any reason during the 
3 month period before Screening. For treatment with IVIG, subjects may be called in for 
unscheduled visits between regularly scheduled dosing with IP according to the SOE. 
7.6 
Prohibited Therapy and Concomitant Treatments / Interventions 
7.6.1 Prohibited Therapy and Medications 
Treatments for ABMR (including CABMR) and TCMR are not allowed within 3 months 
prior to the start of Screening with the exception of steroids. If treatment for ABMR 
(including CABMR) or TCMR (other than steroids*) was given between 3 to 12 months of 
Screening, a repeat kidney biopsy and DSA analysis are required at least 6 weeks after the 
end of treatment to confirm continuing CABMR and presence of HLA DSA and to determine 
eligibility (see Section 5.2). * A maximum dose of 2g of methylprednisolone intravenously 


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(or dose equivalent of other steroids), followed by a taper to the original maintenance steroid 
dose is allowed. 
mTOR inhibitors (everolimus, sirolimus) are not allowed within 4 weeks prior to the start of 
Screening or during the study. Subjects may discontinue mTOR inhibitors and switch to 
another suitable immunosuppressant and be treated for at least 4 weeks prior to Screening for 
eligibility. 
Subjects already taking belatacept at Screening may continue to take belatacept for the 
duration of the study. 
Administration of live vaccines (eg, measles, mumps, and rubella; varicella zoster) is 
prohibited within the 6 weeks prior to the start of Screening and during the study. It is 
recommended that all subjects be brought up to date with all immunizations in agreement 
with current immunization guidelines within 6 weeks prior to the start of Screening. During 
the 5-month safety follow-up period following the last dose of IP, live vaccines, and any 
additional immunosuppressive therapies should be administered only after careful 
consideration of the risk / benefit profile by the health care provider. 
In addition, the following are prohibited during the study: 
• Anti-IL-6 / IL-6R mAbs (both approved and investigational). 
• Belatacept, unless subject is already taking belatacept at the start of Screening. 
• Eculizumab. 
• IVIG and PLEX: 
o Screening: IVIG and PLEX are prohibited for any reason for the 3-month period prior 
to Screening. 
o During the study1: IVIG and PLEX may be administered only to subjects who 1) have 
hypogammaglobulinemia at any point during the study, 2) meet the 40% decline in 
eGFR (from Baseline) endpoint and who have received > 12 months of IP (see 
Section 7.5.3). 
 Double-blind medication and IVIG should be administered 2 weeks apart due to 
potential binding of IVIG to clazakizumab. For treatment with IVIG, subjects may 
be called in for unscheduled visits between regularly scheduled dosing with IP 
according to the SOE. 
 DSA testing, per the SOE should occur ≥ 2 weeks after administration of IVIG. 


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 Pharmacokinetic samples for the assessment of clazakizumab will be collected for 
subjects that receive IVIG as defined in Table 9. 
• Proteasome inhibitors (eg, bortezomib). 
• Rituximab. 
• T cell depleting agents (eg, alemtuzumab, anti-thymocyte globulin [except for acute 
TCMR]). 
• Other IPs / treatments. 
1 In a specific clinical setting only (ie, worsening DSA and / or worsening proteinuria, AND 
pathology showing stable to worsening cg score or other measure[s] of chronic pathology on 
recent / updated biopsy, accompanied by a worsening measure[s] of activity [eg, ptc, g, C4d]), 
consideration for use of this medications must be discussed with the Medical Monitor prior to 
its use. 
7.6.2 
Allowed Concomitant Medications / Interventions 
The following concomitant medications are permitted during the study: 
• Antidiabetic agents (eg SGLT2 inhibitors). 
• Anti-hypertensive agents (eg, ACEIs, ARBs). 
o ACEIs and ARBs should be started, and dose should be stable for at least 2 months 
prior to Screening Visit and not planned to be increased. 
• Background immunosuppressants: Subjects are expected to be on background 
immunosuppression per standard of care. Recommended dosing / target levels for AZA, 
CNIs, MMF / MPA are: 
o AZA 
 Recommended AZA dose: 1.0 to 2.0 mg/kg/day. 
Note: In case of neutropenia / thrombocytopenia or viral infection, the dose of AZA may be 
reduced as indicated in Table 5 and Table 6, respectively. 
• CNIs: Investigators should attempt to achieve recommended CNI target trough levels 
within the Screening Period and maintain these levels throughout the study 
o Recommended target tacrolimus plasma trough levels: 5 to 8 ng/mL. 
o Recommended target cyclosporine plasma trough levels: 50 to 150 ng/mL. 


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Note: In case of viral infection, the CNI target trough level may be modified as indicated in 
Table 6. Given the potential for drug-drug interactions between clazakizumab and CNIs, 
CNIs will be monitored every 2 weeks following a change in CNI dose until target trough 
levels are achieved (see Section 8.3.1). 
• MMF / MPA (or equivalent after approval by the Medical Monitor). 
o 
Recommended MMF dose: 1.0 to 2.0 g/day. 
o 
Recommended MPA dose: 720 to 1440 mg/day. 
Note: In case of neutropenia / thrombocytopenia, viral infection, or severe 
hypogammaglobulinemia, the dose of MMF / MPA may be reduced as indicated in, Table 6 
and Table 7, respectively. 
Note: The next administration of IP and any DSA testing as per the SOE should occur 
≥ 2 weeks after lymphocyte immune globulin / anti-thymocyte globulin therapy. 
• Low dose corticosteroids (prednisone / prednisolone ≤ 10 mg/day). 
• Treatment for acute TCMR allowed: pulse steroid (eg, IV methylprednisone 1000 mg, or 
oral prednisone 200 mg/day [or equivalent] and taper to Baseline level over 2 weeks). 
• Lymphocyte immune globulin / anti-thymocyte globulin therapy is allowed for TCMR 
Banff ≥ IIa, V1 lesion. 
• Treatment with oral valganciclovir or IV ganciclovir is permitted for CMV infection as 
described in Section 7.5.2. 
• Trimethoprim / sulfamethoxazole or inhaled pentamidine or oral dapsone (required – see 
Section 7.6.3). 
Subjects already taking belatacept at Screening may continue to take belatacept for the 
duration of the study but otherwise, subjects may not begin treatment with belatacept (or 
switch from a CNI) during the study (see Section 7.6.1). 
While the administration of live (attenuated) vaccines should be avoided during the study 
(see Section 7.6.1), inactivated (killed or toxin) vaccines, subunit / conjugate vaccines, or 
vaccines based on novel, non-live virus technology (messenger RNA [mRNA] and protein 
subunit) such as the COVID-19 vaccine, are acceptable and should be administered based on 
local practice and treatment recommendations. Further novel vaccines if developed and 
approved for use (eg, vector vaccines) should be discussed with the Medical Monitor and 
Sponsor. 


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Additional treatments may be used as medically indicated, according to the Investigator’s 
medical judgment. In general, the use of herbal and homeopathic medicines (eg, St. John’s 
Wort, echinacea, goldenseal, Schisandra sphenanthera extracts) is strongly discouraged. 
Any concomitant treatment given for any reason during the course of the study must be 
recorded in the eCRF and in the subject’s medical records, including dosage, start and stop 
dates, and reason for use. 
Similar to Actemra / RoActemra [Actemra® Prescribing Information (USA), 2017; Actemra® 
Product Monograph (Canada), 2018; RoActemra® Summary of Product Characteristics (EU), 
2018], a reduction in systemic exposure to clazakizumab when given in combination with 
CYP P450 substrates, cannot be excluded (see Section 8.3.1). 
7.6.3 
Required Background (Prophylactic) Therapy 
All subjects will be required to take prophylactic treatment for PJP; these drugs will be 
prescribed and supplied by the investigational sites. For the first year of the study (ie, from 
Screening up to and including Week 52), PJP prophylaxis should be administered per the 
dosing guidelines in Section 7.1.3. For the remainder of the study (ie, after Week 52), PJP 
prophylaxis should be continued at the discretion of the Investigator. 
If the subject is already taking trimethoprim / sulfamethoxazole prior to entry in the study, the 
dose should be stable for at least 1 week before the Screening Visit. If a subject is not on 
trimethoprim / sulfamethoxazole prior to entry in the study (and is not already receiving a 
suitable alternative therapy approved by the Investigator), it is recommended that treatment 
with trimethoprim / sulfamethoxazole should be started approximately 1 week before the 
Day 1 Baseline Visit (Visit 2). 
If the subject is already receiving another suitable Investigator-approved therapy for PJP 
prophylaxis (see Section 7.1.3.2), the subject should remain on that therapy and not start 
trimethoprim / sulfamethoxazole. Subjects who are intolerant to trimethoprim / 
sulfamethoxazole and not already receiving a suitable Investigator-approved suitable 
alternative therapy should be started on atovaquone (mepron), inhaled pentamidine or oral 
dapsone for approximately 1 week before the Day 1 Baseline Visit (Visit 2) based on 
consultation with the Medical Monitor. 


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8. 
Risks / Precautions 
8.1 
Identified Risks 
The safety profile of clazakizumab based on previous clinical studies is consistent with its 
anti-IL-6 blocking activity. Identified risks associated with clazakizumab administration 
include the following: infections, LFT abnormalities, changes in hematology parameters (ie, 
neutropenia and thrombocytopenia), dyslipidemia (ie, hypercholesterolemia and 
hypertriglyceridemia), GI perforations, and injection site reactions [see the CSL300 
Investigator’s Brochure]. 
8.1.1 
Infections 
IL-6 is important in innate and adaptive immune responses during infections, and IL-6 
blockade can potentially promote infections. 
In the clinical development program to date, the overall risk of infection with clazakizumab is 
comparable to other disease-modifying antirheumatic drugs (DMARDs) such as MTX or 
adalimumab, even when MTX and other DMARDs and oral corticosteroids have been used 
concomitantly. For further details regarding the identified risk of infection with 
clazakizumab, please consult the CSL300 Investigator’s Brochure. 
As clazakizumab could reduce immune response to infections, clazakizumab should not be 
administered to subjects with systemic active bacterial, viral, or fungal infections, or subjects 
who meet certain laboratory criteria that could predispose subjects to infections (eg, low 
absolute neutrophil count). 
Prior studies have shown that even at low doses, clazakizumab can suppress CRP for several 
weeks after the last dose, which could potentially mask infections. Therefore, Investigators 
should be vigilant for any signs or symptoms of infection even after IP discontinuation, 
according to protocol instructions. 
Infections should be monitored and treated according to standard of care; for serious and 
opportunistic infections, Investigators should consider modifying the dose of IP, withholding 
or discontinuing treatment with IP and / or reducing background immunosuppression. 
Decisions regarding dose modification, withholding, or discontinuation, of IP should be made 
in consultation with the Medical Monitor. 


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8.1.1.1 
Viral Monitoring for BKV, CMV, and EBV Infection 
During the trial, routine monitoring for BKV, CMV, and EBV infection will be performed by 
plasma PCR test at Screening and every 4 to 24 weeks thereafter as detailed in the SOE (see 
Table 1 and Table 2). In the event of positive results, recommendations for modification of 
the dose of IP and / or background immunosuppression and criteria for recommended 
withholding or discontinuation of IP are provided in Section 7.5.2. Decisions regarding dose 
modification, withholding, discontinuation, or restarting of IP should be made in consultation 
with the Medical Monitor. 
These guidelines should be followed for any other clinically significant infection. 
8.1.1.2 
Viral Monitoring for COVID-19 Infection 
Subjects with an active COVID-19 infection at Screening are not eligible for inclusion in the 
study (see Exclusion Criterion 34.A9). No routine COVID-19 rapid antigen test or PCR 
testing is required during the Treatment Period unless clinically indicated. If a subject tests 
positive for COVID-19 during the Treatment Period, background immunosuppressive 
medications should be managed per local medical practice. The IP may be continued, 
however the decision regarding discontinuation and restarting of IP should be made in 
consultation with the Medical Monitor. 
8.1.2 
Liver Function Test Abnormalities 
Treatment with clazakizumab may infrequently be associated with elevated transaminases. In 
the clinical development program to date, increases in LFTs were mostly mild to moderate 
(CTCAE Grade 1 or 2) in severity, and clinically significant increases (Grade 3 and above) 
occurred only in a few patients. These clinically significant increases were invariably 
reported in subjects who had other predisposing factors which may have contributed to the 
LFT abnormalities. No cases of Hy’s Law were observed and the abnormalities in LFTs 
resolved without clinical sequelae. 
In studies in advanced cancer, where clazakizumab was administered (without MTX) at 
320 mg IV, no clinically significant effects were seen on LFTs. 
Subjects with evidence of significant liver disease and significant alcohol or illegal drug use 
are excluded from studies with clazakizumab. 
Liver function tests and hepatobiliary AEs should be closely monitored. 


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During the trial, routine monitoring of LFTs will be performed at Screening and every 
4 to 8 weeks thereafter as detailed in the SOE (see Table 1 and Table 2). In the case of mild to 
moderate LFT abnormalities, the dose of clazakizumab may be modified, and in the case of 
severe LFT abnormalities (CTCAE Grade ≥ 3), treatment with clazakizumab should be 
withheld or discontinued (see Table 5). Decisions regarding dose modification, withholding, 
discontinuation, or restarting of IP should be made in consultation with the Medical Monitor. 
To ensure subject safety, the most recent LFTs will be reviewed prior to dosing (see 
Section 9.2.2). 
8.1.3 Hematology Parameters 
Treatment with clazakizumab is associated with decreased numbers of platelets and 
neutrophils. In the clinical development program to date, reductions of platelets and 
neutrophils were mostly mild or moderate and without clinical consequences. 
Platelets and neutrophils should be carefully monitored. During the trial, a CBC will be 
evaluated at Screening and every 4 to 8 weeks thereafter as detailed in the SOE (see Table 1 
and Table 2). In the case of mild to moderate neutropenia or thrombocytopenia, the dose of 
clazakizumab and / or background immunosuppression may be modified, and in the case of 
severe neutropenia or thrombocytopenia (CTCAE Grade ≥ 3), treatment with clazakizumab 
should be withheld or discontinued (see Table 5). Decisions regarding dose modification, 
withholding, discontinuation, or restarting of IP should be made in consultation with the 
Medical Monitor. 
To ensure subject safety, the most recent neutrophil and platelet results will be reviewed prior 
to dosing (see Section 9.2.2). 
8.1.4 Dyslipidemia 
Treatment with clazakizumab may be associated with dyslipidemia. In the clinical 
development program to date, modest increases in total cholesterol and triglyceride levels 
were observed. The increases tended to occur early after the first drug administration and 
remained relatively stable thereafter. The clinical implication of these elevated lipids is 
unclear. 
Routine monitoring of lipid levels should be performed for subjects being treated with 
clazakizumab. During the trial, cholesterol and triglycerides will be assessed at Day 1 
Baseline Visit (Visit 2) and every 4 to 8 weeks thereafter as detailed in the SOE (see Table 1 
and Table 2). 


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8.1.5 Gastrointestinal Perforation 
Treatment with clazakizumab may be associated with gastrointestinal perforation. 
Subjects with a history of GI perforation; diverticular disease defined as clinically significant 
diverticulosis (except if disease has been fully excised and subject has recovered from 
surgery) or diverticulitis (except if disease has been fully excised and subject has recovered 
from surgery); or inflammatory bowel disease (except fully excised ulcerative colitis and 
subject has recovered from surgery) should not be treated with clazakizumab and are 
excluded from the study (Section 5.3). For further details regarding the identified risk of GI 
perforation with clazakizumab, please consult the CSL300 Investigator’s Brochure. 
8.1.6 Injection Site Reactions 
Injection site reactions have been reported with SC administration, and most frequently 
reported as erythema and rash. Reactions have been mild or moderate and have resolved 
without treatment. 
8.2 
Potential Risks 
Potential risks with clazakizumab treatment have been identified based on known risks 
associated with TCZ, sarilumab, prolonged immunosuppressive therapy, and other biologics 
used in the treatment of RA. 
8.2.1 Demyelination 
Demyelinating events were observed in TCZ trials. It is unclear whether TCZ administration 
was associated with such events. In the clinical program to date, 1 demyelinating event 
(demyelinating polyneuropathy) considered possibly related to treatment with clazakizumab 
was reported in 1 subject in a study in RA. 
8.2.2 Malignancies 
Malignancies are known risks associated with prolonged immunosuppression. Malignancies 
are identified as a potential risk for therapies that modulate the immune system and should be 
monitored in this context during the clazakizumab trials. Malignancies have been observed in 
clinical trials with other IL-6 antagonists [Actemra® Prescribing Information (USA), 2017; 
Kevzara® Prescribing Information (USA), 2017; Actemra® Product Monograph (Canada), 
2018; RoActemra® Summary of Product Characteristics (EU), 2018]. 


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In the clinical program to date, malignancies considered possibly related to treatment with 
clazakizumab were reported in 4 subjects in a study in RA: breast cancer, squamous cell 
carcinoma of the skin, invasive ductal breast carcinoma, and gastric cancer. 
8.2.3 Immunogenicity 
As a mAb, the development of anti-drug antibodies (ADAs) is a potential risk. Such 
antibodies could theoretically lead to reduced efficacy or have safety consequences. To date, 
ADAs have not been detected in healthy volunteers treated with clazakizumab. ADAs were 
detected in some subjects in studies of RA and PsA. 
Anti-clazakizumab antibodies will be monitored during the course of the study as detailed in 
the SOE (see Table 1 and Table 2). 
8.2.4 Infusion Related (Allergic) Reactions 
To date, no infusion reactions have been associated with clazakizumab administered by IV 
infusion. 
As with any protein therapeutic, there is a risk of a serious allergic reaction. Clazakizumab 
should not be administered to subjects who have had any previous allergic reactions to mAbs. 
Allergic reactions should be treated with standard of care. Subjects who have developed 
significant allergic reaction to study drugs should not be rechallenged. 
8.3 
Additional Warnings and Precautions 
8.3.1 
Drug Interactions 
No formal clinical drug interaction studies of clazakizumab have been performed. 
As a mAb, direct PK interactions with other drugs are not anticipated. However, in vitro 
studies showed that clazakizumab has a similar effect to TCZ in reversing the IL-6 effect on 
the down-regulation of mRNA levels of multiple CYP enzymes [CSL300 Investigator’s 
Brochure]. Therefore, treatment with clazakizumab may restore CYP enzyme-mediated drug 
clearance, resulting in a potential lowering of systemic exposure of drugs metabolized by 
CYP enzymes, as has been observed with TCZ (see Actemra / RoActemra prescribing 
information [Actemra® Prescribing Information (USA), 2017; Actemra® Product Monograph 
(Canada), 2018; RoActemra® Summary of Product Characteristics (EU), 2018]). 
This effect may be particularly important for CYP enzyme substrate drugs that have a narrow 
therapeutic index where the dose is individually adjusted. In the labeling of TCZ and 


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sarilumab, 2 approved anti-IL-6R mAbs, it is recommended that, upon initiation or 
discontinuation of these mAbs, therapeutic monitoring of effect (eg, warfarin) or drug 
concentration (eg, theophylline, cyclosporine) be performed and the individual dose of the 
CYP enzyme substrate drugs be adjusted as needed [Actemra® Prescribing Information 
(USA), 2017; Kevzara® Prescribing Information (USA), 2017; Actemra® Product Monograph 
(Canada), 2018; RoActemra® Summary of Product Characteristics (EU), 2018]. Similarly, 
caution should be exercised when coadministering clazakizumab with CYP3A4 substrate 
drugs where decrease in effectiveness is undesirable (eg, hormonal contraceptives, 
3-hydroxy-3-methyl-glutaryl-co-enzyme A reductase inhibitors). 
Note: Given the potential for drug-drug interactions between clazakizumab and CNIs, CNI 
trough levels will be monitored at Year 1: Visits 2 (Baseline) through 6, 8, 10, 12, 14, and 16; 
Year 2 through EOT: every second visit (Q8W) starting with Visit 18 through the EOT / Early 
Withdrawal Visit (for subjects taking a concomitant CNI). At these visits, treatment with 
CNIs is to be withheld until after sample collection for determination of CNI levels. CNIs 
will also be monitored every 2 weeks following a change in CNI dose, withholding, 
discontinuation, or restarting of IP, until target CNI trough levels are achieved. 
After Year 1, CNI levels may be checked per local practice through local laboratories, 
including being a part of evaluating any significant changes in creatinine. Locally drawn CNI 
levels may qualify for monitoring if drawn within the specified interval of ± 2 weeks. 
Routine monitoring of CNI levels are summarized as per the SOE (see Table 1 and Table 2). 
With prior alignment and permission from CSLB, CNI monitoring may be conducted locally 
during Year 1. If monitored locally during Year 1,CNI monitoring should be conducted at the 
same laboratory throughout the study, ie beginning from and including the Baseline CNI 
level. Also, if CNI monitoring is conducted locally in Year 1, a sample should be drawn and 
submitted to the central laboratory each time CNI levels are assessed as per the schedule 
described in the SOE (see Table 1 and Table 2). 
8.3.2 
Overdose 
There are no specific antidotes or measures to take in the event of an overdose of 
clazakizumab injection. Subjects should be treated with the appropriate supportive care. 
8.3.3 
Women of Childbearing Potential 
A WOCBP, ie fertile, following menarche and until becoming post-menopausal unless 
permanently sterile, as defined in the European “Heads of Medicines Agencies” 2014 CTFG 
document “Recommendations related to contraception and pregnancy testing in clinical 


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trials”. Permanent sterilization methods include hysterectomy, bilateral salpingectomy and 
bilateral oophorectomy. 
A post-menopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high follicle stimulating hormone (FSH) level in the post-menopausal range 
may be used to confirm a post-menopausal state in women not using hormonal contraception 
or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a 
single FSH measurement is insufficient. 
There are no adequate well-controlled studies in pregnant or lactating women. In nonclinical 
studies, an increase in the number of monkeys with retention of the placenta at parturition 
was observed at clazakizumab doses corresponding to 34 and 340 times the planned human 
dose of 12.5 mg Q4W in this study. These doses are expected to generate exposures 
approximately 48 and 480 times higher, respectively, than the human doses of 12.5 mg SC 
injection, Q4W. In 3 of the 5 monkeys with retained placentas, the resulting excessive uterine 
hemorrhage led to moribund status in the mothers. 
There have been pregnancy cases in clinical trials. For the latest information, please refer to 
the CSL300 Investigator’s Brochure. 
All subjects of childbearing potential being treated with clazakizumab (and their partners) 
must be informed of this risk, and use adequate contraception, as defined in the study 
protocol (see Section 5.4). Administration of clazakizumab may decrease the efficacy of 
hormonal contraceptive methods; therefore, a WOCBP subject using a hormonal 
contraceptive method must also supplement with a barrier method of contraception 
(preferably male condom) (see Section 5.4). 
Under no circumstances shall clazakizumab be administered to women known to be pregnant 
or lactating. Women who have a confirmed positive pregnancy test during the study will be 
permanently discontinued from IP but continue in the study as described in Section 9.2.5.3. 
All pregnancies must be reported to CSLB and the CRO within 24 hours of awareness and in 
accordance with reporting procedures (see Section 10.3.3). 
For further details, see the CSL300 Investigator’s Brochure. 


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9.
Study Procedures
9.1 
Description of Study Assessments 
9.1.1 
Clinical Laboratory Assessments 
All samples will be analyzed at the central laboratory using standard validated methods (see 
the Laboratory Manual for contact details). Local laboratories may be utilized for 
unscheduled safety analyses between visits and where applicable; results must be recorded on 
the eCRF. 
Samples for the following efficacy and safety assessments will be collected in accordance 
with the SOE in Table 1 (Year 1) and Table 2 (Year 2 to SFV / CTEV). All blood and urine 
samples should be collected prior to dosing at the clinic visit. A summary of all laboratory 
assessments is provided in Table 8. 
Table 8 
Summary of Laboratory Assessments 
Test Type 
Test Parameters 
Collection 
Clinical 
Chemistry 
(serum) 
•
BUN or Urea
•
Chloride
•
CO2
•
Creatinine
•
LFTs (AST, ALT,
alkaline phosphatase,
GGT, total bilirubin,
direct bilirubin, INR)
•
hsCRP
•
Potassium
•
Sodium
Year 1: Visits 1 (Screening), 2, 4, 5, 6, 8, 10, 12, 14, and 
16. 
Year 2 through EOT: every second visit (Q8W) starting 
with Visit 18 through the EOT / Early Withdrawal Visit / 
SFV / Q6M (for subjects who discontinued IP) / CTEV. 
•
Fasting glucose(a)
Year 1: Visits 2, 4, 5, 6, 8, 10, 12, 14, and 16. 
Year 2 through EOT: every second visit (Q8W) starting 
with Visit 18 through the EOT / Early Withdrawal Visit / 
SFV / Q6M (for subjects who discontinued IP) / CTEV. 
Lipids (serum)(a)  • 
Cholesterol (total, HDL, 
and LDL), fasting 
•
Triglycerides, fasting
Year 1: Visits 2, 4, 5, 6, 8, 10, 12, 14, and 16. 
Year 2 through EOT: every second visit (Q8W) starting 
with Visit 18 through the EOT / Early Withdrawal Visit / 
SFV / Q6M (for subjects who discontinued IP) / CTEV. 
Hematology 
•
CBC
o
Hb
o
Hematocrit
o
Red blood cell count
o
White blood cell
count
Year 1: Visits 1 (Screening), 2, 4, 5, 6, 8, 10, 12, 14, and 
16. 
Year 2 through EOT: every second visit (Q8W) starting 
with Visit 18 through the EOT / Early Withdrawal Visit / 
SFV / Q6M (for subjects who discontinued IP) / CTEV. 


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Test Type 
Test Parameters 
Collection 
o 
White blood cell 
differential (absolute 
and %) 
o 
Platelet count 
Serology 
• 
HIV 
• 
HBsAg 
At Visit 1 (Screening) (unless known seropositive history). 
Viral monitoring 
(plasma PCR) 
(see 
Section 9.1.1.1) 
• 
Hepatitis C RNA 
At Visit 1 (Screening). 
• 
COVID-19 RNA 
At Visit 1 (Screening)(b). 
• 
BKV, CMV, EBV, DNA 
Viral PCR monitoring 
Year 1: Visits 1 (Screening), 4, 5, 6, 8, 10, 12, 14, and 16. 
Year 2 through EOT/ Early Withdrawal Visit 
(approximately every sixth visit [Q24W]): Visits 22, 28, 
34, 40, 46, 52, 58, 64, 68, 74, 80, 86, 92, and EOT / Early 
Withdrawal / CTEV. 
Urinalysis 
• 
Dipstick chemical profile 
with optional 
microscopic profile if 
dipstick is abnormal 
At Visit 1 (Screening). 
• 
UACR spot urine test 
At Visits 1 (Screening), 6, 9, and 15. 
Year 2 through EOT / Early Withdrawal Visit 
(approximately every sixth visit [Q24W]): Visits 20, 26, 
32, 38, 44, 50, 56, 62, 68, 72, 78, 84, 90, and EOT / Early 
Withdrawal / SFV / Q6M (for subjects who discontinued 
IP) / CTEV. 
Pregnancy test 
• 
POCT urine pregnancy 
test for WOCBP (any 
positive results will be 
confirmed by a serum 
test at the central 
laboratory)(c) 
At all visits except Visit 3 (Visits 1, 2, and 4 through EOT) 
/ SFV / CTEV. 
Special tests 
• 
IgG (see Section 9.1.1.2)  Year 1: Visits 1 (Screening), 6, 9, 12, and 15. 
Year 2 through EOT: every fourth visit (Q16W) starting 
with Visit 18 through the EOT / Early Withdrawal Visit / 
CTEV. 
• 
eGFR (MDRD4) (see 
Section 9.1.1.3) 
Year 1: all visits except Visit 3. 
Year 2 through EOT: every second visit (Q8W) starting 
with Visit 18 through the EOT / Early Withdrawal Visit / 
SFV / Q6M (for subjects who discontinued IP) / CTEV. 
• 
DSA MFI scores (for 
anti-HLA antibodies) 
(see Section 9.1.1.4) 
Year 1: Visits 1 (Screening)(d), 2, 9, and 16. 
Year 2 through EOT: Visits 28, 42, 54, 68, 80, 94, and the 
EOT / Early Withdrawal Visit / SFV / Q12M (for subjects 
who discontinued IP) / CTEV. 
• 
DSA titers (for anti-HLA 
antibodies) (see 
Section 9.1.1.4) 
Year 1: Visits 2 (Baseline), 16 and the EOT / Early 
Withdrawal Visit. 


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Test Type 
Test Parameters 
Collection 
• 
Plasma IL-6 (total and 
free)(e) (see 
Section 9.1.1.6) 
Year 1: Visits 2 (Baseline), 6, 9, and 15. 
Year 2 through EOT / Early Withdrawal Visit 
(approximately every sixth visit [Q24W]): Visits 20, 26, 
32, 38, 44, 50, 56, 62, 68, 72, 78, 84, 90, and EOT / Early 
Withdrawal / SFV / CTEV. 
• 
Serum clazakizumab (e,f) 
(see Section 9.1.1.7) 
Year 1: Visits 2 (Baseline), 6, 9, and 15. 
Year 2 through SFV: (approximately every sixth visit 
[Q24W]): Visits 20, 26, 32, 38, 44, 50, 56, 62, 68, 72, 78, 
84, 90, and EOT / Early Withdrawal, and SFV / CTEV. 
 
• 
Immunogenicity (ADA) 
(see Section 9.1.1.8) 
Year 1: Visits 2 (Baseline), 6, 9, and 15. 
Year 2 through SFV (approximately every sixth visit 
[Q24W]): Visits 20, 26, 32, 38, 44, 50, 56, 62, 68, 72, 78, 
84, 90, and EOT / Early Withdrawal, and SFV / CTEV. 
 
• 
MPA levels (see 
Section 9.1.1.9) 
At Visit 2 (Baseline), as clinically indicated during the 
Treatment Period, and EOT / Early Withdrawal Visit / 
CTEV. 
 
• 
CNI levels (see 
Section 9.1.1.10) 
Year 1: Visits 2 through 6, 8, 10, 12, 14, and 16. 
Year 2 through EOT: every second visit (Q8W) starting 
with Visit 18 through the EOT / Early Withdrawal Visit / 
CTEV. 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; BKV = polyoma BK virus; BUN = blood urea nitrogen; 
CBC = complete blood count; CMV = cytomegalovirus; CNI = calcineurin inhibitor; CTEV = common treatment end 
visit; DSA = donor-specific antibodies; EBV = Epstein-Barr virus; eGFR = estimated glomerular filtration rate; EOT = 
end of treatment; GGT = Gamma-glutamyl transferase; Hb = hemoglobin; HBsAg = hepatitis B surface antigen; HDL = 
high density lipoprotein; HIV = human immunodeficiency virus; HLA = human leukocyte antigen; hsCRP = high-
sensitivity C-reactive protein; IgG = immunoglobulin G; IL-6 = interleukin 6; INR = international normalized ratio; 
IP = investigational product; LDL = low density lipoprotein; MDRD4 = Modification of Diet in Renal Disease-4; 
MFF = mycophenolate mofetil; MFI = mean fluorescence intensity; MPA = mycophenolic acid; PCR = polymerase 
chain reaction; POCT = point of care test; SFV = safety follow-up visit; Q6M = every 6 months; UACR = urine albumin 
creatinine ratio; WOCBP = women of childbearing potential. 
Notes: 
 
a 
At least 10 hours of fasting is required for determination of fasting glucose and for lipids / triglycerides. If the subject 
failed to fast, samples should still be collected and processed with failure to fast recorded on the laboratory requisition 
and as a protocol deviation. (Glucose and lipids / triglycerides will not be assessed at Visit 1.) 
b 
Subjects must have a negative rapid antigen test or PCR test result during the Screening Period as near to Day 1 
(Baseline Visit [Visit 2]) as possible. Subjects must be without symptoms attributable to COVID-19 for at least 1 month 
prior to the start of Screening. Additional testing during the trial may be performed at the discretion of the Investigator if 
clinically indicated. 
c 
POCT urinary pregnancy test prior to every dose of IP. For subjects who permanently discontinued investigational 
treatment with clazakizumab / placebo, this assessment will be conducted for an additional 5 months following the last 
dose of IP. 
d 
At Screening, local laboratory DSA results will be reviewed by the central HLA reviewer to confirm eligibility for entry 
into the study. If the presence of HLA DSA is confirmed within 6 months prior to the start of Screening, the test does not 
need to be repeated for eligibility. 
e 
Additional blood samples may be taken for those participating in the PK / PD Substudy (see Table 3). 
f 
Additional blood samples will be taken for those subjects that receive IVIG treatment (see Table 9). 
9.1.1.1 
Viral Monitoring (Plasma PCR) 
Viral monitoring will be performed using plasma PCR. Further details are provided in the 
Laboratory Manual. 


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HCV infection will be tested at Visit 1 (Screening) by PCR detection of viral RNA. 
Subjects not known to have been previously infected with COVID-19 must have a negative 
rapid antigen test or PCR test result during the Screening Period as near to the Day 1 Baseline 
Visit (Visit 2) as possible. 
BKV, CMV and EBV will be monitored throughout the study by Viral PCR detection of DNA 
at Year 1: Visits 1 (Screening), 4, 5, 6, 8, 10, 12, 14, and 16; Year 2 through EOT/ Early 
Withdrawal Visit (approximately every sixth visit [Q24W]): Visits 22, 28, 34, 40, 46, 52, 58, 
64, 68, 74, 80, 86, 92, and EOT / Early Withdrawal / CTEV. 
Note: PCR testing for BKV, CMV, EBV, and HCV will be conducted at the central laboratory. 
9.1.1.2 
Monitoring for Hypogammaglobulinemia (IgG) 
Monitoring for hypogammaglobulinemia will be performed by measuring IgG levels at the 
central laboratory. Further details are provided in the Laboratory Manual. 
• IgG levels will be determined at Year 1: Visits 1 (Screening), 6, 9, 12, and 15. Year 2 
through EOT: every fourth visit (Q16W) starting with Visit 18 through the EOT / 
Early Withdrawal Visit / CTEV. 
9.1.1.3 
eGFR 
Estimated glomerular filtration rate will be determined using the MDRD4 equation 
[Levey et al, 2006]: 
eGFR = 175 x (serum creatinine [mg/dL])-1.154 x (Age)-0.203 x (0.742 if female; 
1 otherwise) x (1.212 if black; 1 otherwise) 
The eGFR will be determined by the central laboratory at all visits except Visit 3 (Year 1); 
Year 2 through EOT: every second visit (Q8W) starting with Visit 18 through the EOT / Early 
Withdrawal Visit SFV / Q6M (for subjects who discontinued IP) / CTEV. 
eGFR should be assessed by the central lab for subjects who permanently discontinued 
treatment with IP and continues to attend in-clinic study visit. This may be complemented by 
additional eGFR results that are obtained between in-clinic visits and may be taken by a local 
laboratory. 


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9.1.1.4 
DSA Titers and MFI Scores 
DSA for HLA (Class I and Class II) will be determined using single-antigen bead-based 
assays at the central laboratory. Further details are provided in the Laboratory Manual. 
• DSA for MFI scores will be determined at Year 1: Visits 1 (Screening), 2 (Baseline), 9, 
and 16; Year 2 through EOT: Visits 28, 42, 54, 68, 80, 94 and the EOT / Early 
Withdrawal Visit / SFV / Q12M (for subjects who discontinued IP) / CTEV. 
• DSA for titers will be determined at Year 1: Visits 2 (Baseline),16, and the EOT / Early 
Withdrawal Visit. 
At Screening, local laboratory DSA results will be reviewed by the central HLA reviewer to 
confirm eligibility for entry into the study. If the presence of HLA DSA is confirmed within 
6 months prior to the start of Screening, the test does not need to be repeated for eligibility. If 
the central HLA reviewer disagrees with the local laboratory results, the Screening DSA test 
may be repeated once by the central laboratory and the repeated results must be reviewed by 
the central HLA reviewer to confirm DSA eligibility criteria. To be considered for 
determination of study eligibility, the DSA analysis must be performed and should occur at 
least 6 weeks after the end of any prior treatment for ABMR (including CABMR) or TCMR, 
in order to show continuing CABMR. In addition, treatments for ABMR or TCMR are not 
allowed within 3 months prior to the start of Screening with the exception of steroids. 
In cases where local DSA testing is unavailable at the site, Screening DSA analysis will be 
conducted by the central laboratory and reviewed by the central HLA reviewer to confirm 
eligibility. 
9.1.1.5 
Plasma hsCRP 
Plasma hsCRP levels will be measured using a validated assay by a central laboratory. 
Further details are provided in the Laboratory Manual. 
Plasma hsCRP levels will be measured at Year 1: Visits 1 (Screening) 2, 4, 5, 6, 8, 10, 12, 14, 
and 16. Year 2 through EOT: every second visit (Q8W) starting with Visit 18 through the 
EOT / Early Withdrawal Visit / SFV / every 6 months (Q6M) (for subjects who discontinued 
IP) / CTEV. 
For those participating in the PK / PD Substudy, plasma hsCRP will also be measured before 
dosing on Day 8 (168 h), Visit 4 (before dosing), Visit 9 (Week 24 [before dosing], 72 h and 
120 h after Visit 9 IP injection]), Week 25 (168 h after Visit 9 IP injection), Week 26 (336 h 
after Visit 9 IP injection), Week 27 (504 h after Visit 9 IP injection) as per Table 3. These 


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measurements are in addition to those taken as part of the main study. Note: Assessment of 
hsCRP levels is not required if the subject has been permanently discontinued from treatment 
with IP. 
9.1.1.6 
Plasma IL-6 
Total IL-6 (ligand bound / unbound to soluble IL-6R and bound / unbound to clazakizumab) 
and free IL-6 (ligand unbound to soluble IL-6R and unbound to clazakizumab) levels will be 
measured using a validated SIMOA® assay by a central laboratory. Further details are 
provided in the Laboratory Manual. 
In the main study, plasma IL-6 levels (total and free) will be determined at Year 1: Visits 2 
(Baseline), 6, 9, and 15; Year 2 through EOT / Early Withdrawal Visit (approximately every 
sixth visit [Q24W]): Visits 20, 26, 32, 38, 44, 50, 56, 62, 68, 72, 78, 84, 90, and EOT / Early 
Withdrawal / SFV / CTEV. 
For those participating in the PK / PD Substudy, plasma IL-6 will also be measured at Week 1 
(Day 8 [168 h]), Week 4 / Visit 4 (before dosing), Week 24 (Day 3 [72 h after Visit 9 IP 
injection], Day 5 [120 h after Visit 9 IP injection]), Week 25 (Day 7 [168 h after Visit 9 IP 
injection]), Week 26 (Day 14 [336 h after Visit 9 IP injection]), Week 27 (Day 21 [504 h after 
Visit 9 IP injection]) as per Table 3. These measurements are in addition to those taken as part 
of the main study. Note: Assessment of IL-6 levels is not required if the subject has been 
permanently discontinued from treatment with IP. 
9.1.1.7 
Serum Clazakizumab 
A validated enzyme-linked immunosorbent assay method will be used to measure 
concentrations of clazakizumab in serum. Samples will be analyzed by the central laboratory. 
Pharmacokinetic samples are to be drawn prior to administration of IP. Those samples drawn 
for the PK / PD Substudy and for IVIG treatment are described below. 
In the main study, serum clazakizumab concentrations will be determined at Year 1: Visits 2 
(Baseline), 6, 9, and 15; Year 2 through SFV: (approximately every sixth visit [Q24W]): 
Visits 20, 26, 32, 38, 44, 50, 56, 62, 68, 72, 78, 84, 90, and the EOT / Early Withdrawal Visit, 
and the SFV / CTEV. Note: Assessment of clazakizumab levels is not required if the subject 
has been permanently discontinued from treatment with IP. 
In a separate PK / PD Substudy, subjects that consented to additional blood draws, serum 
clazakizumab will be measured at Visit 2 (Baseline), Day 8 (168 h), Visit 4 /Week 4 (before 
dosing), Visit 9 (Week 24 [before clazakizumab dose, 72 h and 120 h after the Visit 9 IP 


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injection]), Week 25 (Day 7 [168 h after Visit 9 IP injection]), Week 26 (Day 14 [336 h after 
Visit 9 IP injection]), and Week 27 (Day 21 [504 h after Visit 9 IP injection]) as per Table 3. 
These measurements are in addition to those taken as part of the main study. 
For all subjects that go on to receive IVIG, the following blood samples for measurement of 
clazakizumab concentration in serum will be taken as defined in Table 9. 
Table 9 
Pharmacokinetic Sample Collection for Subjects Receiving IVIG 
Activity 
Analyte 
Sampling 
Timepoint 
Timepoint 
Window 
Relative to 
IVIG 
Treatment 
Notes 
Blood 
Draw 
Clazakizumab 
Before dose of IVIG 
Up to -2 weeks 
prior to IVIG 
dosing. 
Optional if the subject has been on 
study for longer than 24 weeks. Blood 
draw can coincide with IP 
administration visit. Sample must be 
taken prior to administration of IVIG. 
For Subjects Receiving Only One Dose of IVIG 
Blood 
Draw
Clazakizumab 2 weeks after the 
IVIG treatment  
±2 days 
Blood draw can coincide with the next 
visit for clazakizumab administration 
and should be drawn prior to 
administration of clazakizumab. 
For Subjects Receiving Multiple Doses of IVIG 
Blood 
Draw 
Clazakizumab 
2 weeks after each 
IVIG treatment for 
the remainder of 
IVIG treatment 
±2 days 
Blood draw can coincide with the next 
visit for clazakizumab administration 
and should be drawn prior to 
administration of clazakizumab. 
IP = investigational product; IVIG = intravenous immunoglobulin 
9.1.1.8 
Immunogenicity 
A validated electrochemiluminescence immunoassay method will be used to measure titers of 
clazakizumab antibodies in serum. Samples will be analyzed by the central laboratory. 
Further details are provided in the Laboratory Manual. 
Plasma anti-clazakizumab antibody levels will be measured at Year 1: Visits 2 (Day 1, 
Baseline), 6, 9, and 15; Year 2 through SFV: (approximately every sixth visit [Q24W]): 
Visits 20, 26, 32, 38, 44, 50, 56, 62, 68, 72, 78, 84, 90, and the EOT / Early Withdrawal Visit, 
and the SFV / CTEV. 
Note: Assessment of anti-clazakizumab antibody levels is not required if the subject has been 
permanently discontinued from treatment with IP. 


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9.1.1.9 
MPA Levels 
MPA levels in serum / plasma will be measured by a validated quantitative liquid 
chromatography-tandem mass spectrometry (LC-MS / MS) method at a central laboratory. 
Further details are provided in the Laboratory Manual. 
For subjects taking concomitant MMF / MPA, MPA levels will be measured at Visits 2 
(Baseline), as clinically indicated per investigator discretion during the Treatment Period, and 
the EOT / Early Withdrawal Visit / CTEV. At these visits, treatment with MMF / MPA is to be 
withheld until after blood sample collection for determination of MPA levels. 
9.1.1.10 CNI Levels 
CNI (tacrolimus and cyclosporine) trough levels in serum / plasma will be measured by a 
validated quantitative LC-MS / MS method at a central laboratory. Further details are 
provided in the Laboratory Manual. 
For subjects taking a concomitant CNI, CNI trough levels will be measured as described in 
the SOE (See Table 1 and Table 2). At these visits, treatment with CNIs is to be withheld until 
after sample collection for determination of CNI levels. 
CNIs will also be monitored Q2W following a change in CNI dose, withholding, 
discontinuation, or restarting of IP, until target CNI trough levels are achieved (see 
Section 8.3.1). 
After Year 1, CNI levels may be checked locally through local laboratories. CNI monitoring 
will be continued as described in the SOE, blood samples for CNI monitoring have to be 
drawn within the specified interval of ± 2 weeks from study drug administration. All CNI 
values from central and local laboratories are required to be entered into the subject eCRFs 
by the study team. It is the site’s responsibility to determine if the measured levels are within 
the expected range and if any intervention needs to be taken. In case of any issue as described 
in Section 8.3.1, repeat levels should be determined and reported. 
With prior alignment and permission from CSLB, CNI monitoring may be conducted locally 
during Year 1. If monitored locally during Year 1,CNI monitoring should be conducted at the 
same laboratory throughout the study, ie beginning from and including the Baseline CNI 
level. Also, if CNI monitoring is conducted locally in Year 1, a sample should be drawn and 
submitted to the central laboratory each time CNI levels are assessed as per the schedule 
described in the SOE (see See Table 1 and Table 2). 


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Note: Attendance at Visit 3 is required only if the subject is taking a CNI. 
9.1.1.11 Biomarkers and Pharmacogenomics Research 
Leftover blood samples for biomarker and pharmacogenomics research will be frozen and 
stored for future analysis. Possible evaluations may include analysis of biomarkers to further 
characterize disease manifestation of CABMR, PK / PD and potential safety signals. Samples 
will be stored up to 2 years after study completion. Additional details on storage are provided 
in the ICF. 
9.1.2 
Physical Examinations 
At Visit 1 (Screening), a complete physical examination as per standard of care will be 
conducted by either the Investigator or a sub-Investigator who is a physician. An abbreviated 
physical examination will be conducted at Year 1: Visits 2 (Baseline), 4, 5, 6, 9, 12, 15: 
Year 2 through EOT: every fourth visit (Q16W) starting with Visit 18 through the EOT /Early 
With drawal visit; these limited examinations may be completed by other qualified staff. 
Subject weight will be recorded at each physical examination. Height will be recorded at 
Visit 1 only. 
Where possible, at each study site the same person should perform all physical examinations 
for a given subject, throughout the study. 
9.1.3 
Vital Signs 
Vital signs will be measured at Year 1: Visits 1 (Screening), 2 (Baseline), 4, 5, 6, 9, 12, 15; 
Year 2 through EOT: every fourth visit (Q16W) starting with Visit 18 through the EOT / 
Early Withdrawal Visit. 
All assessments will be taken after the subject has been at rest in a sitting position for 
5 minutes. To avoid variability, the same method of obtaining body temperature should be 
used throughout the study. 
The following vital signs will be measured: 
• Blood pressure (systolic and diastolic) 
• Heart rate 
• Body temperature (°C or °F) 
• Respirations 


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9.1.4 
Standard 12-lead Electrocardiogram 
The electrocardiogram (ECG) will be a standard 12-lead tracing performed at the 
investigational site, assessed by a qualified physician at the investigational site, and retained 
as a source document. Results including any abnormalities will be recorded in the eCRF. 
Electrocardiograms will be recorded digitally after the subject has been in a resting, supine 
position for at least 5 minutes. Significant abnormalities, including findings that may prompt 
discontinuation of IP should be discussed with the Medical Monitor. 
Electrocardiograms will be performed at Year 1: Visits 1 (Screening), 6, 9, and 15; Year 2 
through EOT: 28, 42, 54, 68, 80, 94, and the EOT / Early Withdrawal Visit / CTEV. 
9.1.5 
Tuberculosis Screening 
Screening for active and latent TB is required to determine subject eligibility to enroll in this 
study. The following procedures are required: 
• A complete physical examination and medical history to evaluate exposure to TB and 
whether subjects with a history of latent TB (without active TB) completed a documented 
course of prophylactic treatment. 
• Chest X-ray. 
• QuantiFERON-TB Gold interferon-γ release assay. (Note: local QuantiFERON-TB Gold 
testing is acceptable.) 
If a positive result is obtained for the interferon-γ release assay, the test should not be 
repeated. For an indeterminate result, the assay may be repeated 1 time. If the second test is 
positive or indeterminate, the result should be considered positive for that subject. A third test 
may not be performed. 
For eligibility in the study, subjects with a history of latent TB must not have a history of 
active TB and must have documented evidence of a documented course of prophylactic 
treatment. 
Subjects who have newly diagnosed TB should have IP discontinued and managed according 
to the local standard of care. 
Note: a subject being rescreened is not required to have a repeat chest X-ray for TB screening 
if the first Screening chest X-ray was normal and conducted within 6 months from the start 
date of rescreening. 


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9.1.6 
Renal Biopsy 
Biopsy-proven CABMR (according to Banff 2015 diagnostic criteria [Loupy et al, 2017]) 
within 12 months prior to the start of Screening is required for assessment of subject 
eligibility to enroll in this study. A repeat biopsy is to be performed if previous biopsy is not 
within 12 months prior to the start of Screening and no intervening treatments have been 
administered. The local pathologist’s diagnosis must be reviewed by a central pathologist to 
confirm eligibility for entry into the study. To be considered for determination of study 
eligibility, the biopsy should be performed at least 6 weeks after the end of any prior 
treatment for ABMR (including CABMR) or TCMR, in order to show continuing CABMR. 
In addition, treatments for ABMR or TCMR are not allowed within 3 months prior to the start 
of Screening with the exception of steroids. 
Repeat biopsies per-protocol will be performed at Visit 16 (Week 52 [window -2 to 
+ 6 weeks]). Unscheduled biopsies may be performed at any time if clinically indicated and, 
after local review for diagnostic purposes, should be sent to the central pathologist for 
analysis. If a for-cause biopsy has been performed within 2 months of Week 52, a repeat 
biopsy at Week 52 is not required. 
9.1.7 
Health-Related Quality of Life 
HRQoL will be assessed using the tools described below. The data will be collected 
electronically for the visits reflected in the SOE. Subjects in the trial will enter their data 
through the electronic clinical outcomes assessment (eCOA) solution (see Section 15.2.1). 
PRO assessments should be completed before other medical procedures and assessments are 
performed whenever possible. 
HRQoL data will be collected electronically through the use of validated patient-reported 
outcome assessments twice a year for the first 2 years of the study and once a year in the last 
3 years of the study at Visits 2, 9, 16, 23, 29, 42, 55, 68, 81, 94, at the EOT / Early 
Withdrawal Visit), the SFV / Q6M visit (for subjects who discontinued IP) / CTEV. Subjects 
who are randomized before the availability of the eCOA solution will not complete HRQoL 
questionnaires. 
9.1.7.1 
EQ-5D-5L 
The EuroQol 5 dimensions questionnaire (EQ-5D)-5L is a generic quality of life assessment 
that provides a simple descriptive profile of the subject’s health state and a single visual 
analogue scale index value for overall health that can be used in the clinical and economic 
evaluation of health care as well as in population health surveys [Herdman et al, 2011; 


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Janssen et al, 2013]. It will be performed in countries where validated language versions of 
the questionnaires are available. 
The EQ-5D-5L descriptive profile of health states consists of the following 5 domains: 
mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. Within each 
domain, there are a series of questions with 5 response levels: no problems, slight problems, 
moderate problems, severe problems, and extreme problems or unable to perform task 
depending on the concept measured. A unique health state is defined by combining 1 level 
from each of the 5 domains. Each health state is referred to in terms of a 5-digit code. The 
visual analogue scale records the subject’s self-rated overall health on a vertical numerical 
scale where the endpoints are ‘Best imaginable health state’ (100) and ‘Worst imaginable 
health state’ (0). 
9.1.7.2 
Kidney Disease Quality of Life Questionnaire – 36 
The Kidney Disease Quality of Life 36 (KDQoL-36) survey is a short form that includes the 
SF12 as a generic core plus the burden of kidney disease, symptoms / problems of kidney 
disease, and effects of kidney disease scales from the KDQoL-SF [Chong K. et al, 2018]. 
There is also a KDQoL-36 Summary Score (KSS) which is a composite of items from the 
KDQoL-36’s kidney targeted scales and is useful when kidney targeted HRQoL needs to be 
summarized in a single score [Peipert et al, 2019]. 
9.1.7.3 
Functional Assessment of Chronic Illness Therapy – Fatigue Scale 
The FACIT Fatigue scale is a 13-item patient-reported measure of fatigue with a 7-day recall 
period. Items are scored on a 0 to 4 response scale with anchors ranging from “Not at all” to 
“Very Much So”. To score the FACIT Fatigue, all items are summed to create a single fatigue 
scale with a range of 0 to 52 [Acaster et al, 2015]. 
9.2 
Schedule of Events 
For a detailed SOE (including all protocol-required assessments, visits, and visit windows) 
please refer to Table 1 (Year 1) and Table 2 (Year 2 to SFV). 
9.2.1 
Screening Visit (Assessment Visit 1) 
The Screening Period starts on the date the first Screening assessment is completed after 
signing the ICF. The Screening Visit (Visit 1) will take place within 42 days prior to Visit 2 
(Baseline, Day 1). Every effort should be made to perform all visit assessments on the same 
day. If necessary, it is acceptable to conduct assessments over multiple days and Investigators 
are encouraged to complete all assessments within 1 week. The initial Screening assessments 


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performed over this 42-day period will include provision of informed consent; review of 
inclusion / exclusion criteria; complete physical examination (including weight and height); 
vital signs measurements, including weight and height; medical history (including historical 
serology for viral infections [HIV, HBsAg, HCV, CMV, and EBV; and test for HIV and 
HBsAg if seronegative or unknown]); a urine pregnancy test (for WOCBP); TB screening 
(QuantiFERON-TB Gold and Chest X-ray); 12-lead ECG; blood and urine sample collection 
for central laboratory assessments per SOE, eGFR, IgG monitoring, DSA MFI scores (if not 
confirmed within 6 months prior to the start of Screening), Renal biopsy ( if previous biopsy 
is not within 12 months) prior to the start of Screening, standard urinalysis dipstick; spot 
urine collection (for determination of UACR); serology for HIV and HBsAg if seronegative 
or history unknown; DNA Viral PCR monitoring for BKV, CMV, and EBV and for HCV 
RNA. A rapid antigen test or PCR test for COVID-19 RNA (if applicable per Exclusion 
Criterion 34.A9); AE monitoring, administration of prophylactic antibiotic (as per the SOE), 
and review of prior and concomitant medications and entry criteria. With Sponsor approval, 
individual screening laboratory assessments may be repeated as appropriate to confirm 
eligibility. 
Baseline eGFR is defined as an average of 2 pre-treatment measurements up to 8 weeks 
apart. 
Any AEs that occur during the Screening Period (after informed consent but before Day 1 
Baseline Visit [Visit 2]) will be recorded as medical history. Note: Any AE that meets the 
definition of an SAE (see Section 10.1.3) must be immediately reported to CSLB (or its 
delegate [eg, CRO]) within 24 hours of site awareness (see Section 10.3.2). 
Informed consent must be in place prior to washout of prohibited medications. If more than 
30 days passes between signing informed consent and the Screening Visit, it must be 
re-signed and re-dated at Screening to reaffirm the subject’s continued interest to participate 
in the study. 
If a subject has not undergone a qualifying kidney biopsy within 12 months prior to the start 
of Screening, one can be performed after signing consent, provided no intervening treatments 
have been administered and the results can be obtained and reviewed prior to randomization. 
The local pathologist’s biopsy diagnosis must be reviewed by a central pathologist to confirm 
eligibility for entry into the study. 


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At Screening, local laboratory results for DSA will be reviewed by the central HLA reviewer 
to confirm DSA eligibility criteria. If the presence of HLA DSA is confirmed within 6 months 
prior to the start of Screening, the test does not need to be repeated for eligibility. If the 
central HLA reviewer disagrees with the local laboratory results, the central laboratory may 
repeat the Screening DSA test once; the repeat results must be reviewed by the central HLA 
reviewer to confirm DSA eligibility criteria. 
In cases where local DSA testing is unavailable at the site, Screening DSA will be conducted 
by the central laboratory and reviewed by the central HLA reviewer to confirm eligibility. 
A subject determined to be a screen failure for either clinical or administrative reasons may 
be rescreened twice. Note: a subject being rescreened is not required to have a repeat chest 
X-ray for TB screening if the first screening chest X-ray was without clinically relevant 
findings and conducted within 6 months from the start date of rescreening. In addition, 
laboratory assessments do not need to be repeated if the prior Screening laboratory 
assessments were deemed acceptable for entry into the study and were conducted within 
3 months of the prior Screening date. 
9.2.2 
Treatment Procedures 
Throughout the Treatment Period, subjects will return to the clinic Q4W for investigational 
treatment with clazakizumab / placebo until the subject permanently discontinues IP, 
withdraws from the study, experiences allograft loss, dies, or reaches the CTED, whichever 
occurs first. Per the SOE (see Table 1 and Table 2), dosing with IP is scheduled to occur on 
Day 1 Baseline (Visit 2) through the CTED. 
Before dosing, the following assessments will be conducted at Day 1 Baseline (Visit 2) 
through the CTED: 
• AEs and concomitant medications (will be collected and recorded prior to the conduct of 
any other study assessments). 
• Urine pregnancy test for WOCBP. 
• Blood collection for the central laboratory analysis of eGFR. 
• Review of the most recent safety laboratory tests (clinical chemistry, CBC, lipid, and 
hsCRP) and BKV, CMV & EBV DNA Viral PCR monitoring) results from a prior visit 
(scheduled or otherwise) to confirm if the subject is eligible to receive IP according to the 
safety limits for these criteria or if the dose of IP should be modified, temporarily 


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withheld, permanently discontinued, or restarted and / or if modification of the dose of 
background immunosuppression is recommended (see Section 7.5). 
• Every effort should be made to start treatment with prophylactic antibiotic for PJP 
approximately 1 week prior to starting IP. 
Additional assessments will be conducted prior to dosing, as detailed in the SOE, and include 
the following: 
• A check of all inclusion / exclusion criteria (Visit 2 [Baseline, Day 1] only). 
• Randomization (Visit 2 [Day 1] only). 
• Abbreviated physical examination (including vital signs). 
• ECG. 
• Blood and urine sample collection for additional central laboratory analyses as detailed in 
Table 8 and in the SOE. A minimum of 10 hours of fasting are required for determination 
of fasting glucose and lipids / triglycerides. At relevant visits per the SOE, MMF / MPA 
and CNIs are to be withheld until after collection of the blood sample for determination of 
MPA levels and CNI trough levels. 
• Renal biopsy (Visit 16; may be performed at an earlier visit if clinically indicated). 
• DSA MFI scores. 
• DSA titers. 
• IL-6 levels (total and free). 
• HRQoL. 
At Visit 3, the only assessment conducted will be blood sample collection for monitoring of 
CNI trough levels. Therefore, attendance at this visit is required only if the subject is taking a 
CNI. As noted above, CNIs are to be withheld until after collection of the blood sample for 
determination of CNI trough levels. 
9.2.2.1 
Optional Home Health Visits 
At some sites, home / workplace visits may be offered as an option instead of in-clinic visits 
for certain visits during the treatment phase (Table 1, Table 2, and Appendix 2). Home / 
workplace visits will be conducted by a qualified home health service provider. This service 
may not be available for all subjects at all sites. 


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Prior to each home / workplace visit, the Investigator will review the most recent LFT and 
CBC analyses and viral monitoring results from a prior visit (scheduled or otherwise) to 
confirm if the subject is eligible to receive IP according to the safety limits for these criteria 
or if the dose of IP should be modified, temporarily withheld, permanently discontinued, or 
restarted, and / or if modification of the dose of background immunosuppression is 
recommended (see Section 7.5). Note: if a dose modification (including withdrawal, 
discontinuation, or restart) of the IP and / or background immunosuppression is required, the 
subject should be called for an in-clinic visit. 
If the subject is confirmed as eligible to receive IP, the site pharmacy will be notified to 
dispense IP. IP will be sent by courier to the subject’s home / workplace where it will be 
received by the home health service provider. 
A home health service provider will travel to the subject’s home / workplace and conduct the 
following assessments prior to dosing (if applicable): 
• AEs and concomitant medications (will be collected and recorded prior to the conduct of 
any other study assessments). 
• Pregnancy test for WOCBP. 
• Blood collection for the central laboratory analysis of eGFR and blood collection for PK / 
PD Substudy sample analysis. 
Additional assessments will be conducted before dosing every 4 to 24 weeks, as detailed in 
the SOE, and include the following: 
• Abbreviated physical examination (including vital signs). 
• ECG (every 52 weeks). 
• Blood and urine sample collection for additional central laboratory analyses as detailed in 
Table 8 and in the SOE. A minimum of 10 hours of fasting are required for determination 
of fasting glucose and lipids / triglycerides. At relevant visits per the SOE, MMF / MPA 
and CNIs are to be withheld until after collection of the blood sample for determination of 
MPA levels and CNI trough levels. 
Following all assessments, the home health service provider will administer the IP as 
applicable. 


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The schedule of mandatory in-clinic visits is summarized in Table 10. Note: an in-clinic 
visit is required if a subject meets the primary efficacy endpoint (composite all-cause 
allograft loss). Furthermore, at the discretion of the Investigator, a subject may be required 
to attend additional in-clinic visits if clinically indicated (eg, because of an AE). 
Table 10 
Schedule of Mandatory In-Clinic Visits 
Visit Number (Visit Day / Week) 
Mandatory In-Clinic Visit 
Visit 1 (Screening) 
 
Visit 2 (Day 1) 
 
Visit 4 (Week 4) 
 
Visit 6 (Week 12) 
 
Visit 9 (Week 24) 
 
Visit 15 (Week 48) 
 
Visit 16 (Week 52) 
 
Visit 22 (Week 76) 
 
Visit 28 (Week 100) 
 
Visit 34 (Week 124) 
 
Visit 40 (Week 148) 
 
Visit 46 (Week 172) 
 
Visit 52 (Week 196) 
 
Visit 58 (Week 220) 
 
Visit 64 (Week 244) 
 
Visit 70 (Week 268) 
 
Visit 76 (Week 292) 
 
Visit 82 (Week 316) 
 
Visit 88 (Week 340) 
 
Visit 94 (Week 364) 
 
EOT / Early Withdrawal 
 
SFV 
 
Q6M after permanent DC of IP 
 
CTEV 
 
CTEV = common treatment end visit; EOT = End of Treatment; Q6M = every 6 months; SFV = safety follow-up visit; 
Note:  An in-clinic visit is required if a subject meets the primary efficacy endpoint (composite all-cause allograft loss); and, 
at the discretion of the Investigator, if clinically indicated (eg, because of an AE). 
All other visits can be home / workplace visits unless the subject is required to be seen at an 
in-clinic visit at the discretion of the Investigator (eg, even if a visit was previously planned 
to take place at home or workplace). 


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9.2.3 
Modifications to the Visit Schedule Due to Extraordinary 
Circumstances 
Visits 3 through 94 / EOT as described in Section 9.2 of the protocol, may be conducted as 
remote visits during extraordinary circumstances, with permission from the Investigator. 
Note: Remote visits will be allowed only where home health service providers are 
available and are allowed by local regulation. Table 11 summarizes the site visits allowed 
to be completed as remote visits. 
Table 11 
Schedule of “Mandatory In-clinic” Visits that may be Completed 
as Remote Visits During Extraordinary Circumstances 
Visit Number (Visit Day / 
Week) 
Assessments Not Available During Remote Visits 
All Regions 
Outside North America 
Visit 4 (Week 4) 
– 
APE 
Visit 6 (Week 12) 
ADA, Clazakizumab, ECG 
APE 
Visit 9 (Week 24) 
ADA, Clazakizumab, ECG 
APE 
Visit 15 (Week 48) 
ADA, Clazakizumab, ECG 
APE 
Visit 22 (Week 76) 
ADA, Clazakizumab 
APE 
Visit 28 (Week 100) 
ADA, Clazakizumab, ECG 
APE 
Visit 34 (Week 124) 
ADA, Clazakizumab 
APE 
Visit 40 (Week 148) 
ADA, Clazakizumab 
APE 
Visit 46 (Week 172) 
ADA, Clazakizumab 
APE 
Visit 52 (Week 196) 
ADA, Clazakizumab 
APE 
Visit 58 (Week 220) 
ADA, Clazakizumab 
APE 
Visit 64 (Week 244) 
ADA, Clazakizumab 
APE 
Visit 70 (Week 268) 
ADA, Clazakizumab 
APE 
Visit 76 (Week 292) 
ADA, Clazakizumab 
APE 
Visit 82 (Week 316) 
ADA, Clazakizumab 
APE 
Visit 88 (Week 340) 
ADA, Clazakizumab 
APE 
Visit 94 (Week 364) 
ADA, Clazakizumab 
APE 
ADA = anti-drug antibody; APE = abbreviated physical examination (including vital signs); ECG = electrocardiogram. 
Note: An in-clinic visit must be completed if a subject meets the primary efficacy endpoint (composite all-cause allograft 
loss). 
All scheduled study procedures and assessments should be completed at any remote visit 
except for the following: 
•
All regions:
o
Anti-clazakizumab antibody (ADA).
o
Clazakizumab drug level, ECG, renal biopsy.


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• Outside North America: 
o Abbreviated physical examination (including vital signs). 
The following site visits are not permitted to be completed remotely: 
• Visit 1 (Screening). 
• Visit 2 (Day 1, Baseline). 
• Visit 16 (Week 52). 
• EOT / Early Withdrawal Visit. 
• CTED Visit. 
9.2.4 
End of Treatment (or Early Treatment Withdrawal) Procedures 
When a subject completes the study (ie, reaches any of the non-fatal composite all-cause 
allograft loss endpoints, or if the subject is withdrawn early, or if the CTED is reached), all 
assessments for EOT / Early Withdrawal will be completed per the SOE. For further 
information on withdrawal procedures and criteria, see Section 5.5. 
Assessments at EOT / Early Withdrawal will include the following: 
• AEs and concomitant medications (recorded prior to the conduct of other study 
assessments). 
• Abbreviated physical examination (including vital signs) and ECG. 
• Pregnancy test for WOCBP. 
• Blood and urine sample collection for central laboratory analyses (safety laboratory tests 
[clinical chemistry, CBC, lipids, hsCRP], BKV, CMV, and EBV DNA Viral PCR 
monitoring, IgG monitoring, DSA MFI scores, DSA titers, eGFR, UACR, IL-6 levels 
[total and free]). A minimum of 10 hours of fasting is required for determination of 
fasting glucose and lipids / triglycerides. MMF / MPA and CNIs are to be withheld until 
after collection of the blood sample for determination of MPA levels and CNI trough 
levels. 
• Clazakizumab drug levels and anti-clazakizumab antibodies. 
• Renal biopsy (if the subject withdrawal on or after Visit 6 [Week 12] and prior to Visit 16 
[Week 52], and the subject has not had a biopsy within this period). 
• HRQoL including the EQ-5D-5L, KDQoL-36, and the FACIT Fatigue Scale. 


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Subjects who permanently discontinued investigational treatment with clazakizumab / 
placebo, and who have not reached a composite endpoint of all-cause allograft loss will 
continue in the study as described in Section 9.2.5.3. Following the in-clinic EOT / Early 
Withdrawal Visit within 4 weeks of receiving the last dose of IP, all subjects will be asked to 
return for 2 in-clinic Safety Follow-up Visits, 3 and 5 months after receiving the last dose of 
IP. In addition, all subjects will be contacted by telephone call 1, 2, and 4 months after last 
dose of IP for monitoring for new AEs, SAEs, or pregnancies.Thereafter, the subject will be 
asked to return in 6-month intervals until the CTED is reached to collect renal function and 
allograft status data. If a subject is unable to return for 6-monthly follow-up visits, he / she 
will be asked to agree to be contacted at CTED to collect allograft and survival status. 
Depending on the timing of early treatment discontinuation, this follow-up may consist of 
assessments conducted at regularly scheduled visits per-protocol and / or monthly follow-up 
TCs as needed and the SFV to complete 5 months of safety monitoring following their last 
dose of IP. Subjects who permanently discontinued treatment with IP ≥ 5 months before their 
EOT Visit (and complete the remainder of the study visits) will not require any follow-up 
TCs. 
Only if a subject is unable / unwilling to continue in the study will he / she be withdrawn 
from the study. Every effort should be made before the subjects withdraws from the study, 
either voluntarily or at the Investigator’s discretion, to undergo EOT assessments and safety 
follow-up as it is in the best interest of the subject. If possible, the subject will return for an 
in-clinic EOT / Early withdrawal visit within 4-weeks of the subject’s last dose of IP. If the 
subject agrees to the safety follow-up following the EOT/ Early withdrawal visit, the subject 
will be asked to return for 2 in-clinical Safety Follow-up Visits, 3 and 5 months after the last 
dose of IP. Subjects may be called in for a clinic visit during the 5-month Follow-up period at 
the discretion of the investigator (see Section 5.5). Subjects who withdraw consent from 
further participation from all aspects of study participation will not undergo further 
assessments. 
9.2.5 
Study Procedures Based Upon Subject Disposition 
Every effort should be made to retain subjects in the study and ensure attendance to the 
scheduled study visits up to the CTED, including those required after early discontinuation of 
IP. Detailed procedures for subjects who reach any of the non-fatal composite all-cause 
allograft loss or irreversible loss of allograft function endpoints, discontinue IP, withdraw 
from study, or are still on treatment until the CTED are outlined below. 
 


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9.2.5.1 
Subjects Who Reach the Endpoint of “Sustained 40% Decline in 
eGFR from Baseline” 
Subjects who reach the endpoint of sustained 40% decline in eGFR from Baseline (but did 
not reach a non-fatal endpoint components of allograft failure) will continue to receive 
double-blind medication until they reach any of the other primary endpoints of allograft loss. 
The subject will remain in the study attending all regular clinic visits and undergoing all 
assessments per the SOE. IVIG and PLEX may be administered at the discretion of the PI to 
these subjects if they have completed the Week 52 visit. Double-blind medication and IVIG 
should be administered 2 weeks apart due to potential binding of IVIG to clazakizumab. For 
treatment with IVIG, subjects may be called in for unscheduled visits between regularly 
scheduled dosing with IP according to the SOE. 
9.2.5.2 
Subjects Who Met Any of the Other Composite Non-fatal All-
cause Allograft Loss Endpoints 
Subjects will return for an in-clinic visit to undergo all assessments per the EOT / Early 
Withdrawal Visit schedule (Table 1 or Table 2). Following the EOT / Early Withdrawal Visit, 
all subjects will be contacted monthly by TC for 5 months after the last dose of IP for 
monitoring of new AEs, SAEs, or pregnancies. Subjects may be called in for a clinic visit 
during the 5-month Follow-up period at the discretion of the Investigator. 
An in-clinic SFV will be performed after the 5-month Follow-up period. Assessments 
performed at the SFV are as follows: 
• Pregnancy test (for WOCBP), safety laboratory tests (clinical chemistry, CBC, lipids, hs-
CRP), DSA MFI scores, eGFR, UACR, and IL-6 levels (total and free). 
• AEs and concomitant medications (recorded prior to the conduct of other study 
assessments). 
• Blood sample collection for clazakizumab serum levels and for anti-clazakizumab 
antibodies. 
9.2.5.3 
Subjects Who Permanently Discontinued Investigational Product 
The reason for IP discontinuation should be documented at the time of discontinuation. 
Subjects who discontinue IP for any reason will remain in the study and be followed for 
composite all-cause allograft loss and irreversible loss of allograft function events, or until 
the CTED is reached, whichever occurs first.  


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Subjects who subsequently reach the endpoint of  sustained (≥ 60 days) 40% decline in eGFR 
from Baseline will continue to remain in the study and will be followed for all-cause allograft 
loss events, or until subject withdraws from the study, or until the CTED is reached, 
whichever occurs first. 
If possible, the subject should return for an in-clinic visit within 4-weeks of the last dose of IP 
for an EOT / Early Withdrawal Visit to undergo all assessments per Table 1 or Table 2. 
Following the EOT / Early Withdrawal Visit, all subjects will be asked to return for 2 in-
clinic Safety Follow-up Visits, 3 and 5 months after receiving the last dose of IP. In addition, 
all subjects will be contacted by TC 1, 2, and 4 months after the last dose of IP for monitoring 
for new AEs, SAEs, or pregnancies. Thereafter, the subject will be asked to return in 6-month 
intervals until the CTED is reached to collect renal function and allograft status data. If a 
subject is unable to return for 6-monthly follow-up visits, he / she will be asked to agree to be 
contacted at CTED to collect allograft and survival status.  
• Note: Subjects who permanently discontinue treatment with IP ≥ 5 months before their 
EOT visit (and complete the remainder of the study visits) will not require any follow-up 
TCs. 
An in-clinic SFV should be performed after the 5-month Follow-up period. Assessments 
performed at the SFV are as follows: 
• 
Pregnancy test (for WOCBP), safety laboratory tests (clinical chemistry, CBC, lipids, hs-
CRP), DSA MFI scores, eGFR, UACR, and IL-6 levels (total and free). 
• 
AEs and concomitant medications (recorded prior to the conduct of other study 
assessments). 
• 
Blood sample collection for clazakizumab serum levels and for anti-clazakizumab 
antibodies. 
9.2.5.4 
Subjects Who Withdraw from the Study (ie, Withdrawal of 
Consent from Further Participation in the Study, Including any 
Contact by Study Site Personnel) 
The reason should be documented at the time of withdrawal. 
Every effort should be made before the subjects withdraws from the study, either voluntarily 
or at the Investigator’s discretion, to undergo EOT assessments and safety follow-up as it is 
in the best interest of the subject. If possible, the subject will return for an in-clinic EOT / 
Early withdrawal visit within 4-weeks of the subject’s last dose of IP (Table 1 or Table 2).  


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If the subject agrees to the safety follow-up following the EOT/ Early withdrawal visit, all 
subjects will be asked to return for 2 in-clinic Safety Follow-up Visits, 3 and 5 months after 
receiving the last dose of IP. In addition, all subjects will be contacted by TC 1, 2, and 4 
months after the last dose of IP for monitoring for new AEs, SAEs, or pregnancies. 
An in-clinic SFV should be performed after the 5-month Follow-up period. Assessments 
performed at the SFV are as follows: 
• 
Pregnancy test (for WOCBP), safety laboratory tests (clinical chemistry, CBC, lipids, hs-
CRP), DSA MFI scores, eGFR, UACR, and IL-6 levels (total and free). 
• 
AEs and concomitant medications (recorded prior to the conduct of other study 
assessments). 
• 
Blood sample collection for clazakizumab serum levels and for anti-clazakizumab 
antibodies. 
If a subject refuses an EOT / Early withdrawal visit, safety follow-up TCs, and /or SFV, the 
reason for refusal should be fully documented in the subject’s source document and recorded 
in the electronic case report form (eCRF). 
9.2.5.5 
Subjects Who are Still on Study When the Common Treatment 
End Date is Reached 
Once the CTED is reached, the study will be closed. As per Section 4.4, clazakizumab will be 
offered to all study subjects at the discretion of the treating physician after the completion of 
the study. 
Subjects who are still receiving IP, subjects in the 5-month safety follow-up period, and 
subjects who are being followed Q6M will return for an in-clinic CTEV. Subjects who are 
being followed for allograft and survival status will be contacted by telephone. The CTEV 
should occur within 4 weeks of the CTED being reached in order to complete the SOE 
assessments as described in Table 1 and Table 2. 
Assessments performed at the CTE Visit are as follows: 
• AEs and concomitant medications (recorded prior to the conduct of other study 
assessments). 
• Abbreviated physical examination (including vital signs) and ECG. 
• Pregnancy test for WOCBP. 


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• Blood and urine sample collection for central laboratory analyses (safety laboratory tests 
[clinical chemistry, CBC, lipids, hsCRP], BKV, CMV, and EBV DNA Viral PCR 
monitoring, IgG monitoring, DSA MFI scores, eGFR, UACR, IL-6 levels [total and 
free]). A minimum of 10 hours of fasting is required for determination of fasting glucose 
and lipids / triglycerides. MMF / MPA and CNIs are to be withheld until after collection 
of the blood sample for determination of MPA levels and CNI trough levels. 
• Clazakizumab drug levels and anti-clazakizumab antibodies. 
• HRQoL including the EQ-5D-5L, KDQoL-36, and the FACIT Fatigue Scale. 
After the CTEV, any SAE, adverse event of special interest (AESI), AE assessed as related to 
IP, or pregnancy discovered by the Investigator for 5 months after each individual subject’s 
last dose of IP is to be reported on the SAE Data Collection form (paper) to CSLB GCSP and 
will be documented in the CSLB safety database only. 
9.2.6 
Unscheduled Visits 
Unscheduled visits may be performed during the study for safety reasons. Only the data 
relevant to the purpose of the visit will be collected in the source documents and eCRF. 
Subjects who permanently discontinued treatment with IP may be called into the clinic for an 
unscheduled visit at the discretion of the Investigator. Subjects who permanently 
discontinued investigational treatment with clazakizumab / placebo and who have not 
reached an endpoint of composite all-cause allograft loss or death, will remain in the study 
and will be asked to return for 2 in-clinic Safety Follow-up Visits, 3 and 5 months after last 
dose of IP. Thereafter, the subject will be asked to return in 6-month intervals until CTED is 
reached to collect renal function and allograft status data as described in Section 9.2.5.3. 
10. Evaluation, Recording and Reporting of Adverse Events, Serious 
Adverse Events, and Special Situations 
10.1 
Definitions 
10.1.1 Definition of Adverse Event 
An AE is defined as any untoward medical occurrence or worsening of a preexisting medical 
condition in a clinical investigation subject administered IP and that does not necessarily 
have a causal relationship with this treatment. An AE can therefore be any unfavorable and 
unintended sign (such as an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of IP, whether considered related to the IP or not. 


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A treatment-emergent AE (TEAE) is defined as any AE after exposure to IP or any AE 
present prior to exposure that worsens in either intensity or frequency following the first 
administration of the IP. 
10.1.2 Definition of Adverse Drug Reaction 
In the pre-approval clinical experience with a new IP or its new usages, particularly as the 
therapeutic dose(s) may not be established, all noxious and unintended responses to an IP 
related to any dose should be considered ADRs. The phrase "responses to an IP" means that a 
causal relationship between an IP and an AE is at least a reasonable possibility, ie, the 
relationship cannot be ruled out. For instructions regarding determination of causality, see 
Section 10.2.2. 
10.1.3 Definition of Serious Adverse Event 
An SAE is defined as any AE or suspected adverse reaction that, in the view of either the 
Investigator or Sponsor, results in any of the following outcomes: 
• Death. 
• A life-threatening AE. (Note: the term life-threatening in definition of an SAE refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to 
an event which hypothetically might have caused death if it was more severe.) 
• Inpatient hospitalization or prolongation of existing hospitalization. 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• Congenital anomaly / birth defect. 
• Important medical events (see below). 
Important medical events that may not be life-threatening, nor require hospitalization, nor 
result in death may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. Examples of such medical events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 


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The following hospitalizations are not considered SAEs in this study: 
• A visit / admission to the emergency room and / or any other hospital department for 
< 24 hours (unless considered an important medical or life-threatening event). 
• Elective surgery planned prior to signing informed consent for this study. 
• Admissions as per-protocol for a planned medical / surgical procedure (eg, renal biopsy). 
• Routine health assessment requiring admission for Baseline / trending of health status (eg, 
routine colonoscopy). 
• Medical / surgical admission other than to remedy ill health and planned prior to entry 
into the study. Appropriate documentation is required in these cases. 
• Admission encountered for another life circumstance that carries no bearing on health 
status and requires no medical / surgical intervention (eg, lack of housing, economic 
inadequacy, caregiver respite, family circumstances, administrative reason). 
The Investigator is encouraged to discuss with the Sponsor or Medical Monitor any AEs for 
which the issue of seriousness is unclear or questionable. 
10.1.4 Definition of Adverse Events of Special Interest 
AESIs are AEs of scientific or medical concern for which ongoing monitoring and rapid 
communication is important. These may include events that are either specific to the IP or 
events that, in general, may be of clinical significance with any medicinal product under 
development. As such, an AESI may or may not be related to the IP. AESIs should be 
reported following expedited reporting procedures as described for SAEs (Section 10.3.2) 
regardless of seriousness and causality. 
For clazakizumab, the following AESIs have been defined: LFT abnormalities, neutropenia, 
thrombocytopenia, hyperlipidemia, GI perforations, hypersensitivity and anaphylaxis, 
malignancy, and opportunistic infections. Each of these AESIs is discussed in detail in the 
following sections. Details regarding a temporary or permanent dose reduction to 6.25 mg SC 
Q4W are provided in Section 7.5. 
10.1.4.1 Liver Function Test Abnormalities, Neutropenia, 
Thrombocytopenia, and Hyperlipidemia 
Throughout the trial, subjects will have regular hematology and biochemical laboratory tests 
to monitor for abnormal LFTs, neutropenia, thrombocytopenia, and hyperlipidemia. In 
general, these and any other abnormal test results that meet CTCAE (Version 5.0) definition 


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of Grade 3 (severe) or higher should be considered an AESI and IP should be withheld or 
discontinued, in consultation with the Medical Monitor. 
Specifically, as detailed in Section 5.6, IP should be withheld or discontinued for subjects 
who meet any of the following criteria. 
If the following laboratory abnormalities are observed an AESI should be reported: 
• AST / ALT > 5 x ULN. 
• Total bilirubin > 3 x ULN. 
• AST / ALT > 3 to ≤ 5 x ULN and total bilirubin ≥ 2 x ULN (or INR > 1.5). 
• Neutrophil count < 1000 cells per mm3. 
• Platelets < 50,000 cells per mm3. 
• Total cholesterol > 400 mg/dL (> 10.34 mmol/L), irrespective of Baseline level. 
• Triglyceride > 500 mg/dL (> 5.7 mmol/L), irrespective of Baseline level. 
10.1.4.2 Gastrointestinal Perforation 
Gastrointestinal perforation is an identified risk of treatment with anti-IL-6 antibodies and 
must be reported as an AESI (see Section 8.1.5). 
10.1.4.3 Hypersensitivity and Anaphylaxis 
Hypersensitivity reactions and anaphylaxis meeting the definition of the Joint NIAID / FAAN 
Second Symposium [Sampson et al, 2006] on Anaphylaxis should be reported as AESIs: 
• Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal 
tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-tongue-uvula) and 
at least one of the following: 
o Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced peak 
expiratory flow, hypoxemia). 
o Reduced blood pressure or associated symptoms of end-organ dysfunction (eg, 
hypotonia (collapse), syncope, incontinence). 
10.1.4.4 Malignancy 
Any new malignancy or progression of preexisting malignancy (excluding non-melanoma skin 
cancers [squamous cell or basal cell carcinoma]) should be reported as AESIs. 


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10.1.4.5 Opportunistic Infections 
Throughout the trial, monitoring for potential infections will follow the recommendations of 
the American Society of Transplantation [Humar and Michaels, 2006] and the KDIGO 
guideline [Kidney Disease: Improving Global Outcomes, 2009]. Recognized viruses that 
cause significant morbidity in kidney transplant recipients such as BKV, CMV and EBV will 
be monitored by PCR at regular 4- to 24-week intervals as detailed in the SOE. 
The following infections should be reported as AESIs: 
•
Any bacterial pneumonia or bronchitis.
•
Any gram-negative bacteria GI infections (including Salmonella (enterica serotypes,
Typhimurium and Enteritidis), Shigella, Campylobacter, Escherichia coli, and
Clostridium difficile).
•
BKV nephropathy.
•
CMV infections / disease (eg, hepatitis, colitis, pneumonitis, retinitis).
•
Cryptosporidiosis with Cryptosporidium.
•
Invasive candidiasis.
•
Invasive mycosis which includes cryptococcosis, histoplasmosis, aspergillosis and
coccidioidomycosis.
•
JC virus infection (progressive multifocal leukoencephalopathy).
•
Hepatitis B virus and HCV infections.
•
Human papillomavirus (HPV) disease.
•
HIV infection.
•
Pneumocystis pneumonia with Pneumocystis jirovecii.
•
Mycobacterium tuberculosis infections and other mycobacterium infections (eg,
Mycobacterium kansasii, Mycobacterium avium).
•
Non-CMV viral diseases including herpes simplex virus Type 1 (HSV-1) and Type 2
(HSV-2) disease, varicella zoster virus disease, human herpesvirus-8 (HHV-8) disease.
•
Toxoplasmosis infections with Toxoplasma gondii.
•
Severe respiratory syndrome coronavirus 2 (SARS-CoV-2) infections (COVID-19).


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The above list is not meant to be complete and other infections which are not commonly 
observed in the kidney transplant population should also be considered an AESI by the 
Investigator or Sponsor. 
Specifically, as detailed in Section 5.6.4, IP should be permanently discontinued for subjects 
who meet any of the following laboratory criteria and these abnormalities should be reported 
as AESIs: 
•
BKV ≥ 10,000 copies/mL (≥ 3200 IU/mL; ≥ 3.51 log IU/mL) or biopsy-proven BKV
nephropathy.
•
EBV ≥ 10,000 copies/mL (≥ 20,400 IU/mL; ≥ 4.31 log IU/mL) or post-transplant
lymphoproliferative disorder or primary EBV infection in seronegative recipient.
10.2 
Classification of Adverse Events 
10.2.1 Severity Classification 
The severity of all AEs should be assessed and graded according to the National Cancer 
Institute’s CTCAE Version 5.0 [NCI, 2017] (see Table 12). 
Table 12 
Adverse Event Severity Grading 
Grade (Severity) 
Description 
Grade 1 (mild) 
Asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
Grade 2 (moderate) 
Minimal, local or non-invasive intervention indicated, limiting age-appropriate 
instrumental activities of daily living (eg, preparing meals, shopping for 
groceries or clothes, using the telephone, managing money, etc.). 
Grade 3 (severe) 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living (eg, bathing, dressing and undressing, 
feeding self, using the toilet, taking medications, and not bedridden). 
Grade 4 (life-threatening) 
Life-threatening consequences: urgent intervention indicated. 
Grade 5 (death) 
Death related to AE. 
AE=Adverse event. 
Source: National Cancer Institute’s CTCAE Version 5.0 [NCI, 2017]. 
The term severe is often used to describe the intensity (severity) of a specific event; however, 
the event itself may be of relatively minor medical significance (eg, a severe headache). This 
is not the same as “serious”, which is based on the subject / event outcome or action criteria 
as described in Section 10.1.3. Seriousness, not severity, serves as a guide for defining 
regulatory reporting obligations. 


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Note: AEs of severity Grades 4 and 5 fulfill the definition of an SAE and require expedited 
reporting (see Section 10.3.2). 
10.2.2 Relationship to Investigational Product 
For all collected AEs, the clinician who examines and evaluates the subject will determine the 
AE’s causality based on temporal relationship and his / her clinical judgment. The degree of 
certainty about causality will be graded using 2 categories (related / unrelated) as shown in 
Table 13. 
Table 13 
Adverse Event Relationship to Investigational Product 
Term 
Relationship 
Description 
Related 
Yes 
The temporal relationship of the clinical event to IP administration indicates 
a causal relationship, and other drugs, therapeutic interventions or 
underlying conditions do not provide a sufficient explanation for the 
observed event. 
Unrelated 
No 
The temporal relationship of the clinical event to IP administration does not 
indicate a causal relationship, or other drugs, therapeutic interventions or 
underlying conditions provide a sufficient explanation for the observed 
event. 
IP = investigational product. 
10.2.3 Outcome Categorization 
Outcome of AEs should be classified as follows: recovered / resolved (ie, without sequelae); 
recovered / resolved with sequelae; recovering / resolving; not recovered / not resolved; fatal; 
or unknown (if follow-up is not possible). 
If the outcome of an SAE is reported as recovered / resolved with sequelae, the Investigator 
should specify the kind of sequelae on the SAE form. If the outcome of an SAE is reported as 
unknown, it should be recorded as continuing at the end of the study. 
10.2.4 Preexisting and Worsening of Medical Condition 
A preexisting medical condition is one that is present at the Screening Visit and prior to 
randomization. Such conditions should be recorded on the medical history eCRF. A 
preexisting medical condition should be recorded as an AE only if the frequency, severity, or 
character of the condition worsens during the study. When recording such events on the AE 
eCRF, it is important to convey the concept that the preexisting condition has changed by 
including applicable descriptors (eg, “more frequent headaches”). 


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Note: If a preexisting medical condition meets the definition of an SAE (see Section 10.1.3) it 
must also be immediately reported to CSLB (or its delegate [eg, CRO]) within 24 hours of 
site awareness (see Section 10.3.2). 
10.2.5 Symptoms of the Disease Under Study 
Signs and symptoms of the disease under study will not be classed as AEs if they are within 
the normal day-to-day fluctuation of the disease. An explanation of these circumstances must 
be written in the source documents. Worsening of disease symptoms, however, will be 
recorded as an AE, and clearly marked on the eCRF as worsening of the signs or symptoms. 
10.2.6 Clinical Laboratory Evaluations 
A change in the value of a safety laboratory investigation should be reported as an AE if the 
change is considered clinically relevant in the opinion of the Investigator. 
10.2.7 Physical Examinations and Vital Signs 
Worsening of any physical examination findings or vital signs, or any new physical 
examination findings are to be reported as an AE if the change is considered clinically 
relevant in the opinion of the Investigator, or in the case of vital signs, if a shift from a normal 
to a pathological value is observed, or a further worsening of an already pathological value is 
observed and similarly, the change is considered clinically relevant. 
10.2.8 Special Situations 
All special events including medication error must be documented in the subject’s eCRF and 
source documentation. If any such event meets the criteria for seriousness, the event must be 
reported as an SAE. 
Special situations which may apply are: overdose, medication error, food or drug interaction, 
or an unexpected therapeutic effect. 
10.3 
Reporting Procedures for Adverse Events, Serious Adverse Events 
and Pregnancy 
10.3.1 Reporting of Adverse Events 
All AEs either observed by the Investigator or one of his / her medical collaborators, or 
reported by the subject spontaneously, or in response to a direct question, will be noted in the 
subject’s eCRF and source documents. This applies to all AEs regardless of presumed 


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relationship to the study treatment, including the IP and placebo arm. Adverse events leading 
to dose modification, withholding, or discontinuation of IP should also be collected. 
For all AEs, the date of onset, relationship to IP, any action taken, date of resolution (or the 
fact that it is continuing or has become chronic), outcome, intensity (worst at any point 
during the event), and whether the AE was serious or not at any time during the event will be 
recorded. In order to establish the duration of any SAE, the dates of hospitalization and 
discharge or dates of meeting other SAE criteria will be recorded. 
Where possible, the Investigator should report a diagnosis rather than individual signs and 
symptoms or abnormal laboratory values. However, if an aggregate of signs and / or 
symptoms cannot be medically characterized as a single diagnosis or syndrome at the time of 
reporting, each individual event should be recorded in the eCRF. If a diagnosis is known, the 
underlying medical diagnosis of an event should be recorded by preference in the listing of 
individual symptoms. 
The Investigator should use standard medical terminology / concepts and avoid 
colloquialisms and abbreviations. Only 1 AE term should be recorded in each event field in 
the eCRF. 
The AE reporting period will begin at the time the ICF is signed by the subject, and 
1 Screening procedure is performed, and continues for 5 months after the last dose or date of 
withdrawn consent. All AEs that occur during the Screening Period are to be recorded as 
medical history. Any AE that meets the definition of an SAE (see Section 10.1.3) must also 
be immediately reported to CSLB (or its delegate [eg, CRO]) within 24 hours of site 
awareness (see Section 10.3.2). 
Serious adverse events persisting at the time of study completion will be followed by the 
Investigator through contact with the subject until resolution or stabilization has occurred (or 
the subject is lost to follow-up and cannot be contacted) and recorded in the source 
documents. Non-serious AEs ongoing at the end of the Follow-up period (5 months after the 
last dose) will be recorded as ongoing and will not be followed up further. 
If the subject reports an AE, it is the Investigator’s responsibility to acquire sufficient 
information in order to assess causality. This may require additional laboratory testing, 
physical examinations, telephone contacts, etc. 
To avoid bias in eliciting AEs, subjects should be asked a non-leading question, such as 
“How are you feeling?” It is also important to question the subject in a non-leading way 


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about changes in their health or concomitant medication usage since their last visit. This 
information should be collected prior to completion of assessments at all study visits. In 
addition, any symptoms / conditions reported during assessments and deemed to be clinically 
significant by the Investigator will be considered AEs. 
10.3.2 Reporting of Serious Adverse Events 
This study will comply with all applicable regulatory requirements and adhere to the full 
requirements of ICH Topic E2A (Clinical Safety Data Management: Definitions and 
Standards for Expedited Reporting). 
The occurrence of an SAE, whether related or unrelated, must be immediately reported to 
CSLB (or its delegate [eg, CRO]) within 24 hours of site awareness by email or facsimile as 
follows: 
Email: adverse.events.global@cslbehring.com (email is the preferred option) 
FAX: +49-6421-39-4775 
The Investigator is responsible for submitting an SAE to the Institutional Review Board 
(IRB) / Independent Ethics Committee (IEC) per local reporting requirements. Detailed SAE 
reporting procedures will be specified in separate study instructions. 
All SAEs (“related” or “not related”) will be reported once the ICF is signed, and 1 screening 
procedure has been completed. In addition, all SAEs will be reported for 5 months after the 
last dose or consent is withdrawn. If the Investigator has not seen the subject at a clinic visit 
at the end of the reporting period, the Investigator must make reasonable efforts to contact the 
subject to inquire about SAEs. In case of withdrawal of consent, the reporting period ends at 
the time of withdrawal. 
All SAEs will be followed until satisfactory resolution or until the site Investigator deems the 
event to be chronic or stable, or the subject is lost to follow-up. Other supporting 
documentation of the event may be requested by the Sponsor and should be provided as soon 
as possible. In circumstances where the Investigator is unable to contact the subject, the 
Investigator must provide a written statement to CSLB confirming that the subject is lost to 
follow-up. 
The onset date of the SAE is defined as the date the signs and symptoms / diagnosis became 
serious. The resolution date of the SAE is defined as when the symptoms resolve, or the event 
is considered chronic or stable, and / or if the seriousness criteria are no longer applicable. 


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SAEs that are ongoing at the time of death will have an outcome of “unknown” recorded. 
SAEs resulting in a fatal outcome will have an outcome of “fatal” recorded. 
Any SAE considered to have a causal relationship (ie, “related”) to the IP and discovered by 
the Investigator at any time after the study will be reported. A rationale for the assessment of 
a causal relationship must be provided by the Investigator. Any safety information that is 
obtained after the end of the Follow-up period (ie, 5 months after the last dose of IP) will be 
documented in the safety database only. 
A death occurring during the study or which comes to the attention of the Investigator within 
5 months after the last dose or date of withdrawn consent, whether considered treatment 
related or not, must be reported to CSLB. Preliminary reports will be followed by detailed 
descriptions which will include copies of hospital case reports, autopsy reports / certificates 
and other documents when requested and applicable. 
Additional follow-up information, if required or available, must be submitted within 24 hours 
of the Investigator (or site) awareness of the information. 
The Investigator is encouraged to discuss with the study Medical Monitor when the issue of 
seriousness is unclear or questionable. 
10.3.3 Reporting of Pregnancy 
Any pregnancy occurring in a female subject, or in the female partner of a male subject 
during the study or for 5 months after the last dose of IP, should be reported to CSLB (or its 
delegate [eg, CRO]) within the same timelines as an SAE (ie, within 24 hours of the 
Investigator being notified). A pregnancy form should be used to record and report all 
pregnancies. The Investigator should counsel the subject (or in the case of a male subject, the 
subject’s partner) and discuss the risks of continuing with the pregnancy and any possible 
effects on the fetus. A female subject must immediately inform the Investigator if she 
becomes pregnant during the study. Monitoring of the pregnancy in a female subject should 
continue until conclusion of the pregnancy. In case of a pregnancy in the female partner of a 
male subject, the Investigator should obtain informed consent of the pregnant partner prior to 
monitoring of the pregnancy. 
Women who have a confirmed positive pregnancy test during the study will be permanently 
discontinued from IP and remain in the study and continue to attend all regular clinic visits 
and undergoing all assessments per the SOE and must continue to comply with all aspects of 
the protocol. 


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The outcome of all such pregnancies (including normal births) should be followed up and 
documented. Obtaining a subject’s or partner’s pregnancy outcome will be done using a 
special consent form. Every effort should be made to gather information regarding the 
pregnancy until the outcome has been determined. It will be the responsibility of CSLB, 
together with the appropriate support of the Investigator, to obtain this information. 
Pregnancy in and of itself is not an SAE. However, complications of pregnancy such as 
abortion (spontaneous or induced), premature birth, or congenital abnormality are considered 
SAEs and will be reported. 


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11. Data and Safety Monitoring Board Procedures 
A DSMB will be constituted to protect the safety of study subjects. The DSMB will review 
cumulative study data to evaluate safety, study conduct, scientific validity, and data integrity. 
The DSMB will receive blinded eCRF data in the form of tables and listings (prepared by an 
independent statistician) and review subject status changes and dosing decisions (where 
appropriate). Where appropriate, the DSMB may receive unblinded data (on a subject level or 
treatment group level) that should be reviewed in a closed session. The data should include, 
but is not limited to, demographics, subject enrollment, Baseline characteristics, AE data, 
SAE data (by severity and causality), laboratory data, dose adjustments, protocol adherence, 
and subject withdrawals. The DSMB will evaluate the progress of the trial, assess data quality 
and timeliness, subject recruitment, accrual and retention, and subject benefit versus risk. In 
addition, the DSMB will monitor external factors relevant to the trial, for example scientific 
and therapeutic developments that may affect subjects safety or ethical status. Based on the 
observed benefits or adverse effects, the DSMB will make recommendations to CSLB 
concerning continuation, termination, or modifications of the trial. 
A charter document explaining the working procedures and responsibilities of the DSMB will 
be created and finalized after the first DSMB operational meeting and before any data review 
meetings. 
As detailed in Section 12.11, the DSMB will conduct formal interim safety reviews after 
approximately 50 subjects per group and 100 subjects per group, respectively, have been 
randomized and received at least 1 dose of IP. Further safety reviews may be conducted at the 
discretion of the DSMB. A formal interim efficacy analysis (IA #2) will be conducted on the 
surrogate eGFR endpoint when approximately 200 subjects have completed at least 52 weeks 
of study participation. The adequacy of the planned sample size for this analysis will be 
reevaluated once approximately 100 subjects have been randomized and completed at least 
52 weeks of study participation (IA #1). An independent statistician (external to the study 
Sponsor) will perform these unblinded interim efficacy and safety analyses and will prepare 
all interim data for the DSMB. Detailed procedures for maintaining the blind will be 
specified in the DSMB charter and / or Data Access Plan. 


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12. Statistical Analysis 
The purpose of this study is to investigate the superiority of clazakizumab relative to placebo. 
12.1 
Statistical Methods 
All statistical analyses will be performed using SAS Version 9.4 or later (SAS Institute Inc. 
SAS / STAT, Cary, NC, US). Detailed methodology and statistical analyses of the data 
collected in this study will be documented in a Statistical Analysis Plan (SAP), which will be 
finalized prior to study completion. A general overview of the planned methodology is 
provided below. Any deviation from the SAP will be detailed in the final clinical study report. 
The primary and secondary efficacy analyses will be based on an Intention-to-Treat (ITT) and 
Per-protocol (PP) Analysis Set. Safety evaluations will be based on the Safety Analysis Set. 
Unless otherwise stated, all statistical testing will be two-sided and will be performed using a 
significance (alpha) level of 0.05. Two-sided 95% confidence intervals will be provided when 
relevant. 
Continuous variables will be summarized using descriptive statistics, including number of 
subjects (n), mean, median, standard deviation, minimum and maximum. 
For categorical variables, summaries will include counts of subjects and percentages. 
Percentages will be rounded to one decimal place. 
For summary purposes, Baseline will be defined as the last available predose value; all 
summaries will be presented by treatment group, unless otherwise specified. 
All statistical analyses will be based on the diagnosis and Banff scoring from the central 
pathologist. 
All statistical DSA analyses will be based on the results from the central laboratory. 
12.2 
Sample Size and Power Calculations 
As summarized in Section 2, a non-interventional historical, prospective cohort study 
(modeling exercise) was conducted to quantify the relationship between change in eGFR and 
risk of allograft failure in patients diagnosed with acute / active ABMR or CABMR following 
kidney transplantation. Using data from this modeling exercise, sample sizes based on eGFR 
data collected for a period of up to 52 weeks after diagnosis of ABMR, and assuming a 
50% reduction in the rate of eGFR decline, were estimated for the risk of composite all-cause 


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allograft loss or irreversible loss of allograft function and “working backwards,” for the 
interim analysis of the surrogate 52-week eGFR endpoint. 
Assuming a rate of composite all-cause allograft loss or irreversible loss of allograft function 
survival of 24.7%% for the placebo arm over a period of approximately 48 months, at least 
221 composite all-cause allograft loss or irreversible loss of allograft function events 
(expected to accrue in 316 subjects) will be required to provide 80% power (two-sided alpha 
of 0.05) to detect a 31% reduction in the relative risk of allograft loss in the clazakizumab 
group compared to the placebo group, assuming clazakizumab can reduce the slope of eGFR 
decline by 50% (see Table 14). A relative risk reduction of 31% would improve the 4-year 
graft survival rate from 24.7%% to 38.3%. Approximately 350 subjects (175 per group) will 
be enrolled to allow for 10% loss to follow-up and withdrawals. 
Table 14 
Sample Size Estimates for Composite All-cause Allograft Loss or 
Irreversible Loss of Allograft Function Based on eGFR Data 
Restricted to 52 Weeks Post-Diagnosis of Active ABMR 
Scenario 
All-Cause Graft 
Survival or 
Irreversible Loss at 4-
Years Post Diagnosis 
of Active ABMR 
Hazard Ratio, λ 
Total Number of 
Events / Total 
Number of Subjects 
Power=80% 
Mean eGFR 
0 0.247 
1.000 
– 
50% improvement in slope(a) 
 0.383 
0.686 
221/316 
ABMR=Antibody-mediated rejection; eGFR=Estimated glomerular filtration rate. 
Notes:  
a Relative to the average slope change for the mean eGFR scenario, slope = -0.753, based on eGFR data restricted to first 
12 months post-diagnosis of ABMR. 
Source: Modeling Report, Section 10, Table 9-2-1b. 
Once approximately 100 subjects (50 per group) have been randomized and completed at 
least 52 weeks of study participation, reestimation (IA #1) of the planned sample size of 
200 subjects will be conducted using the inverse normal method with pre-specified 
information rates (0.5556, 1) to control the Type I error rate. Observed data from subjects not 
completing / not reaching Week 52 will also be included in the analysis. The sample size 
reestimation ensures a power of 95.9%, when the assumed difference between treatment 
groups in the 52-week eGFR of 4.515 mL/min/1.73 m2 and a common standard deviation of 
9.252 mL/min/1.73 m2 (effect size = 4.515/9.252 = 0.488).The average sample size under 
these assumptions is 202 subjects (corresponding to approximately 224 randomized subjects, 
assuming 10% loss to follow-up or withdrawals). When the assumed eGFR effect size is 
0.368, then the power is 79.6% and the average sample size is 218 subjects (approximately 
242 randomized subjects). The sample size for the interim efficacy analysis surrogate 


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endpoint (IA #2) will not exceed a total of 250 subjects with at least 52 weeks of study 
participation (approximately 280 randomized subjects). 
The interim efficacy analysis (IA #2) will be performed when approximately 200 (100 per 
group) subjects have been randomized and completed at least 52 weeks of study participation 
to evaluate the difference between the treatment groups. Observed data from subjects not 
completing / not reaching Week 52 will also be included in the analysis. As shown in Table 
15, a fixed sample size of 180 subjects (90 per group) will have 90% power (two-sided alpha 
of 0.05) to detect a minimum difference in the 52-week eGFR of 4.515 mL/min/1.73 m2 
between the treatment groups (assuming eGFR declines at a rate of 
0.75 mL/min/1.73 m2/month in the placebo treated group and that clazakizumab reduces 
eGFR decline by 50%). The sample size determination for the fixed design is based on a 
two-sided alpha of 0.05 and a common standard deviation of 9.252 mL/min/1.73 m2 for the 
mean eGFR change from Baseline to Week 52 (effect size = 4.515/9.252 = 0.488). The 
planned sample size has been increased to a minimum of 200 subjects to allow 10% for 
subjects lost to follow-up or withdrawals. 
Table 15 
Sample Size Estimates for Change in eGFR (mL/min/1.73 m2) at 
52 Weeks After Diagnosis of Active ABMR 
Scenario 
eGFR 
Baseline 
eGFR 
52 Weeks 
% Change 
from Baseline 
Slope (eGFR 
Change / Month) 
Sample Size for 
Power= 90%(a)
Mean eGFR 
45.577 
36.547 
-19.8%
-0.753
50% improvement 
in slope(b) 
45.577 
41.062 
-9.9%
-0.376
180 
Notes: ABMR=antibody-mediated rejection; eGFR=estimated glomerular filtration rate. 
a Standard deviation of the difference in eGFR from Baseline at 12 months after diagnosis of ABMR = 9.252, when 
restricted to 12-month eGFR data. 
b Relative to the average slope change for the mean eGFR scenario, slope = -0.753, based on eGFR data restricted to first 12 
months after diagnosis of ABMR. 
Source: Modeling Report, Section 10, Table 9-2-1a. 
12.3 
Pharmacokinetic Analyses 
For all subjects, serum concentrations of clazakizumab will be listed and summarized by 
nominal timepoint. The following descriptive statistics will be presented for plasma 
concentration summaries: n, arithmetic mean, standard deviation (SD), CV%, median, 
geometric mean, minimum, and maximum. 
For subjects participating in the PK / PD Substudy, serum concentration-time data will be 
used to perform noncompartmental analysis using WinNonLin® version 5.2 (or higher). PK 
parameters will be calculated and summarized descriptively. 


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When applicable, the following PK parameters will be derived and summarized (for those 
participating in the PK / PD Substudy): 
• Time of maximum concentration (Tmax, Tmax ss). 
• Maximum concentration (Cmax, Cmax ss). 
• Trough concentration (Ctrough, Ctrough ss). 
• Area under the concentration-time curve (AUC0-tau) at steady state. 
If the data allow, additional PK parameters will be derived. The following descriptive 
statistics will be presented for all PK parameters, except for Tmax: n, arithmetic mean, SD, 
CV%, median, geometric mean, minimum and maximum. For Tmax, n, median, minimum and 
maximum will be summarized. 
12.4 
Pharmacodynamic Analyses 
For subjects in the PK / PD Substudy, plasma IL-6 (total and free) and serum hsCRP will be 
summarized for all timepoints. The following descriptive statistics will be presented: n, 
arithmetic mean, SD, CV%, median, geometric mean, minimum, and maximum. A graphical 
profile of mean (SD) may also be presented. Exploratory analyses and / or modeling 
approaches may be used to investigate the relationship between serum clazakizumab 
concentrations with plasma IL-6 and / or serum hsCRP. 
12.5 
Analysis Sets 
All decisions regarding definition of analyses sets will be made prior to unblinding. 
12.5.1 Intention-to-Treat Set 
The ITT set will consist of all subjects who meet the following criteria: 
• Received at least 1 dose of IP. 
• Had a Baseline assessment and at least 1 post-Baseline assessment. 
Subjects in the ITT set will be analyzed using the intention-to-treat principle (ie, according to 
randomized treatment assignment). The ITT set will be used for tables of efficacy and 
demography, as well as relevant listings. The ITT will be the primary set for analysis of the 
primary efficacy endpoint. 


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12.5.2 Per-Protocol Set 
The PP set will consist of all subjects who satisfy the ITT criteria and have no major protocol 
deviations that impact the primary efficacy endpoint for the final or interim analysis (as 
defined in the SAP). 
Subjects in the PP set will be analyzed using the ITT principle (ie, according to randomized 
treatment assignment). 
12.5.3 Safety Analysis Set 
The Safety Analysis Set consists of all randomized subjects who have received at least 1 dose 
of IP. The subjects in the Safety Analysis Set will be analyzed according to the actual 
treatment received. 
12.5.4 Pharmacokinetic Analysis Set 
The PK Analysis Set consists of all subjects in the Safety Analysis Set with at least 
1 quantifiable PK concentration of IP after administration. 
12.5.5 Pharmacokinetic / Pharmacodynamic Substudy Analysis Set 
The PK / PD Substudy Analysis Set consists of all subjects in the Safety Analysis Set who 
consent to be a part of the PK / PD Substudy and have at least 1 quantifiable PK 
concentration of IP after administration. 
Protocol violations that may impact PK analysis will be defined in detail in the Blinded Data 
Review Meeting before database lock. 
12.6 
Baseline and Demographic Characteristics 
Baseline disease and demographic characteristics will be summarized using descriptive 
statistics for the ITT set, grouped according to treatment group. The number and percent of 
subjects in each category of the randomization stratification factors will also be summarized 
by treatment group. 
Medical history will be summarized by the Medical Dictionary for Regulatory Activities 
(MedDRA, Version 21 or later) System Organ Class (SOC) and PT, according to treatment 
group. Prior medications will be categorized using WHO Drug (March 2018 or later) and 
summarized according to treatment group. Note: All AEs that occur during the Screening 
Period are to be recorded as medical history. 


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12.7 
Investigational Product 
The total amount of IP given will be calculated for each subject and will be compared to the 
amount expected to be given for each subject. Treatment compliance will be calculated for 
each subject and summarized using descriptive statistics. 
12.8 
Concomitant Therapy 
Concomitant medications will be categorized using WHO Drug (March 2018 or later) and be 
summarized according to treatment group. 
12.9 
Efficacy Evaluations 
Primary Estimand 
The primary interest is to quantify the treatment effect of clazakizumab using a composite 
clinical endpoint. The primary estimand in line with the primary objective of the study is 
described as follows: 
• Population: the target patient population defined by the eligibility criteria and the ITT 
analysis set. 
• Variable: Time-to-event of composite all-cause allograft loss or irreversible loss of 
allograft function or all-cause death. 
• Intercurrent event: intercurrent events are captured through the variable definition. 
• Population level summary: hazard ratio of clazakizumab relative to placebo for composite 
all-cause allograft loss or irreversible loss of allograft function or all-cause death. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the time to composite all-cause allograft loss or irreversible 
loss of allograft function, defined as occurrence of any of the following components: 
• 
eGFR < 15 mL/min/1.73 m2* 
• 
return to dialysis* 
• 
allograft nephrectomy 
• 
retransplantation 
• 
death from any cause, or 
• 
a sustained (≥ 60 days) 40% decline in eGFR from Baseline. 
*total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days. 


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If the eGFR < 15 mL/min/1.73 m2 is the only component reached, the value must be 
sustained over at least 60 days and must be confirmed by a repeat measurement after 
≥60 days from the date of the first measurement. The confirmatory measurement of 
eGFR < 15 mL/min/1.73 m2 done at least 60 days from the initial measurement must be 
processed by the central laboratory. 
A stratified log rank test will be used to compare the median time-to-event between each 
treatment arm. Incidence rates and hazard ratios will also be presented. 
To assess the robustness of the primary efficacy analysis, the primary efficacy variable will 
be repeated in sensitivity analyses using the PP set. An additional sensitivity analysis will 
address the nature of composite all-cause allograft loss or irreversible loss of allograft 
function as a recurrent event. 
All efforts will be made to minimize missing data. Subjects who permanently discontinued 
treatment with IP, and who have not reached an endpoint of composite all-cause allograft loss 
or death, will remain in the study. Following the EOT / Early Withdrawal Visit within 
4 weeks of receiving the last dose of IP, all subjects will be asked to return for 2 in-clinic 
Safety Follow-up Visits, 3 and 5 months after receiving the last dose of IP. In addition, all 
subjects will be contacted by telephone call 1, 2, and 4 months after last dose for IP for 
monitoring for new AEs, SAEs, or pregnancies. Thereafter, the subject will be asked to return 
in 6-month intervals until the CTED is reached to collect renal function and allograft status 
data. Subjects who permanently discontinued IP treatment due to loss of their allograft will 
undergo EOT assessments and be contacted monthly for 5 months after the last dose of IP, 
followed by an in-clinic SFV per protocol. 
Additional details will be documented in the SAP. 
12.9.1 Secondary Efficacy Endpoints 
The following secondary efficacy endpoints will be analyzed: 
• Time to composite all-cause allograft loss, defined as: 
o eGFR < 15 mL/min/1.73 m2* 
o return to dialysis* 
o allograft nephrectomy 
o retransplantation, or 


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o death from any cause. 
• Incidence and time to irreversible loss of allograft function as defined by a 40% decline in 
eGFR from Baseline. 
• Incidence of composite all-cause allograft loss or irreversible loss of allograft function, 
defined by the occurrence of any of the following components: 
o eGFR < 15 mL/min/1.73 m2* 
o return to dialysis* 
o allograft nephrectomy 
o retransplantation 
o death from any cause, or 
o a sustained (≥ 60 days) 40% decline in eGFR from Baseline. 
• Incidence and time to death-censored allograft loss, defined as: 
o eGFR < 15 mL/min/1.73 m2* 
o return to dialysis* 
o allograft nephrectomy, or 
o retransplantation. 
• Change in mean eGFR from Baseline to EOT. 
• Change in spot UACR from Baseline to EOT. 
• Change in DSA titers and MFI scores from Baseline to EOT. 
• Change in Banff lesion grading score (2015 criteria [Loupy et al, 2017]) of pre-treatment 
to post-treatment (Week 52) kidney biopsies. 
• Incidence of acute rejection episodes (TCMR and ABMR) from Baseline to EOT. 
• Overall subject survival. 
*total cumulative duration of sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days. 
If the eGFR < 15 mL/min/1.73 m2 is the only component reached, the value must be 
sustained over at least 60 days and must be confirmed by a repeat measurement after 
≥60 days from the date of the first measurement. The confirmatory measurement of 


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eGFR < 15 mL/min/1.73 m2 done at least 60 days from the initial measurement must be 
processed by the central laboratory. 
12.9.2 Pharmacokinetic / Pharmacodynamic Endpoints 
The pharmacokinetic endpoints for those participating in the PK / PD Substudy will include 
the following: 
• Maximum concentration (Cmax, Cmax ss). 
• Trough Concentration (Ctrough, Ctrough ss). 
• Area under the concentration-time curve (AUC0-tau ss) at steady state. 
• Time of maximum concentration (Tmax, Tmax ss). 
Details of the analysis of secondary endpoints will be documented in the SAP. 
12.9.3 Exploratory Analyses 
Exploratory analyses may be considered prior to unblinding and will be described fully in the 
SAP. 
Analyses will be performed to evaluate the PD of clazakizumab (IL-6 [total and free] and / or 
hsCRP, or others) following SC injection in kidney transplant recipients with CABMR. 
Analyses will be performed to evaluate the relationship between clazakizumab PK 
parameters and PD parameters (IL-6 [total and free] and / or hsCRP) using a PK / PD 
modeling approach. 
hsCRP and IL-6 (free and total) levels, plasma clazakizumab concentrations, presence of 
anti-clazakizumab antibodies, and other evaluations / assessments will be presented 
descriptively and fully described in the SAP. 
Exploratory Endpoints 
PK / PD Endpoints: 
The PD endpoints for subjects who consent to participate in the PK / PD Substudy will 
include the following: evaluation of IL-6 (total), IL-6 (free), and hsCRP. 
• Baseline and change from Baseline of free interleukin 6 (IL-6) in plasma. 
• Baseline and change from Baseline of total interleukin 6 (IL-6) in plasma. 


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• Baseline and change from Baseline of hsCRP levels in serum. 
• Correlation of hsCRP and IL-6 (total and free) to plasma clazakizumab plasma 
concentration. 
Other Exploratory Endpoints 
• HRQoL associated with the treatment of CABMR to Week 52 as well as to EOT. 
• Change from Baseline in eGFR at 2 years. 
• 40% decline in eGFR accompanied by the Investigator’s decision to supplement the 
therapy by additional treatment. 
12.9.4 Additional Analyses 
CNI and MPA levels will be measured during the study. An analysis will be conducted to 
analyze the concentrations of these drugs. A comparison of these concentrations between the 
clazakizumab and placebo groups will be used to determine whether or not there have been 
any meaningful drug-drug PK interactions after initiation of IP. The analysis will also 
investigate and account for any significant differences in the doses of these drugs during the 
trial between the clazakizumab and placebo groups. 
12.10 Safety Evaluations 
The following safety endpoints will be evaluated and analyzed using descriptive statistics: 
• TEAE, serious TEAEs, and AESIs. 
• Viral infection monitoring for BKV, CMV, and EBV by plasma PCR. 
• Laboratory tests including LFTs, CBC, plasma lipids, high-sensitivity CRP. 
• Vital signs, ECGs, and physical examination. 
• Incidence of anti-clazakizumab antibodies. 
All AEs will be coded using MedDRA Version 21 or later and presented according to SOC 
and PT. All AEs, including laboratory test abnormalities, will be graded according to the 
CTCAE Version 5.0 or later [NCI, 2017]. 
The AE reporting period will begin at the time the ICF is signed by the subject, and 
1 screening procedure is performed, continues for 5 months after the last dose (ie, SFV; or 


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date of withdrawn consent). Only TEAEs (ie, AEs occurring on or after the date of the first 
dose of IP) will be summarized in the clinical study report. 
Frequency distributions and individual listings of all TEAEs and laboratory marked 
abnormalities will be generated and summarized according to treatment group. 
Clinical laboratory test results at each time point and changes from Baseline will be provided. 
Shift tables for the hematology and biochemistry laboratory parameters, comparing values 
low, normal and high using the standard reference ranges, will be presented for the Baseline 
laboratory measurement versus the endpoint measurement for each subject. 
No formal statistical tests on the treatment difference will be performed for any safety 
analyses. All safety presentations will be performed on the Safety Analysis Set. 
Change from Baseline in vital signs, ECG, and physical examinations will also be presented 
descriptively. 
12.11 Safety Reviews and Interim Analyses 
Once approximately 50 subjects per group have been randomized and received IP, an interim 
safety review will be conducted by the DSMB. A second safety review will be conducted 
after approximately 100 subjects per group have been randomized and received IP. Further 
safety interim reviews will be determined at the discretion of the DSMB. Two formal interim 
analyses will also be conducted: 
IA #1 for sample size reestimation: After approximately 100 subjects (50 per group) have 
been randomized and completed at least 52 weeks of study participation, a formal interim 
analysis will be conducted by an independent statistician to assess the adequacy of the sample 
size for the interim efficacy analysis of the 52-week eGFR endpoint (see IA #2 below). 
Observed data from subjects not completing / not reaching Week 52 will also be included in 
the analysis. The DSMB will review and approve the recommendation of the independent 
statistician. IA #1 may result in an increase in the number of subjects included in IA #2. 
Details of the sample size reestimation are provided in Section 12.2. 
IA #2: An interim efficacy analysis of the 52-week eGFR endpoint (ie, change in mean eGFR 
from Baseline to Week 52) is planned when approximately 200 subjects (100 per group) have 
been randomized and completed at least 52 weeks of study participation. Observed data from 
subjects not completing / not reaching Week 52 will also be included in the analysis. Details 
of the sample size estimation are provided in Section 12.2. The number of subjects included 


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in this interim efficacy analysis may be increased by IA #1. If IA #2 shows a statistically 
significant (p ≤ 0.05) and clinically meaningful treatment effect on eGFR between the 
clazakizumab and placebo treatment groups, the results will be submitted to regulatory 
authorities for expedited marketing approval. If this analysis does not reach statistical 
significance, then the study will continue until 221 composite all-cause allograft loss or 
irreversible loss of allograft function events have been observed. Any decision to stop the 
study in the event of non-significant effect on eGFR or to increase the sample size for the 
primary efficacy endpoint (time to composite all-cause allograft loss or irreversible loss of 
allograft function) would be made based on the recommendation of the DSMB after review 
of the totality of the data, ie, observed effect on eGFR, updated predicted survival based on 
the model using data observed in the study, and safety data. Note: the DSMB can recommend 
stopping the study for safety reasons at any time. 
The interim efficacy endpoint will be analyzed using a mixed model repeated measures 
approach. The model will include terms for treatment, stratification factors, Baseline eGFR 
and other pre-defined covariates. 
Sensitivity analyses will include the following: 
• Missing values imputed using the mean of the observed values at that time point within 
the same treatment group. 
• The delta adjustment method will be used to estimate the tipping point beyond which the 
active treatment would have an unfavorable effect. 
• Nonparametric rank-based method where subjects will first be ranked on the time point 
that they last provided data, and then by the value of eGFR at that visit. A Wilcoxon rank 
sum test will then be applied to compare treatment groups using the ranks. 
A consulting group external to the study Sponsor will perform these unblinded interim 
efficacy and safety analyses and will prepare all interim data for the DSMB. 
A DSMB charter will be created and finalized after the first DSMB operational meeting and 
before any data review meetings. Detailed procedures for maintaining the blind will be 
specified in the DSMB charter and / or Data Access Plan. 


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13. Study Ethical Considerations 
13.1 
Ethical Conduct of the Study 
The study will be conducted according to the principles of the World Medical Association’s 
Declaration of Helsinki [World Medical Association, 2013] and the International Council for 
Harmonisation [ICH, 1996] guidelines for Good Clinical Practice (GCP) CSLB will ensure 
that the study complies with all local, federal or country-specific regulatory requirements. 
The Investigator must ensure the anonymity of all subjects participating in the study. Each 
subject will be assigned a unique subject identification number that should be used on all 
forms associated with the subject’s samples or documents that will be supplied to the Sponsor 
(or CRO) or to any party completing testing on behalf of the Sponsor (eg, samples for central 
laboratory analyses). Data privacy will be maintained according to local and federal 
requirements and will not be released without the written permission of the subject (or the 
subject’s guardian), except as necessary for monitoring and auditing by CSLB, its designee, 
the Food and Drug Administration (FDA) or other applicable Regulatory Authority, or the 
IRB / IEC. 
All unpublished information concerning the IP, as well as any information concerning the 
business or operations of CSLB or its affiliates that have been provided by or on behalf of the 
Sponsor to the Principal Investigator and all employees and coworkers involved with this 
study (“Study Personnel”), are confidential and will remain the confidential information and 
sole property of CSLB. This includes, without limitation, information concerning the clinical 
indications for the IP, its formula, methods of manufacture, regulatory, marketing and 
strategic information, and all other scientific, nonclinical or clinical data relating to it. Study 
Personnel must agree to use the information only for the purposes of carrying out this study 
and for no other purpose unless prior written permission is obtained from Sponsor’s 
authorized representative, and not to disclose, or use Sponsor’s confidential information for 
any purpose other than performance of the study. Prior written agreement from the Sponsor’s 
authorized representative must be obtained for the disclosure of any said confidential 
information to other parties. 
13.2 
Informed Consent 
A written informed consent in compliance with Part 50 of Title 21 of the Code of Federal 
Regulations (CFR), with the Declaration of Helsinki, ICH guidelines, federal and / or local 
regulations, and advance approval by the IRB / IEC shall be obtained from each subject prior 
to entering the study or performing any unusual or non-routine procedure that involves risk to 
the subject, including washout of any medications. 


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Before recruitment and enrollment, each prospective subject will be given a full explanation 
of the study and be allowed to read the approved ICF. Once the Principal Investigator or 
authorized designee is assured that the subject understands the implications of participating in 
the study, the subject will be asked to give consent to participate in the study and sign and 
date the ICF. 
The Principal Investigator is responsible for maintaining the originally signed ICF document 
according to record retention requirements. Each subject will be given a copy of the ICF. 
If more than 30 days elapses between date of consent and Screening Visit, the subject should 
be asked to re-sign and re-date the consent form at Screening to reaffirm continued interest in 
study participation. 
If any non-administrative, institution-specific modifications to study-related procedures are 
proposed or made by the site, the consent should be reviewed by the Sponsor and / or its 
designee, if appropriate, prior to IRB / IEC submission. Once reviewed, the consent will be 
submitted by the Principal Investigator or authorized designee to his or her IRB / IEC for 
review and approval prior to the start of the study. If the ICF is revised during the course of 
the study, all actively participating subjects must sign the revised form, unless otherwise 
indicated, ie, administrative changes. 
13.3 
Institutional Review Board 
Federal regulations and the ICH guidelines require that approval be obtained from an IRB / 
IEC prior to participation of human subjects in research studies. Prior to the study onset, the 
protocol, ICF, advertisements or materials to be used for subject recruitment, and any other 
written information to be provided to the subject must be approved by the IRB / IEC. Any 
amendments to the protocol or ICF will require review and approval by the IRB / IEC before 
the changes are implemented to the study. Documentation of all IRB / IEC submissions / 
approvals and of the IRB / IEC compliance with ICH Guideline E6 will be maintained by the 
site and will be available for review by CSLB or its designee. 
All IRB / IEC approvals should be authorized by the IRB / IEC chairman or designee and 
must identify the IRB / IEC name and address, the clinical protocol by title and / or protocol 
number, detail the specific documents reviewed, and the date that approval and / or a 
favorable opinion was granted. 
The Principal Investigator or authorized designee is responsible for obtaining continuing 
review of the clinical research at intervals not exceeding 1 year or as otherwise specified by 


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the IRB / IEC. The Principal Investigator or sub-Investigator must supply CSLB or its 
designee with written documentation of continued review of the clinical research. 
The IRB / IEC is expected to maintain the confidentiality of the protocol and related 
information. 


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14. Quality Control and Quality Assurance 
The Investigator must ensure that all trial-related site source data, study-related documents 
and reports will be available, and that the provision of direct access for monitoring and 
auditing by CSLB or its designees will be permitted. In addition, the Investigator must ensure 
that all trial-related site source data, study-related documents, and reports will be made 
available for inspection by the appropriate Regulatory Authority and review by the 
IRB / IEC. 
The Investigator is responsible for notifying CSLB in advance of an impending regulatory 
inspection. He / she may request that CSLB provide support for preparation, if necessary, and 
is required to provide updates on the ongoing activities during the inspection and submit any 
citations / objectionable findings (ie, FDA 483) and is required to share any follow-up 
responses to the outcome. 
Accurate and reliable data collection will be assured by verification and cross-check of the 
eCRFs against the Investigator’s records by the Study Monitor (source document 
verification). The Study Monitor will also review the Investigator’s drug accountability 
records to ensure that the drug supplies are stored and dispensed appropriately. A 
comprehensive validation program will verify the data and queries will be generated for 
resolution by the Investigator. Throughout the study, CSLB or its designates may review data 
as deemed necessary. 


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15. Administrative Procedures 
15.1 
Sponsor’s Responsibilities 
15.1.1 Study Supplies 
Study sites will be provided with supplies required to manage the study. This will include but 
not be limited to the following: 
• Investigator file(s) (for filing of all study-related documentation). 
• Contact list of all relevant study personnel. 
• Documentation and directions for use of relevant study questionnaires. 
• eCRF and completion guidelines. 
• All study forms (eg, SAE, pregnancy, drug accountability, etc.). 
15.1.2 Insurance 
CSLB confirms that it carries liability insurance which protects non-employee physicians or 
Investigators against claims for which they may become liable as a result of damages caused 
by CSLB products used in clinical studies. Insurance coverage is not extended to damages 
that the Investigators or third parties may suffer by reason of acts of commission or omission 
on the part of such Investigators or third parties and that are not in accordance with accepted 
common medical practices (lege artis procedures). CSLB will reimburse the subject for all 
study-related injuries provided that the injury does not arise from the subject’s misuse of the 
IP or failure to follow the Investigator’s instructions. 
15.1.3 Financial Disclosure and Obligations 
Principal Investigators and sub-Investigators are required to provide financial disclosure 
information to allow CSLB to submit the complete and accurate certification or disclosure 
statements required under Part 54 of Title 21 of the CFR and the Qualified Investigator 
Undertaking (QIU) form. In addition, the Principal Investigator or sub-Investigators must 
provide to the Sponsor a commitment to promptly update this information if any relevant 
changes occur during the course of the investigation and for 1 year following the completion 
of the study. 
15.1.4 Investigator Training 
All Investigators and their study personnel will receive training regarding the study 
procedures and GCP / regulations specific to the conduct of clinical trials. This training will 
be documented and will take place prior to enrollment and throughout the study as necessary. 


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It is the Investigator’s responsibility to ensure appropriate personnel receive ongoing training 
on important study updates or protocol modifications. 
15.1.5 Study Monitoring 
In accordance with current GCP and ICH guidelines, the study will be monitored by the 
Sponsor and / or Sponsor's representatives at all stages of study conduct from inception to 
completion. This monitoring will be in the form of site visits and other communication and 
will include review of original source documents and eCRFs. The Sponsor’s Medical 
Monitor or representative will notify the Principal Investigator prior to conducting any 
investigational site visit. The frequency of these visits will depend upon the progress of the 
study, and will include monitoring to assess facilities and equipment, recruiting, record-
keeping, protocol adherence, data collection, AE reporting, and other factors. 
The Study Monitor, as a representative of CSLB, has the obligation to follow the study 
closely. In doing so, the Study Monitor will visit the Principal Investigator and study facility 
at periodic intervals, in addition to remote review of data and maintaining necessary 
telephone, fax, email, and letter contact. Subject confidentiality will be maintained in 
accordance with local requirements. 
It is the Study Monitor's responsibility to inspect source documents and the eCRFs 
throughout the study, to verify adherence to the protocol and the completeness, consistency 
and accuracy of the data being entered on them. The Study Monitor must have access to 
source documents, laboratory test reports and other subject records needed to verify the 
entries on the eCRF. The Study Monitor will also perform drug accountability and review the 
Investigator’s regulatory files to assure completeness of documentation in respect to clinical 
study conduct. The Investigator (or his / her deputy) agrees to co-operate with the Monitor to 
ensure that any problems detected during monitoring visits are resolved. 
15.1.6 Medical Monitoring 
CSLB will provide an independent Medical Monitor, a medical expert who advises the study 
Investigators and study monitors regarding protocol and subject safety questions. The role of 
the Medical Monitor is to review all AEs / SAEs on a regular basis throughout the study, to 
advise the Investigators on study-related medical questions or problems as needed, and to 
evaluate cumulative subject safety data and make recommendations regarding the safe 
continuation of the study. The Medical Monitor will remain blinded throughout the conduct 
of the clinical study unless unblinding is warranted to optimize management of an AE / SAE 
or for other safety reasons. 


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15.2 
Investigator’s Responsibilities 
Medical supervision is the responsibility of the Principal Investigator named on the FDA 
Form 1572, trial attestation form and / or QIU. The Investigator may delegate day-to-day 
activities to a sub-Investigator listed on these forms but retains overall responsibility for 
ensuring that the study is conducted properly and in accordance with the study protocol. The 
Investigator is required to provide the Sponsor / CRO with his / her own curriculum vitae and 
applicable licensure, as well as those of the personnel assuming significant responsibility in 
the study (eg, sub-Investigators). The Investigator is responsible for ensuring that the study is 
conducted according to applicable health authorities (eg, Health Canada, Therapeutic Goods 
Administration, European country-specific health authorities, or FDA), sound medical 
practices, and in compliance with applicable regulations (eg, 21 CFR, ICH, European Union 
Directive and relevant country-specific requirements). 
15.2.1 Reporting and Recording of Data 
It is the responsibility of the Investigator to record essential information in the medical 
records in accordance with national regulations and requirements. The Investigator is 
responsible for ensuring the accuracy, completeness, legibility and timelines of the data 
recorded in the eCRF. 
The Principal Investigator agrees to maintain accurate source documentation as part of the 
case histories and to accurately enter this information in the eCRFs. These source documents 
are distinct from the eCRFs and are designed to record all observations and other data 
pertinent to the investigation on each subject. The CRO will supply the eCRFs for site 
completion via the electronic data capture system. These eCRFs are to be completed as 
instructed in the eCRF completion guidelines, which will be distributed to the sites under 
separate cover. 
The eCRFs will be reviewed and the source documents verified by the Study Monitor during 
routine monitoring visits, in accordance with the Clinical Monitoring Plan, to ensure that data 
in the eCRFs are accurate and complete. 
The Investigator (or delegate) will have access to all eCOA data entered at site and / or all 
data reported within the subject eDiary via a secure, role-based web portal provided by an 
external eCOA system provider. The eCOA system provider will transfer a copy of the source 
data across to CSL’s clinical data warehouse at a pre-defined frequency via a secure data 
channel for systematic review by the CSL clinical team. 


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The eCOA provider engaged for this study is responsible for providing a solution that 
conforms to all pertinent regulations. The solution is not in any way intended as a substitute 
for normal medical care of the subject. The vendor provides the service of hosting of the 
eCOA data on behalf of the study Investigators, until such a time as the Investigator is in 
receipt of a certified archive copy of all diary data relating to subjects at that site and has 
confirmed it is readable. 
15.2.2 Study Records 
It is the responsibility of the Investigator to ensure that a current disposition record of IP 
(those supplied by CSLB) is maintained at each study site where IP is inventoried and 
dispensed. Records or logs must comply with applicable regulations and guidelines and 
should include the following: 
• Amount received and placed in storage area. 
• Amount currently in storage area. 
• Label identification number or batch number. 
• Amount dispensed to and used by each subject, including unique subject identifiers. 
• Amount transferred to another area / site for dispensing or storage. 
• Non-study disposition (eg, expired, lost, wasted). 
• Amount destroyed at study site or returned to CSLB, if applicable. 
• Dates and signature / initials of person responsible for IP dispensing / accountability, as 
per the Delegation of Authority Form. 
Samples should be retained for bioavailability / bioequivalence, with appropriate tracking 
details (collection date / time etc) and be shipped to the central laboratory when requested. 
CSLB will provide forms to facilitate inventory control if the investigational site does not 
have an established system that meets these requirements. 
15.2.3 Record Retention 
Essential documents should be retained until at least 25 years after the formal discontinuation 
or completion of the clinical trial. These documents should be retained for a longer period, 
however, if required by the applicable regulatory requirements or by an agreement with 
CSLB. 


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CSLB will notify the Investigator / institution when the study records are no longer needed. 
If the Investigator withdraws from the study (eg, relocation, retirement), the records must be 
transferred to a mutually agreed upon designee (eg, another Investigator, IRB, EC, IEC). 
Notice of such transfer will be given in writing to CSLB. 
The Investigator must inform CSLB immediately if any documents are lost, damaged, to be 
transferred to another facility, or to be transferred to a different owner. 
The Investigator must contact CSLB prior to destroying any records associated with the 
study. 
15.2.4 Protocol Violations and Deviations 
The Principal Investigator or designee must document and explain in the subject’s source 
documentation any deviation from the approved protocol and should take measures to 
prevent the deviation from recurring. A deviation from the protocol is an unintended and / or 
unanticipated departure from the procedures and / or processes approved by the Sponsor and 
the IRB / IEC and agreed to by the Principal Investigator. Protocol violations and deviations 
will be communicated by the Medical Monitor throughout the study. The Principal 
Investigator will be notified of violations and / or deviations in writing by the Medical 
Monitor. The IRB / IEC should be notified of all protocol violations and deviations according 
to local IRB / IEC reporting requirements. 


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16. Procedure for Modification of Protocol or Premature Termination of 
the Study 
16.1 
Protocol Waivers, Deviations and Violations 
Protocol waivers shall not be permitted except where necessary to eliminate an immediate 
hazard to subjects (see Section 15.2.4). Deviations from the protocol will be assessed as 
minor or major on a case-by-case basis. The criteria describing the deviation(s) and how they 
will be handled will be documented in the SAP. 
16.2 
Protocol Amendments 
The study shall be conducted as described in this approved protocol. Protocol amendments, 
except where necessary to eliminate an immediate hazard to subjects, must be made only 
with the prior approval of CSLB. Each applicable Regulatory Authority / IRB / IEC will 
review and approve amendments prior to their implementation. Regulatory Authority / IRB / 
IEC approval need not be obtained prior to removal of an immediate hazard to subjects. 
16.3 
Study Termination 
CSLB reserves the right to terminate the study in its entirety or at a site at any time. Reasons 
for termination may include (but are not limited to) unsatisfactory subject enrollment with 
respect to quality and / or quantity, a site is unable to comply with the requirements of the 
protocol or GCP, or data recording is inaccurate and / or incomplete. 
In terminating the study, CSLB and the Investigator will assure that adequate consideration is 
given to the protection of the subject’s interests. Both parties will arrange the procedures on 
an individual basis after review and consultation and in accordance with the study contract. 
17. Policy for Publication and Presentation of Data 
CSLB is committed to the timely communication of data from clinical research trials, 
following the Pharmaceutical Research and Manufacturers of America principles 
[PRMA, 2014]. Where possible, authorship will be agreed at the beginning of the study. The 
authors will form a publication committee and this committee will propose and develop 
appropriate scientific manuscripts or abstracts from the study data. Investigators may not 
present or publish partial or complete study results individually. Any manuscript or abstract 
proposed by the Investigators must be reviewed and approved in writing by CSLB before 
submission for publication. Names of all Investigators participating in the study will be 
included in the publication. The publication committee for a study will comprise of authors 
selected in adherence with the International Committee of Medical Journal Editors criteria 
[ICMJE, 2018] for authorship. That is, all authors must meet each of the following 3 criteria: 


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• 
Made a substantial contribution to conception and design or acquisition of data, or 
analysis and interpretation of data. 
• 
Drafted the article or revised it critically for important intellectual content. 
• 
Approved the final version for publication. 
Members of the study steering committee generally fulfill the authorship criteria through 
their involvement in protocol design and review, monitoring of and sometimes direct 
involvement with recruitment, and thus they will usually be part of the publication 
committee. If studies are multicenter, it may be appropriate to assign group authorship. 
In addition, certain CSLB employees involved in the design and conception of the protocol, 
study management and data analysis and interpretation are qualified authors and will be 
included in the publication committee eg, the lead physician, statistician and study project 
manager or their equivalents. 
17.1 Disclosure of Data 
Individual subject medical information obtained as a result of this study is considered 
confidential, and disclosure to third parties other than those noted below is prohibited. 
Subject confidentiality will be further assured by utilizing subject identification code 
numbers to correspond to treatment data in the computer files. 
However, such medical information may be given to the subject’s personal physician, or to 
other appropriate medical personnel responsible for the subject’s welfare. 
In addition, data generated as a result of this study are to be available for inspection upon 
request by FDA or local health authority auditors, the Sponsor’s study monitors, or by the 
IRB / IEC. Therefore, absolute confidentiality cannot be guaranteed. 


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18. References 
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Eskandary F, Regele H, Baumann L, Bond G, Kozakowski N, Wahrmann M, et al. A 
randomized trial of bortezomib in late antibody-mediated kidney transplant rejection. J Am 
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Gaston R, Cecka J, Kasiske B, Fieberg A, Leduc R, Cosio F, et al. Evidence for antibody-
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Hariharan S, McBride M, Cherikh W, Tolleris C, Bresnahan B, Johnson C. Post-transplant 
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Apr 9. 
Hirano T, Taga T, Nakano N, Yasukawa K, Kashiwamura S, Shimizu K, et al. Purification to 
homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). 
Proc Natl Acad Sci USA. 1985;82(16):5490-4. 
Hoffmann-La Roche Inc. Tocilizumab Arthritis Advisory Committee. 2008 Jul 29. 
Humar A, Michaels M. American Society of Transplantation recommendations for screening, 
monitoring and reporting of infectious complications in immunosuppression trials in 
recipients of organ transplantation. Am J Transplant. 2006;6:262-74. 
International Committee of Medical Journal Editors Criteria (ICMJE). Defining the role of 
authors and contributors. C2018 [accessed 2018 Jul 27]. Available from: 
http://www.icmje.org/recommendations/browse/roles-and-responsibilities/defining-the-role-
of-authors-and-contributors.html. 
International Council for Harmonisation (ICH) Harmonised Tripartite Guideline. Guideline 
for good clinical practice. E6 (R1) 1996 Jun 10. 
Janssen M, Pickard A, Golicki D, Gudex C, Niewada M, Scalone L, Swinburn P, Busschbach 
J. Measurement properties of the EQ-5D-5L compared to the EQ-5D-3L across eight patient 
groups: a multi-country study. Qual Life Res. 2013;22(7):1717-27. doi: 10.1007/s11136-012-
0322-4. Epub 2012 Nov 25. 
Jordan S, Choi J, Kim I, Wu G, Toyoda M, Shin B, et al. Interleukin-6, a cytokine critical to 
mediation of inflammation, autoimmunity and allograft rejection: therapeutic implications of 
IL-6 receptor blockade. Transplantation. 2017;101(1):32-44. 
Kasiske B, Israni A, Snyder J, Skeans M. The relationship between kidney function and long-
term graft survival after kidney transplant. Am J Kidney Dis. 2011;57(3):466-75. 
Kawano M, Mihara K, Huang N, Tsujimoto T, Kuramoto A. Differentiation of early plasma 
cells on bone marrow stromal cells requires interleukin-6 for escaping from apoptosis. Blood. 
1995;85(2):487-94. 
Keller T, Wanagat J, Ershler W. Molecular and cellular biology of interleukin-6 and its 
receptor. Front Biosci. 1996;1:d340-57. 


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Kevzara (sarilumab) injection. Prescribing Information. Regeneron Pharmaceuticals, 
Inc./Sanofi-Aventis U.S. LLC, USA. 2017 May. 
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO 
clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 
2009;9 Suppl 3:S1-155. 
Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. AKI 
definition: KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl. 
2012;2:19-36. 
Kulkarni S, Kirkiles-Smith N, Deng Y, Formica R, Moeckel G, Broecker V, et al. 
Eculizumab therapy for chronic antibody-mediated injury in kidney transplant recipients: a 
pilot randomized controlled trial. Am J Transplant. 2017;17(3):682-91. 
Levey A, Coresh J, Greene T, Stevens LA, Yaping Z, Hendriksen S, et al. Using standardized 
serum creatinine values in the modification of diet in renal disease study equation for 
estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247-54. 
Lotz M, Jirik F, Kabouridis P, Tsoukas C, Hirano T, Kishimoto T, et al. B cell stimulating 
factor 2/interleukin 6 is a costimulant for human thymocytes and T lymphocytes. J Exp Med. 
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Loupy A, Haas M, Solez K, Racusen L, Glotz D, Seron D, et al. The Banff 2015 Kidney 
Meeting Report: current challenges in rejection classification and prospects for adopting 
molecular pathology. Am J Transplant. 2017;17(1):28-41. 
Moreso F, Crespo M, Ruiz J, Torres A, Gutierrez-Dalmau A, Osuna A, et al. Treatment of 
chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: a 
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2018;18:927-935. 
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B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp 
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(CTCAE). Version 5.0. 2017 Nov 27. 
Okada M, Kitahara M, Kishimoto S, Matsuda T, Hirano T, Kishimoto T. IL-6/BSF-2 
functions as a killer helper factor in the in vitro induction of cytotoxic T cells. J Immunol. 
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Patel S, Mohan S, Fernandez H, Batal I, Ratner L, Crew J. Tocilizumab stabilizes renal 
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(CAAMR) Am J Transplant. 2017;17(Suppl 3). 


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Peipert J, Nair D, Klicko K, Schatell D, Hays R. Kidney Disease Quality of Life 36-Item 
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_trial_principles_final_0.pdf. 
Piñeiro G, Rovira J, De Sousa-Amorim E, Villarreal J, Sole M, Revuelta I, et al. Treatment of 
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Puliyanda D, Kim I, Choi J, Haas M, Zhang X, Vo A, et al. Safety and efficacy of 
tocilizumab (anti-IL6R, TCZ) therapy in the treatment of chronic antibody mediated rejection 
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19. Appendices 
 


PPD
PPD
PPD
PPD


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Signature of Principal Investigator 
 
Study Title: 
A Pivotal Phase 3 Trial to Evaluate the Safety and Efficacy of 
Clazakizumab for the Treatment of Chronic Active Antibody-
Mediated Rejection in Kidney Transplant Recipients 
Protocol 
Number: 
CSL300_3001 
Site Number: 
 
I have read the Clinical Study Protocol, Amendment 9 titled “A Pivotal Phase 3 Trial to 
Evaluate the Safety and Efficacy of Clazakizumab for the Treatment of Chronic Active 
Antibody-Mediated Rejection in Kidney Transplant Recipients”. 
By signing this Clinical Study Protocol, I agree to conduct the clinical study, after approval 
by an Institutional Review Board or Independent Ethics Committee (as appropriate), in 
accordance with the Clinical Study Protocol, the standards of Good Clinical Practice (as 
defined by the International Council on Harmonisation) and applicable regulatory 
requirements. 
Changes to the Clinical Study Protocol will only be implemented after written approval is 
received from CSL Behring (CSLB) and the Institutional Review Board or Independent 
Ethics Committee (as appropriate) with the exception of medical emergencies. 
I will ensure that study staff fully understand and follow the Clinical Study Protocol. 
 
 
 
(Signature) 
 
 
Date (DD MMM YYYY) 
(Printed name) 
 
 
 
(Title) 
 
 
 


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APPENDIX 2 SUMMARY TABLE OF ALL SCHEDULED STUDY VISITS 
Study Day / 
Week 
Visit Number 
Mandatory 
In-Clinic 
Visit(a) 
Dosing with 
Investigational 
Drug 
Pregnancy 
Test, AEs, and 
Concomitant 
Medications  
eGFR 
Additional 
Assessments 
Per SOE 
Year 1 
Up to -42 days 
(+ 2 days) 
Visit 1 
(Screening)(a) 
X 
 
X 
X 
X 
Day 1 
Visit 2 
(Baseline)(a) 
X 
X 
X 
X 
X 
Week 1 
Visit 3(b, d) 
 
 
 
 
X 
Week 4 
Visit 4(a, d) 
X 
X 
X 
X 
X 
Week 8 
Visit 5(d) 
 
X 
X 
X 
X 
Week 12 
Visit 6(a, d) 
X 
X 
X 
X 
X 
Week 16 
Visit 7(d) 
 
X 
X 
X 
 
Week 20 
Visit 8(d) 
 
X 
X 
X 
X 
Week 24 
Visit 9(a, d) 
X 
X 
X 
X 
X 
Week 28 
Visit 10(d) 
 
X 
X 
X 
X 
Week 32 
Visit 11(d) 
 
X 
X 
X 
 
Week 36 
Visit 12(d) 
 
X 
X 
X 
X 
Week 40 
Visit 13(d) 
 
X 
X 
X 
 
Week 44 
Visit 14(d) 
 
X 
X 
X 
X 
Week 48 
Visit 15(a, d) 
X 
X 
X 
X 
X 
Week 52 
Visit 16(a ,d) 
X 
X 
X 
X 
X 
Year 2 
Week 56 
Visit 17(d) 
 
X 
X 
 
 
Week 60 
Visit 18(d) 
 
X 
X 
X 
X 
Week 64 
Visit 19(d) 
 
X 
X 
 
 
Week 68 
Visit 20(d) 
 
X 
X 
X 
X 
Week 72 
Visit 21(d) 
 
X 
X 
 
 
Week 76 
Visit 22(a, d) 
X 
X 
X 
X 
X 
Week 80 
Visit 23(d) 
 
X 
X 
 
X 
Week 84 
Visit 24(d) 
 
X 
X 
X 
X 
Week 88 
Visit 25(d) 
 
X 
X 
 
 
Week 92 
Visit 26(d) 
 
X 
X 
X 
X 
Week 96 
Visit 27(d) 
 
X 
X 
 
 
Week 100 
Visit 28(a, d) 
X 
X 
X 
X 
X 
Week 104 
Visit 29(d) 
 
X 
X 
 
 


CSL Behring 
Study Number: 
CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
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Date: 10 July 2023 
Confidential 
 
Study Day / 
Week 
Visit Number 
Mandatory 
In-Clinic 
Visit(a) 
Dosing with 
Investigational 
Drug 
Pregnancy 
Test, AEs, and 
Concomitant 
Medications  
eGFR 
Additional 
Assessments 
Per SOE 
Year 3 
Week 108 
Visit 30(d) 
 
X 
X 
X 
X 
Week 112 
Visit 31(d) 
 
X 
X 
 
 
Week 116 
Visit 32(d) 
 
X 
X 
X 
X 
Week 120 
Visit 33(d) 
 
X 
X 
 
 
Week 124 
Visit 34(a, d) 
X 
X 
X 
X 
X 
Week 128 
Visit 35(d) 
 
X 
X 
 
 
Week 132 
Visit 36(d) 
 
X 
X 
X 
X 
Week 136 
Visit 37(d) 
 
X 
X 
 
 
Week 140 
Visit 38(d) 
 
X 
X 
X 
X 
Week 144 
Visit 39(d) 
 
X 
X 
 
 
Week 148 
Visit 40(a, d) 
X 
X 
X 
X 
X 
Week 152 
Visit 41(d) 
 
X 
X 
 
 
Week 156 
Visit 42(d) 
 
X 
X 
X 
X 
Year 4 
Week 160 
Visit 43(d) 
 
X 
X 
 
 
Week 164 
Visit 44(d) 
 
X 
X 
X 
X 
Week 168 
Visit 45(d) 
 
X 
X 
 
 
Week 172 
Visit 46(a ,d) 
X 
X 
X 
X 
X 
Week 176 
Visit 47(d) 
 
X 
X 
 
 
Week 180 
Visit 48(d) 
 
X 
X 
X 
X 
Week 184 
Visit 49(d) 
 
X 
X 
 
 
Week 188 
Visit 50(d) 
 
X 
X 
X 
X 
Week 192 
Visit 51(d) 
 
X 
X 
 
 
Week 196 
Visit 52(a, d) 
X 
X 
X 
X 
X 
Week 200 
Visit 53(d) 
 
X 
X 
 
 
Week 204 
Visit 54(d) 
 
X 
X 
X 
X 
Week 208 
Visit 55(d) 
 
X 
X 
 
 
Year 5 
Week 212 
Visit 56(d) 
 
X 
X 
X 
X 
Week 216 
Visit 57(d) 
 
X 
X 
 
 
Week 220 
Visit 58(a, d) 
X 
X 
X 
X 
X 
Week 224 
Visit 59(d) 
 
X 
X 
 
 
Week 228 
Visit 60(d) 
 
X 
X 
X 
X 
Week 232 
Visit 61(d) 
 
X 
X 
 
 


CSL Behring 
Study Number: 
CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
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Date: 10 July 2023 
Confidential 
 
Study Day / 
Week 
Visit Number 
Mandatory 
In-Clinic 
Visit(a) 
Dosing with 
Investigational 
Drug 
Pregnancy 
Test, AEs, and 
Concomitant 
Medications  
eGFR 
Additional 
Assessments 
Per SOE 
Week 236 
Visit 62(d) 
 
X 
X 
X 
X 
Week 240 
Visit 63(d) 
 
X 
X 
 
 
Week 244 
Visit 64(a, d) 
X 
X 
X 
X 
X 
Week 248 
Visit 65(d) 
 
X 
X 
 
 
Week 252 
Visit 66(d) 
 
X 
X 
X 
X 
Week 256 
Visit 67(d) 
 
X 
X 
 
 
Week 260 
Visit 68(d) 
 
X 
X 
X 
X 
Year 6 
Week 264 
Visit 69(d) 
 
X 
X 
 
 
Week 268 
Visit 70(a, d) 
X 
X 
X 
X 
X 
Week 272 
Visit 71(d) 
 
X 
X 
 
 
Week 276 
Visit 72(d) 
 
X 
X 
X 
X 
Week 280 
Visit 73(d) 
 
X 
X 
 
 
Week 284 
Visit 74(d) 
 
X 
X 
X 
X 
Week 288 
Visit 75(d) 
 
X 
X 
 
 
Week 292 
Visit 76(a, d) 
X 
X 
X 
X 
X 
Week 296 
Visit 77(d) 
 
X 
X 
 
 
Week 300 
Visit 78(d) 
 
X 
X 
X 
X 
Week 304 
Visit 79(d) 
 
X 
X 
 
 
Week 308 
Visit 80(d) 
 
X 
X 
X 
X 
Week 312 
Visit 81(d) 
 
X 
X 
 
 
Year 7 
Week 316 
Visit 82(a, d) 
X 
X 
X 
X 
X 
Week 320 
Visit 83(d) 
 
X 
X 
 
 
Week 324 
Visit 84(d) 
 
X 
X 
X 
X 
Week 328 
Visit 85(d) 
 
X 
X 
 
 
Week 332 
Visit 86(d) 
 
X 
X 
X 
X 
Week 336 
Visit 87(d) 
 
X 
X 
 
 
Week 340 
Visit 88(a, d) 
X 
X 
X 
X 
X 
Week 344 
Visit 89(d) 
 
X 
X 
 
 
Week 348 
Visit 90(d) 
 
X 
X 
X 
X 
Week 352 
Visit 91(d) 
 
X 
X 
 
 
Week 356 
Visit 92(d) 
 
X 
X 
X 
X 
Week 360 
Visit 93(d) 
 
X 
X 
 
 
Week 364 
Visit 94(a, d) 
X 
X 
X 
X 
X 


CSL Behring 
Study Number: 
CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol version: Amendment 9 
Page 4 of 4 
Date: 10 July 2023 
Confidential 
 
Study Day / 
Week 
Visit Number 
Mandatory 
In-Clinic 
Visit(a) 
Dosing with 
Investigational 
Drug 
Pregnancy 
Test, AEs, and 
Concomitant 
Medications  
eGFR 
Additional 
Assessments 
Per SOE 
EOT / Early 
Withdrawal 
Visit (a, c, f) 
EOT 
X 
 
X 
X 
X 
SFV(f) 
Monthly 
Follow-up 
TCs(c) 
 
 
X(e) 
 
X 
Q6M after 
permanently DC 
of IP (a, f) 
 
X 
 
X 
X 
X 
CTEV(a, f)  
 
X 
 
X 
X 
X 
AE = adverse event; CNI = calcineurin inhibitor; Con meds = concomitant medications; CTED = common treatment end 
date; CTEV = common treatment end visit; eGFR = estimated glomerular filtration rate; EOS = End of Study; EOT = End 
of Treatment; IP= investigational product; Q6M = every 6 months; SAE = serious adverse event; SFV = Safety follow-up 
visit; SOE = Schedule of Events; TC = telephone call. 
 
Notes: 
a At some sites, home / workplace visits may be offered as an option instead of in-clinic visits for certain visits during the 
Treatment Period. This service may not be available for all subjects at all sites. In Year 1 of the study, in-clinic visits 
are mandatory at Visit 1 (Screening), Visit 2 (Baseline; Day 1), Visit 4 (Week 4), Visit 6 (Week 12), Visit 9 (Week 24), 
Visit 15 (Week 48), and Visit 16 (Week 52). Thereafter, in-clinic visits are required approximately every 6 months (ie, 
at Visit 22 [Week 76], Visit 28 [Week 100], Visit 34 [Week 124], Visit 40 [Week 148], Visit 46 [Week 172], Visit 52 
[Week 196], Visit 58 [Week 220], Visit 64 [Week 244], Visit 70 [Week 268], Visit 76 [Week 292], Visit 82 [Week 
316], Visit 88 [Week 340], and Visit 94 (Week 364]). An in-clinic visit is required at EOT / Early Withdrawal; if a 
subject meets the primary efficacy endpoint (all-cause composite allograft loss); and, at the discretion of the 
investigator, if clinically indicated (eg, because of an AE). Other scheduled visits can be home / workplace visits. 
b This visit is required only if subject is taking a CNI. 
c Subjects will be contacted monthly by TC (for up to 5 months after last dose of investigational drug) for monitoring of 
new AEs, SAEs, or pregnancies and may be called in for a clinic visit at the discretion of the Investigator.  
d Visit has a ±5-day window.  
e Pregnancy test not required at SFV.  
f Subjects who permanently discontinued treatment with IP for any reason who have not reached an endpoint of allograft 
loss, defined as: eGFR < 15 mL/min/1.73 m2*, return to dialysis*, allograft nephrectomy, retransplantation or death from 
any cause, or subjects with a sustained (≥ 60 days) 40% decline in eGFR from Baseline, who discontinued IP for any 
reason will not be withdrawn; they will remain in the study as described in Section 9.2.5.3. *total cumulative duration of 
sustained eGFR < 15 mL/min/1.73 m2 AND / OR dialysis ≥ 60 days. Following the EOT / Early Withdrawal Visit, 
subjects will be asked to return for 2 in-clinic Safety Follow-up Visits, 3 and 5 months after the last dose of IP. (Note: 
DSA MFI Scores, UACR, and IL-6 levels are not required at the 3-month Safety Follow-up Visit). In addition, all 
subjects will be contacted by telephone call at 1, 2, and 4 months after the last dose of IP for monitoring for new AEs, 
SAEs, or pregnancies. Thereafter, the subject will be asked to return in 6-month intervals until the CTED is reached to 
collect renal function and allograft status data. If a subject is unable to return for 6-monthly follow-up visits, he / she will 
be asked to agree to be contacted at CTED to collect allograft and survival status. The CTEV will be performed within 
4 weeks after the CTED date is reached. 


CSL Behring 
Study Number: 
CSL300_3001 
 
Study Product: 
CSL300, clazakizumab 
 
Protocol Version: Amendment 9 
Page 1 of 55  
10 July 2023 
Confidential  
 
APPENDIX 3 
 
 
Il-6 and Antibody-Mediated Rejection in Kidney Transplant 
Recipients 
 
 
Date: 
04 February 2021 
 
 
 
 
Sponsor Address:  
CSL Behring, LLC. 
1020 1st Avenue 
King of Prussia, PA 19406 
USA 
 
 
 
 
 
 
 
Commercial in Confidence. This document and the information contained herein are proprietary and 
confidential.  This document and the contained information are intended for disclosure to and use by those 
personnel who are under an obligation of confidentiality by a signed agreement with Sponsor (“CSL Behring”).  
This document and the contained information may be disclosed and used only to the extent necessary to conduct 
the clinical study.  Reproduction or disclosure of this document or its contained information is forbidden unless 
at the express request or with the written consent of CSL Behring. 


CSL Behring 
Study Number: 
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Page 2 of 55  
10 July 2023 
Confidential 
 
Table of Contents 
TABLE OF CONTENTS ........................................................................................................2 
1. 
OVERVIEW .....................................................................................................................7 
2. 
CLINICAL SETTING AND UNMET MEDICAL NEED ...........................................9 
3. 
ESTIMATED PREVALENCE OF ABMR – A RARE CONDITION .....................20 
4. 
IL-6 IN MEDIATION OF ABMR ................................................................................23 
4.1 
Expression of IL-6 in Allografts With and Without ABMR .......................................23 
4.2 
Evidence from Nonclinical Studies Supporting the Role of IL-6 in ABMR ...............26 
4.2.1 
Nonclinical Studies with Anti-IL-6R mAbs .............................................................26 
4.2.2 
Additional Nonclinical Studies Supporting the Role of IL-6 in ABMR ..................30 
4.3 
Evidence from Clinical Studies Supporting the Role of IL-6 in ABMR - Studies 
with Anti-IL-6R (TCZ) ................................................................................................36 
4.3.1 
TCZ Treatment Resulted in Reduction of DSA and Improved Graft Survival in 
HLA-Sensitized Renal Allograft Recipients with CABMR and TG ........................36 
4.3.2 
Stabilization of Severe CABMR Progression Following TCZ Treatment in 
Pediatric Renal Transplant Patients Refractory to B Cell Immunotherapy ..............41 
4.3.3 
Improved Renal Function and Reduced DSAs Following TCZ Treatment in 
HLA-Sensitized Patients with Acute ABMR ...........................................................41 
4.3.4 
Increased Treg Cells, Decreased CD4+ T Cell Cytokine Production and 
Decreased Graft Inflammation Following TCZ Treatment in Kidney Transplant 
Recipients..................................................................................................................42 
4.3.5 
Stabilization of Renal Function Following TCZ Treatment in Kidney 
Transplant Recipients with Refractory CABMR ......................................................43 
4.3.6 
Improved Renal Transplant Rates Following TCZ Treatment in 
HLA-Sensitized Patients (Resistant to Desensitization with IVIG + Rituximab 
Therapy ± PLEX) Awaiting Kidney Transplant .......................................................44 
5. 
CONCLUSIONS ............................................................................................................48 
6. 
REFERENCES ...............................................................................................................49 
 


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List of Tables 
Table 1 
Estimated Prevalence of Kidney Transplant Recipients in the US in 
August 2017 According to Data from the USRDS and UNOS and 
Estimated Prevalence of DSA-Positive Recipients ..........................................21 
Table 2 
Estimated ABMR Prevalence in the Union at the End of 2017 According 
to Data from the ERA-EDTA Estimated Prevalence of DSA-Positive 
Recipients .........................................................................................................22 
Table 3 
Baseline Characteristics of CABMR Patients Treated with TCZ ....................36 
Table 4 
DSA and Creatinine Levels Before and After Treatment with TCZ for 
Acute ABMR ...................................................................................................42 
 
List of Figures 
Figure 1 
Kaplan-Meier Analysis of the Impact of Primary or Secondary Local 
Diagnosis of CNI Nephrotoxicity on Kidney Allograft Survival After For-
Cause Biopsy ...................................................................................................10 
Figure 2 
Distribution of Histologic Diagnosis Expressed as Probability Plots 
Conditional on Time of Biopsy Post-Transplantation .....................................11 
Figure 3 
Mechanisms of DSA Mediated Endothelial Injury in Renal Allografts ..........13 
Figure 4 
Proposed Natural History of De Novo DSA ....................................................14 
Figure 5 
Kidney Graft Survival Following CABMR Diagnosis ....................................15 
Figure 6 
Probability of Graft Survival in Patients Who Underwent a Late Biopsy 
and Were Assessed for DSA ............................................................................16 
Figure 7 
Death-Censored Graft Survival by Clinical Phenotype and dnDSA Status ....17 
Figure 8 
Probability of Graft Survival According to DSA Characteristics ....................18 
Figure 9 
Serum Cytokine Levels in Kidney Transplant Recipients with Normal 
Graft Function and Allograft Rejection ...........................................................24 
Figure 10 
IL-6 Expression in the Kidney: Normal Versus CMR and ABMR .................25 
Figure 11 
Anti-IL-6R mAb Significantly Suppressed IgG + Plasma Cells in the 
Bone Marrow and Spleen (ELISpot Assay) .....................................................27 
Figure 12 
Anti-IL-6R mAb Inhibits Anti-HLA-A2 Antibody (Flow-Antibody 
Binding Assay).................................................................................................28 
Figure 13 
Flow Cytometry Analysis of Blood from Non-human Primates Before and 
After Treatment with TCZ and ATG (Before Transplant) ..............................29 


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Figure 14 
Graft Survival in Non-Human Primates Treated with ATG Plus or Minus 
TCZ ..................................................................................................................30 
Figure 15 
Cytokine Production in NK cells, Monocytes and CD8+ T Cells in the 
In Vitro ADCC and MLR Cultures as Detected by CFC.................................31 
Figure 16 
The Effect of TCZ on IFNγ, TNFα, and IL-6 Production in NK Cells, 
Monocytes and CD8+ T Cells in In Vitro ADCC ...........................................32 
Figure 17 
Effect of IL-6 Deficiency on Allograft Tolerance ...........................................33 
Figure 18 
Neutralization of IL-6 In Vivo Promotes Allograft Survival with 
Costimulation Blockade ...................................................................................34 
Figure 19 
Kaplan-Meier Analysis of Graft and Patient Survival Over Time Post 
Treatment with TCZ ........................................................................................38 
Figure 20 
Mean Immunodominant DSA Values for TCZ-Treated Patients ....................38 
Figure 21 
Mean eGFR Value of TCZ-Treated Adult CABMR Patients ..........................39 
Figure 22 
Allograft Phenotype Pre- and Post-TCZ Treatment ........................................40 
Figure 23 
Increased Circulating Treg Cells and Decreased Graft Inflammation 
Following TCZ Treatment in Kidney Transplant Recipients ..........................43 
Figure 24 
Rate of eGFR Decline Before and After TCZ Treatment ................................44 
Figure 25 
Study Design: TCZ Protocol for Desensitization Before- and After 
Transplant ........................................................................................................46 
Figure 26 
Reduction in Immunodominant DSA Following TCZ Treatment ...................47 
 


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Study Number: 
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Confidential 
LIST OF ABBREVIATIONS 
ABMR 
Antibody-mediated rejection 
ACR 
Acute cellular rejection 
ADCC 
Antibody-dependent cellular cytotoxicity  
ATG 
Anti-thymocyte globulin 
C3a 
Complement component 3a 
C4d 
Complement component 4d 
C5a 
Complement component 5a 
CABMR 
Chronic active antibody-mediated rejection 
CMR 
Cell-mediated rejection 
CNI 
Calcineurin inhibitor 
dnDSA 
De novo donor-specific antibodies 
DSA 
Donor-specific antibodies 
eGFR 
Estimated glomerular filtration rate  
EMA 
European Medicines Agency 
ESRD 
End-stage renal disease 
EU28 
European Union (28 countries) 
FcγR 
Fc gamma receptor  
FDA 
Food and Drug Administration 
g 
Glomerulitis 
IFN-γ 
Interferon-gamma 
GVHD 
Graft-versus-host disease  
HLA 
Human leukocyte antigen 
IgG 
Immunoglobulin G 
IL-6 
Interleukin 6 
IL-17 
Interleukin 17 
IL-6R 
Interleukin 6 receptor 
IV 
Intravenous 
IVIG 
Intravenous immunoglobulin 
KDIGO 
Kidney Disease: Improving Global Outcomes 
mAb 
Monoclonal antibody 


CSL Behring 
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MFI 
Mean fluorescence intensity 
MHC 
Major histocompatibility complex 
MLR 
Mixed lymphocyte reaction 
MMF 
Mycophenolate mofetil 
NK 
Natural killer (cell) 
PBMC 
Peripheral blood mononuclear cell 
PLEX 
Plasma exchange  
ptc 
Peritubular capillaritis 
SOC 
Standard of care 
TCMR 
T cell-mediated rejection 
TCZ 
Tocilizumab 
Tfh 
Follicular T helper (cell) 
Th1 
T helper 1 (cell) 
Th2 
T helper 2 (cell) 
TG 
Transplant glomerulopathy 
Th17 
T helper 17 (cell) 
TNFα 
Tumor necrosis factor alpha 
Treg 
Regulatory T (cell) 
Union 
EU28, Norway, Iceland, and Liechtenstein 
US 
United States  
vWF 
Von Willebrand factor 
 


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1. OVERVIEW 
Active antibody-mediated rejection (ABMR), especially chronic active antibody-mediated 
rejection (CABMR), is now recognized as the most common cause of allograft failure after a 
successful kidney transplant. Current standard of care (SOC) anti-rejection treatments target 
cellular-mediated (ie, T cell-mediated rejection [TCMR]) processes and do not affect this 
antibody-mediated process. Currently, there are no approved or effective treatments for 
active ABMR, including CABMR. Robust evidence from well-conducted randomized 
control studies are sparse. The Kidney Disease: Improving Global Outcomes (KDIGO) 2009 
guideline [KDIGO, 2009] recognizes the lack of good quality data and suggests the use of 
one or more of the following (with or without corticosteroids), to treat acute ABMR: plasma 
exchange (PLEX); intravenous immunoglobulin (IVIG); anti-CD20 antibody; and 
lymphocyte-depleting antibody. Recent systematic reviews of treatments for ABMR have 
shown that the situation remains unchanged, even with novel agents targeting B cells, plasma 
cells and the complement system [Roberts et al, 2012; Wan et al, 2018]. No treatment exists 
for the treatment of CABMR and there is no evidence that treatments for acute active ABMR 
are effective for CABMR. Thus, there exists a critical unmet medical need for effective 
treatments of CABMR. 
Based on evidence from both nonclinical and clinical studies, interleukin 6 (IL-6) appears to 
be a critical cytokine involved in CABMR. IL-6 promotes the development and maturation of 
B cells to plasma cells that produce donor-specific antibodies (DSA) targeting the allograft. 
These DSA cause antibody-mediated injury to the allograft via direct activation of 
endothelial cells, complement-dependent cytotoxicity and / or antibody-dependent cellular 
cytotoxicity (ADCC) [Gaston et al, 2010; Thomas et al, 2015; Jordan et al, 2017]. 
Furthermore, IL-6 shapes the T cell immune response resulting in promotion of long-lived 
pro-inflammatory T cells (eg, follicular T helper cells [Tfh], T helper 17 cells [Th17], 
T helper 1 cells [Th1], and T helper 2 cells [Th2]) and inhibition of immune regulatory 
T cells (Treg) that promote immune tolerance. Data from clinical studies using the anti-IL-6 
receptor (IL-6R) monoclonal antibody (mAb) tocilizumab (TCZ) suggest the potential 
benefit of inhibiting IL-6 signaling in the treatment of CABMR. 
Estimates of the prevalence of ABMR in kidney transplant recipients in the US and in 
Europe indicate that ABMR is a rare condition. In the US, the prevalence of DSA+ kidney 
transplant recipients at the end of August 2017 is estimated to range from approximately 
24,343 to 146,056, well below the threshold of 200,000 for designation as a rare condition 
according to FDA requirements for orphan designation. In Europe, the prevalence of DSA+ 


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kidney transplant recipients at the end of 2017 is estimated to range from approximately 0.44 
and 3.52 in 10,000 well below the defined threshold of 5 in 10,000 for designation as a rare 
condition according to the EMA requirements for orphan designation. Not all DSA-positive 
subjects are expected to develop ABMR. 
The sections below present a summary of the clinical setting and unmet medical need for 
effective treatment of CABMR in kidney transplant recipients, followed by summaries of the 
estimated prevalence of ABMR in kidney transplantation in both the US and Europe. Finally, 
summaries of both nonclinical and clinical evidence demonstrating the role of IL-6 in 
mediation of ABMR / CABMR in solid organ transplantation, particularly kidney 
transplantation, are provided. A comprehensive summary of the therapeutic implications of 
IL-6R blockade with respect to allograft rejection is also available in a review by Jordan 
et al, 2016 [Jordan et al, 2017]. 


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2. CLINICAL SETTING AND UNMET MEDICAL NEED 
Kidney transplantation is the treatment of choice for patients with end-stage renal disease 
(ESRD) and is undoubtedly associated with improved survival, better quality of life, and 
reduced costs when compared with maintenance dialysis [O'Connell et al, 2017]. Kidney 
transplant recipients have expected remaining lifetimes estimated at 68 to 85% of that in the 
general population compared to patients with ESRD on dialysis who are expected to live less 
than one-third as long as the general population without ESRD [USRDS, 2016]. Despite 
significant progress in the treatment of acute cellular rejections (ACRs), resulting in marked 
improvements in the short-term survival of kidney allografts, long-term graft survival has not 
improved. Graft survival in the first year post-transplant is over 95%, but death-censored 
graft failure rates beyond the first year have remained relatively unchanged since the late 
1980s: ie, 3 to 5% per year for deceased donor grafts and 2 to 3% per year for living donor 
grafts. By 10 years, 20 to 30% of all kidney allografts will have failed [Stegall et al, 2014]. 
In the past, studies showed that the patients who experienced a primarily T cell-mediated 
early ACR episode, had less favorable long-term graft survival than those who remained 
rejection-free. Thus, it became medical dogma that, to improve long-term graft survival, 
minimizing ACR should be the goal of post-transplant immunosuppression treatment. 
However, while newer immunosuppression treatment protocols have lowered ACR rates 
routinely to < 10% in the first year, late graft loss rates remained relatively unchanged 
[Meier-Kriesche et al, 2004; Lamb et al, 2011]. 
In recent years, the understanding of the causes of late kidney allograft loss has undergone a 
significant change. As histologic studies showed that progressive fibrosis and vasculopathy 
(called chronic allograft nephropathy) were the major causes of late graft loss, and because 
calcineurin inhibitors (CNIs) were known to cause fibrosis, it became widely accepted that 
this late allograft loss was due to CNI nephrotoxicity. This led to multiple studies testing the 
hypothesis that minimizing the dose of CNIs or avoiding these drugs altogether might 
improve CNI nephrotoxicity and thus improve long-term graft survival. Although some 
studies suggested that avoidance of CNIs was safe and associated with better renal function 
over time, other trials showed increased ACR in the patients on CNI-sparing and CNI-free 
therapies and minimal, if any, improvement in renal function [Gaston et al, 2010; Meier-
Kriesche et al, 2004]. Indeed, the DeKAF study [Gaston et al, 2010] showed that patients 
with CNI nephrotoxicity had better long-term graft survival than the patients without CNI 
nephrotoxicity (see Figure 1). 


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Figure 1 
Kaplan-Meier Analysis of the Impact of Primary or Secondary Local 
Diagnosis of CNI Nephrotoxicity on Kidney Allograft Survival After For-
Cause Biopsy 
 
CNI = calcineurin inhibitor. 
Source: Gaston et al, 2010. 
 
Over the last several years, it has become clear that insufficient control of the humoral 
immune response by current immunosuppressive drugs (which primarily target the T cells) is 
the main pathogenic factor responsible for late graft loss. Important advances in the 
development of sensitive assays for the identification of DSA improved understanding of the 
histopathology of ABMR. The growing implementation of molecular diagnostic approaches 
have led to a realization that ABMR is the most common cause of late kidney allograft 
failure, and that there is no treatment currently available to prevent or treat this condition 
[Einecke et al, 2009; Hidalgo et al, 2009; Gaston et al, 2010; Loupy et al, 2012; Sellarés et al, 
2012; Wiebe et al, 2012; Thomas et al, 2015; Wiebe et al, 2015]. It is estimated that more 
than 5,000 renal allografts are lost each year in the US, and approximately 75 to 80% are lost 
due to antibody-mediated injury [Loupy et al, 2012; Wiebe et al, 2012; Aubert et al, 2017]. In 
contrast, TCMRs are common early but progressively disappear over time such that by 


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10 years post-transplant, TCMR episodes are rare (see Figure 2) [Sellarés et al, 2012; 
Halloran et al, 2015]. These investigations have also determined that ABMR is primarily 
caused by the recipient developing DSA, most commonly against human leukocyte antigens 
(HLA) and less commonly against non-HLA antigens present in the donor graft [Opelz, 
2005; Colvin, 2007; Sun et al, 2011; Loupy et al, 2012]. These DSA may be present before 
transplant (ie, preformed because of previous blood transfusion, pregnancy, or previous 
transplant) or develop post-transplant (de novo DSA [dnDSA]). Antibody-mediated rejection 
due to preformed DSA tends to occur early and is associated with superior graft survival 
compared with ABMR due to dnDSA - which usually occurs later (after 1 year post-
transplant) and is associated with histological features of chronic injury (such as transplant 
glomerulopathy (TG) and interstitial fibrosis / tubular atrophy) [Aubert et al, 2017; 
Haas et al, 2017]. 
Figure 2 
Distribution of Histologic Diagnosis Expressed as Probability Plots 
Conditional on Time of Biopsy Post-Transplantation 
ABMR = antibody-mediated rejection; C4d = complement component 4d. 
Notes: 
Distribution of histopathology diagnoses and adherence status in biopsies expressed as probability plots conditional on the 
time of biopsy post-transplantation. The ABMR category includes C4d-positive ABMR, C4d-negative ABMR and 
probable ABMR. 
Source:  Sellarés et al, 2012. 


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The reported rate of development (ie, incidence) and prevalence of dnDSA after kidney 
transplantation varies widely in the literature, reflecting the different methodological assays 
used for detecting DSA, different characteristics of the cohort studied, duration of follow-up, 
and the center’s interest in detecting the presence of these antibodies. Wiebe et al., in a study 
of over 500 adult and pediatric consecutive renal transplants between January 1999 and 
July 2012, showed that the incidence of dnDSA development is approximately 2% per 
annum post-transplant, such that at 10 years post-transplant, approximately 20% of recipients 
will have developed dnDSA [Wiebe et al, 2015]. However, in a smaller cohort, Everly et al. 
found higher incidence rates: ie, 11% of kidney recipients developed dnDSA after the first 
year and approximately 20% are expected to develop dnDSA by the fifth-year post-transplant 
[Everly et al, 2013]. In an international collaborative study of 45 transplant centers, the 
prevalence of DSA against HLA antigens in the kidney transplant population varied from 
approximately 10 to 60%, with an average of 27% [Ozawa et al, 2007].  
It is widely recognized that DSA causes antibody-mediated injury to the allograft via direct 
activation of vascular endothelial cells, complement-dependent cytotoxicity, and / or by 
ADCC [Gaston et al, 2010; Thomas et al, 2015]. These mechanisms of antibody-mediated 
injury are interrelated and are likely to synergize to cause maximal inflammation. For 
example, direct endothelial cell activation by DSA may trigger adhesion of leukocytes, which 
can be enhanced when those leukocytes bind antibody through Fc gamma receptors (FcγRs). 
Activation of complement at the endothelial cell surface may cause production of C3a and 
C5a anaphylatoxins which can act on leukocytes as chemoattractants or further enhance 
endothelial cell activation. 
The histological manifestations of ABMR in the kidney allograft reflect the signatures of 
antibody-mediated injury, specifically vascular endothelial cell changes, and leukocyte 
infiltrates, with or without complement deposition. These histological features include TG, 
peritubular capillary basement membrane multilayering, arterial intimal fibrosis, and 
microvascular inflammation, with or without complement component 4 (C4d) staining 
(Banff 2015 criteria [Loupy et al, 2017]). Figure 3 illustrates the mechanisms whereby DSAs 
causes injury to the transplanted kidney. 


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Figure 3 
Mechanisms of DSA Mediated Endothelial Injury in Renal Allografts 
 
BCL-2 = B cell lymphoma 2; BCL-XL = B cell lymphoma-extra large; C3a = complement component 3a; C4d = 
complement component 4d; C5a = complement component 5a; C5b-9 = complement component C5b and C9 complex; 
CCL2 =  chemokine ligand 2; CCL5 = chemokine ligand 5; CD59 = MAC-inhibitory protein DAF = decay accelerating 
factor; FcγR = Fc gamma receptor; FGFR = fibroblast growth factor receptor; ICAM-1 = intercellular adhesion 
molecule 1; IFN-γ = interferon-gamma; IL-1α = interleukin 1 alpha; IL-6 = interleukin 6; IL-8 = interleukin 8; MAPK 
= mitogen activated protein kinase; MHC = major histocompatibility complex; NK = natural killer cell; PDGF = 
platelet-derived growth factor; Poly = polynuclear cell; TNF = tumor necrosis factor; VCAM-1 = vascular cell 
adhesion protein 1; vWF = von Willebrand factor. 
Notes: 
Anti-MHC antibodies can cause direct injury to the capillary endothelium or indirect injury via complement fixation or 
recruitment of inflammatory cells with Fc receptors. 
Source:  Farkash and Colvin, 2012. 
 
Wiebe et al. have proposed a continuum of antibody-mediated damage based on a model 
adapted from the primate studies of Smith et al. [Smith et al, 2008; Wiebe et al, 2012]. Post-
transplant dnDSA development is preceded by an antibody-free period. It is likely that 
inflammatory events (ie, preceding cellular rejection or graft infection) lead to elevated 
interferon-gamma (IFN-γ) levels, which upregulate HLA expression on endothelial cells and 
stimulate B cell allorecognition and subsequent long-lived plasma cells producing dnDSA. 


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At this point, dnDSA onset may be overlooked without routine post-transplant monitoring of 
stable grafts. Nevertheless, biopsies in stable grafts with dnDSA generally reveal histologic 
changes consistent with microvasculature injury (see Figure 4). 
Figure 4 
Proposed Natural History of De Novo DSA 
C4d = complement component 4d; Cr = creatinine; DSA = donor-specific antibodies; IFTA = interstitial fibrosis and tubular 
atrophy; TG = transplant glomerulopathy. 
Notes: 
This figure shows a proposed model for patients developing de novo DSA as they evolve from transplantation to graft 
failure. 
Source:  Wiebe et al, 2012. 
The belief that DSA causes ABMR is supported by the strong association between the 
development of DSA, especially dnDSA, and late kidney allograft loss. In a retrospective 
pooled analysis, Mohan et al. showed that the presence of DSA detected by solid phase 
assay, even with negative flow cytometry crossmatch, demonstrated a significant increased 
risk for biopsy-proven ABMR and graft loss [Mohan et al, 2012]. In an observational study 
of 123 consecutive patients with biopsy-proven CABMR between 2006 and 2012, with 
follow-up for a median of 9.5 years, Redfield et al. found that 76% of patients lost their grafts 
with a median graft survival of 1.9 years after diagnosis of CABMR (see Figure 5) 
[Redfield et al, 2016]. 


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Figure 5 
Kidney Graft Survival Following CABMR Diagnosis 
 
CABMR = chronic active antibody-mediated rejection; yrs= years. 
Source:  Redfield et al, 2016. 
 
In a study of 145 patients between 7 days and 31 years post-transplant, Hidalgo et al. 
detected DSA in 54 (37%) patients, of which 32 were dnDSA (22% of original patient 
population and 59% of DSA+ subgroup) [Hidalgo et al, 2009]. De novo DSA were more 
frequent in the patients who had late biopsies versus early biopsies, and were associated with 
microcirculation, inflammation and glomerular damage. Importantly, dnDSA correlated with 
reduced graft survival (see Figure 6). 


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Figure 6 
Probability of Graft Survival in Patients Who Underwent a Late Biopsy 
and Were Assessed for DSA 
 
 
DSA = donor-specific antibodies; F = the number of failed grafts; HLA = human leukocyte antigen; neg=Negative; PRA = 
panel-reactive antibodies; Pre-ex = pre-existing. 
*p = 0.001 (log rank test). 
Notes: 
Probability of graft survival in patients in each DSA subgroup was compared to patients with no detectable HLA antibodies 
(PRA neg).  
Source:  Hidalgo et al, 2009. 
 
In a study of a larger consecutive cohort of 508 patients, Wiebe et al. discovered dnDSA in 
64 (13%) patients [Wiebe et al, 2015]. In patients with dnDSA, the rate of estimated 
glomerular filtration rate (eGFR) decline was significantly increased prior to dnDSA onset 
(-2.89 versus 0.65 mL/min/1.73 m2/year, p < 0.0001) and accelerated post-dnDSA onset 
(-3.63 versus -2.89 mL/min/1.73 m2/year, p < 0.0001), supporting the notion that dnDSA 
were contributing to the ongoing alloimmunity and allograft damage. Patients with “clinical” 
dnDSA (ie, evidence of renal dysfunction) had the highest risk of graft loss (see Figure 7). 


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Figure 7 
Death-Censored Graft Survival by Clinical Phenotype and dnDSA Status 
 
dnDSA = de novo donor-specific antibodies. 
Notes: 
Kaplan-Meier plot of renal allograft survival by clinical phenotype and dnDSA status.  
Source:  Wiebe et al, 2015. 
Although most studies have identified dnDSA to be significantly associated with increased 
risk of graft loss, recipients with preformed DSA are also at greater risk of graft loss. 
Loupy et al, 2009] in their study of 806 kidney transplantations performed between 2002 to 
2007, compared a cohort of 54 patients with preformed DSA to a control group of patients 
without preformed DSA [ Loupy, et al 2009]. Four-year graft survival was significantly 
lower in the group with preformed DSA compared to the control group: survival was 86.2% 
and 96.2%, respectively, (p = 0.01, log rank test). In another study of 402 consecutive 
deceased donor kidney transplant recipients, Lefaucher et al. observed a worse 8-year graft 
survival (61%) among patients with preexisting anti-HLA DSA compared to both sensitized 
patients without anti-HLA DSA (93%) and non-sensitized patients (84%) [Lefaucheur et al, 
2010]. Notwithstanding, in a study of 771 kidney biopsy specimens from 2 North American 
and 5 European centers, Aubert et al. compared patients with a biopsy-proven ABMR and 
pre-formed DSA versus patients with rejection and dnDSA [Aubert et al, 2017]. At 8 years 
after ABMR diagnosis, patients with preformed DSA ABMR had significantly superior graft 
Follow-up (Years)


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survival compared with the patients with dnDSA ABMR (ie, 63% versus 34%, 
respectively, p = 0.001) (see Figure 8). 
Figure 8 
Probability of Graft Survival According to DSA Characteristics 
ABMR = antibody-mediated rejection; DSA = donor-specific antibodies; HLA = human leukocyte antigen. 
Notes: 
Early occurrence of preexisting anti-HLA DSA ABMR and superior graft survival compared with de novo anti-HLA DSA 
ABMR.  
Source:  Aubert et al, 2017. 
That the development of DSA is fundamentally linked with ABMR in kidney allografts is 
recognized by the Banff 2015 criteria [Loupy et al, 2017] for diagnosing ABMR. All 3 of the 
following features must be present: histologic evidence of tissue injury, evidence of 
current / recent antibody interaction with vascular endothelium, and serologic evidence of 
DSAs (HLA or other antigens), irrespective of whether preformed or dnDSA. The diagnosis 


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of ABMR is further subdivided into acute / active or chronic active ABMR (ie, CABMR), 
differentiated by the presence of chronic tissue injury such as TG, severe peritubular 
capillary basement multilayering, and / or arterial intimal fibrosis in CABMR. 
Currently, there are no approved or effective treatments for active ABMR, including 
CABMR. The KDIGO 2009 guideline [KDIGO, 2009] recognizes the lack of good quality 
data and suggests the use of one or more of the following (with or without corticosteroids), to 
treat acute ABMR: PLEX; IVIG; anti-CD20 antibody; and lymphocyte-depleting antibody. 
Recent systematic reviews of treatments for ABMR have shown that the situation remains 
unchanged, even with novel agents targeting B cells, plasma cells and the complement 
system [Roberts et al, 2012; Wan et al, 2018]. In the RITUX ERAH study, there was no early 
or late (up to 5 years) benefit with rituximab (an anti-CD20 mAb) administered with IVIG, 
PLEX and corticosteroids in kidney transplant recipients with early acute ABMR [Sautenet 
et al, 2016; Bailly et al, 2017]. More specifically, no evidence of efficacy was seen in studies 
in CABMR with eculizumab (a complement inhibitor), bortezomib (a proteasome inhibitor), 
IVIG, rituximab and PLEX [Kulkarni et al, 2017; Piñeiro et al, 2017; Eskandary et al, 2018; 
Moreso et al, 2018]. No treatment exists for the treatment of CABMR and there is no 
evidence that treatments for acute active ABMR are effective for CABMR. Thus, there exists 
a critical unmet medical need for effective treatments of CABMR. 


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3. ESTIMATED PREVALENCE OF ABMR – A RARE CONDITION 
It is estimated that more than 5,000 renal allografts are lost each year in the US alone, and 
approximately 75 to 80% are lost due to antibody-mediated injury [Loupy et al, 2012; 
Wiebe et al, 2012; Aubert et al, 2017]. Epidemiological data on ABMR in kidney transplant 
recipients is sparse and is not included in rare disease databases such as Orphanet. The 
prevalence of ABMR in kidney transplant recipients has therefore been approximated by 
estimating the prevalence of kidney transplant recipients with DSA (ie, DSA+ recipients) 
living in the US and in the EU28, Norway, Iceland and Liechtenstein (defined as “the Union” 
hereafter in this report).  
Estimation of the Proportion of Kidney Transplant Recipients With ABMR 
The reported rate of development (ie, incidence) and prevalence of dnDSA after kidney 
transplantation varies widely in the literature. Approximately 2% of kidney transplant 
recipients per annum have been reported to develop DSA [Wiebe et al, 2015], and in an 
international collaborative study of 45 transplant centers conducted in 2004 and 2005 by 
Ozawa et al, the prevalence of kidney transplant recipients with DSA varied from 
approximately 10 to 60%, with an average of 28% [Ozawa et al, 2007]. Not all kidney 
transplant recipients with DSA will develop ABMR; therefore, applying the most 
conservative figure of 60% to prevalence data for kidney transplant recipients provides a 
conservative upper estimate of the prevalence of kidney transplant recipients with ABMR.  
Estimation of the Prevalence of Kidney Transplant Recipients With ABMR in the US 
Prevalence data on kidney transplant recipients in the US was obtained from 2 key US 
sources: the United States Renal Data System (USRDS) 2016 Annual Report (which 
provides data current as of 31 December 2013) [USRDS, 2016] and the United Network for 
Organ Sharing (UNOS) data on the number of kidney transplants performed in 2015 to 2017 
[UNOS, 2015; UNOS, 2016; UNOS, 2017] (see Table 1). By combining these data and 
estimating the prevalence of DSA+ recipients based on Ozawa et al., a conservative upper 
estimate of the prevalence of ABMR patients at the end of August 2017 can be made (see 
Table 1) [Ozawa et al, 2007]. 


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Table 1 
Estimated Prevalence of Kidney Transplant Recipients in the US in 
August 2017 According to Data from the USRDS and UNOS and 
Estimated Prevalence of DSA-Positive Recipients 
 
Number of Individuals 
Cumulative number of recipients with a functioning kidney transplant 
in 2014 (based on USRDS data) 
200,907 
Number of kidney transplants in 2015 (UNOS) 
17,878 
Number of kidney transplants in 2016 (UNOS) 
19,060 
Number of kidney transplants from January 2017 to August 2017 
13,110 
Estimated total number of living kidney transplant recipients with a 
functioning kidney transplant in August 2017(a) 
243,426 
Estimate prevalence of DSA+ recipients in August 2017(b) 
24,343 – 146,056 
DSA = donor-specific antibodies; UNOS = United Network for Organ Sharing; USRD = United States Renal Data System. 
Notes:  
a Rough estimate applying the overall 1-year graft survival rate reported by the USRDS for 2013 (ie, 97%) to the total 
number of estimated recipients: ie, 0.97 x (200,907 + 17,878 + 19,060 + 13,110) = 243,426. 
b Based on range of 10 to 60% as reported by Ozawa et al, 2007. 
Source:  Ozawa et al, 2007; USRDS, 2016; UNOS, 2015-2017. 
 
Using the assumption of 10 to 60% being DSA+, the prevalence of DSA+ kidney transplant 
recipients at the end of August 2017 in the US is estimated to range from approximately 
24,343 to 146,056, well below the threshold of 200,000 for designation as a rare condition 
according to FDA requirements for orphan designation. As stated previously, not all 
DSA-positive subjects are expected to develop ABMR. 
Estimation of the Prevalence of Kidney Transplant Recipients With ABMR in the 
Union 
Prevalence data on kidney transplant recipients in the Union was obtained primarily from the 
European Renal Association – European Dialysis and Transplant Association (ERA-EDTA) 
2015 Annual Report [ERA-EDTA, 2017]. By estimating the prevalence of DSA+ recipients 
based on Ozawa et al, 2007, an estimate of the prevalence of ABMR patients at the end of 
2017 can be made (see Table 2). 


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Table 2 
Estimated ABMR Prevalence in the Union at the End of 2017 According 
to Data from the ERA-EDTA Estimated Prevalence of DSA-Positive 
Recipients 
Source of ERA-
EDTA Data 
Estimated Number of Individuals in the Union 
with Functioning Kidney Grafts 
Pre-2016(a) 
2017(b) 
RRT summary data 
197,060 
226,372 
Individual patient data 
279,598 
304,535 
Aggregate patient data 
229,043 
256,660 
 
Source of ERA-
EDTA Data 
Estimated 2015 
Kidney 
Transplant 
Prevalence (per 
10,000) 
Estimated Prevalence at the End of 2017(c) 
Projected 2017 
Kidney 
Transplant 
Prevalence 
(per 10,000) 
Projected 2017 
DSA+ (10%) 
(per 10,000) 
Projected 2017 
DSA+ (60%) 
(per 10,000) 
RRT summary data 
3.82(d) 
4.36 
0.44 
2.62 
Individual patient data 
5.42(e) 
5.87 
0.59 
3.52 
Aggregate patient data 
4.44(f) 
4.95 
0.50 
2.97 
ABMR = antibody-mediated rejection; DSA = Donor-specific antibodies; ERA-EDTA = European Renal Association – 
European Dialysis and Transplant Association; GODT = Global Observatory on Donation and Transplantation; RRT = renal 
replacement therapy; Union = EU28, Norway, Iceland, and Liechtenstein. 
Notes: 
a The number of individuals with functioning grafts pre-2016 was estimated by applying the ERA-EDTA prevalence rates 
for kidney transplant recipients to the total population of the Union at the end of 2015 (ie, 515,862,387 according to 
Eurostat).  
b The number of individuals with functioning grafts at the end of 2017 was estimated by adding the total number of kidney 
transplants performed in 2016 (based on GODT data) and 2017 to the pre-2016 number of individuals. The kidney 
transplant incidence for 2017 was assumed to equal the incidence for 2016 and the 1- and 2-year graft survival 
probabilities from the ERA-EDTA were applied. 
c The projected prevalence for the end of 2017 was calculated by taking the estimated number of individuals in 2017 and 
dividing it by the predicted population at the end of 2017. The predicted population at the end of 2017 was calculated 
by applying the same population growth as was seen in 2016.  
d Based on Table A.3.1 of the ERA-EDTA 2015 Annual Report. 
e Based on Table B.4.8 of the ERA-EDTA 2015 Annual Report. 
f Based on Table C.4.7 of the ERA-EDTA 2015 Annual Report. 
Source: ERA-EDTA, 2015; Eurostat: Population on 1 January 2016 / 2017 [Eurostat, 2017]; Global Observatory on Donation 
and Transplantation [GODT, 2017]; Ozawa et al, 2007. 
 
Using the assumption of 10 to 60% being DSA+, the prevalence of DSA+ kidney transplant 
recipients in the Union at the end of 2017 is estimated to range from approximately 0.44 and 
3.52 in 10,000, which is well below the defined threshold of 5 in 10,000 for designation as a 
rare condition according to the EMA requirements for orphan designation. As stated 
previously, not all DSA-positive subjects are expected to develop ABMR.  


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4. IL-6 IN MEDIATION OF ABMR  
IL-6 is a pleiotropic cytokine that regulates the immune response, inflammation, 
hematopoiesis, and bone metabolism [Keller et al, 1996]. IL-6 also has a range of effects on 
the adaptive immune response. It stimulates B cell differentiation and secretion of antibodies 
and prevents apoptosis of activated B cells [Hirano et al, 1985; Muraguchi et al, 1988; 
Kawano et al, 1995]. IL-6 also activates and induces proliferation of T cells and, in the 
presence of interleukin 2, induces differentiation of mature and immature T cells into 
cytotoxic T cells [Lotz et al, 1988; Okada et al, 1988]. 
IL-6 appears to be a critical cytokine involved in the humoral rejection of kidney allografts 
(ie, ABMR). IL-6 promotes the development and maturation of B cells to plasma cells that 
produce DSA targeting the allograft. These DSA damage the allograft via complement and 
non-complement mediated pathways and induce graft endothelial cells to produce 
inflammatory (eg, p-selectin, vascular cell adhesion molecule-1) and pro-thrombotic (eg, 
von Willebrand factor [vWF]) molecules [Gaston et al, 2010; Thomas et al, 2015; 
Jordan et al, 2017]. Furthermore, IL-6 shapes the T cell immune response resulting in 
promotion of long-lived pro-inflammatory Th cells (eg, Tfh cells, Th17, Th1, and Th2 cells) 
and inhibition of immune Treg cells that promote allograft tolerance. 
Both nonclinical and clinical evidence demonstrating how IL-6 / IL-6R interactions relate to 
CABMR in solid organ transplantation, especially kidney transplantation, are discussed 
below. 
4.1 
Expression of IL-6 in Allografts With and Without ABMR 
Jordan et al (personal communication) have investigated the role of IL-6 over-expression in 
the mediation of ABMR. Initial studies centered on measurement of serum cytokine levels in 
peripheral blood of patients at various times post-kidney transplant (see Figure 9). 


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Figure 9 
Serum Cytokine Levels in Kidney Transplant Recipients with Normal 
Graft Function and Allograft Rejection 
AMR = antibody-mediated rejection; AR = acute rejection; ATN = acute tubular necrosis; Bx = biopsy; CMR = cell-
mediated rejection; CNI = calcineurin inhibitor; IFNγ = interferon-gamma; IL = interleukin; sCr = serum creatinine; 
Tx = transplant. 
Source:  Jordan et al, unpublished data. 
In Figure 9, Panel A, serum cytokines are shown for post-transplant patients who had for 
cause biopsies (blue dots) versus those who did not have biopsies (red dots). As can be seen, 
the IL-6 levels are quite low in patients with quiescent allografts. However, in Figure 9, 
Panel B, patients with ABMR show significant elevations of IL-6 serum levels in concert 
with ABMR onset. The X axis shows time before, time at biopsy and initiation of treatment 
for those showing rejection (time zero), and time after biopsy. IL-6 levels appear to diminish 
with treatment of ABMR. Figure 9, Panel C shows serum cytokine levels in patients who had 
biopsies that did not show allograft rejection. These data suggest that elevations of serum 
IL-6 levels may be involved in the pathogenesis of ABMR and could be used as an early 
marker for allograft dysfunction mediated by antibody injury. 


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To determine if IL-6 is expressed in the biopsies of patients undergoing allograft rejection, 
Jordan et al also examined renal biopsy material from patients with normal kidneys, patients 
with cellular rejection, and patients with ABMR. Sections were stained with anti-sera 
directed at IL-6 and evaluated by morphometric scanning microscopy (see Figure 10). 
Figure 10 
IL-6 Expression in the Kidney: Normal Versus CMR and ABMR 
ABMR = antibody-mediated rejection; CMR = cell-mediated rejection; IL-6 = interleukin 6; tx = transplant. 
Source:  Jordan et al, unpublished data. 
No IL-6+ leukocytes    
   Occasional IL-6+ leukocytes        Numerous IL-6+ leukocytes
A. IL-6 Expression in Kidney Tissue
B. IL-6+ Cells are Significantly Increased in Allografts with ABMR
*p = 0.018
*


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Briefly, Jordan et al showed that the number of IL-6+ cells were significantly increased in 
biopsies demonstrating ABMR compared to cell-mediated rejection (CMR) or normal kidney 
tissue. Figure 10, Panel A shows representative staining of normal kidney tissue, tissue from 
a patient with cellular rejection, and a biopsy from a patient with ABMR. In this instance, 
there are numerous IL-6+ cells in the biopsy of ABMR compared with CMR and normal 
tissue. Figure 10, Panel B shows data from a larger analysis of ABMR biopsies compared to 
other diagnoses. Using morphometric scanning analysis, Jordan et al were able to show a 
significant increase in IL-6 expression in biopsies with ABMR. Altogether, these data 
suggest that IL-6 might play an important role in antibody-mediated injury to allografts. 
Along with the data presented in Figure 9 which demonstrates elevated levels of IL-6 in the 
sera of patients with ABMR, these findings suggest the possibility of IL-6 blockade as a 
potentially important therapy in management of ABMR. 
4.2 
Evidence from Nonclinical Studies Supporting the Role of IL-6 in 
ABMR 
4.2.1 
Nonclinical Studies with Anti-IL-6R mAbs 
4.2.1.1 
Anti-IL-6R Antibodies Attenuate Antibody Recall Responses in a Mouse 
Model of Allo-Sensitization 
Kim et al, 2014 investigated the ability of an anti-IL-6R mAb (mMR16-1) to modify immune 
responses in a mouse model of allo-sensitization in which C57 black mice were presensitized 
with a skin allograft from C57 black HLA-A2 transgenic mice [Wu et al, 2013; Kim et al, 
2014; Jordan et al, 2017]. Sensitized mice were then re-exposed to a second graft with 
1 cohort receiving treatment with anti-IL-6R mAb and a second cohort receiving a control 
antibody.  
Re-exposure of sensitized control mice to HLA-A2+ skin allografts resulted in a surge of 
DSA (anti-HLA-A2 immunoglobulin G [IgG]) [Kim et al, 2014]. Titers of DSA were 
significantly lower in the anti-IL-6R-treated mice compared with isotype controls. Flow 
cytometry analysis of anti-IL-6R-treated mice demonstrated a significant increase in Treg 
cells (Foxp3+ CD4+) and a significant decrease in both Th17 cells (interleukin 21+ CD4+) 
and Tfh cells (CXCR5+ CD4+) compared to isotype antibody-treated controls.  
Finally, using an IgG enzyme-linked immunospot assay (ELISpot), the impact of anti-IL-6R 
on terminally differentiated plasma cells was demonstrated (see Figure 11). Dramatic 
reductions were observed in the anti-HLA-A2 antibody in the supernatants of bone marrow 
and splenic plasma cells for anti-IL-6R-treated animals compared with the isotype controls. 


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As shown in Figure 12, the addition of anti-IL-6R to the plasma cell cultures of isotype 
treated animals showed a similar suppressive effect on anti-HLA-A2 production, thereby 
demonstrating a direct effect of anti-IL-6R on plasma cell antibody production.  
Together, these findings suggest a multifaceted mechanism of anti-IL-6R attenuation of 
antibody recall response to skin allograft, including modulation of a number of immune 
regulatory and effector cells: ie, decreased Th17 and Tfh cells, increased Treg cells, and 
reduced B cell progression to plasmablast, plasma cells, and IgG production. 
Figure 11 
Anti-IL-6R mAb Significantly Suppressed IgG + Plasma Cells in the 
Bone Marrow and Spleen (ELISpot Assay) 
BM = bone marrow; ELISpot = enzyme-linked immune absorbent spot; IgG = immunoglobulin G; IL-6R = interleukin 6 receptor; 
mAb=Monoclonal antibody 
Notes: 
Anti-IL-6R mAb significantly suppressed IgG+ plasma cells in the bone marrow and spleen as demonstrated in an ELISpot assay. 
A: Representative photos of ELISpots produced by bone marrow cells or splenocytes (spleen) from mice of anti-IL-6R group or 
control group, showing a decrease of IgG spots in the bone marrow and spleen of anti-IL-6R-treated mice.  
B: Bar-graph presentation of spot-counts from the anti-IL-6R (n = 3) and the control (n = 4) groups, showing statistically significant 
differences.  
C: Photos of ELISpots produced by bone marrow cells or spleen cells from the control mice, showing evidence of suppression of 
IgG spot formation by in vitro treatment of B cells / plasma cells with anti-IL-6R antibody (mMR16-1) in cultures.  
D: Bar graph presentation of spot-counts from the control bone marrow (n = 4) and spleens (n = 4) with (+mMR16-1) or without 
(mMR16-1) in vitro treatment. **p < 0.01. 
Source: Kim et al, 2014, Figure 5. 


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Figure 12 
Anti-IL-6R mAb Inhibits Anti-HLA-A2 Antibody (Flow-Antibody 
Binding Assay) 
 
DSA = donor-specific antibodies; HLA = human leukocyte antigen; IL-6 = interleukin 6; IgG = immunoglobulin G; mAb = monoclonal 
antibody.  
Notes: Detection of anti-HLA.A2 IgG antibodies in conditioned media of bone marrow cell cultures by flow-antibody binding assay.  
A: Bar graphs show that bone marrow cells from no treatment mice (green bar) produced significantly higher levels of DSA(IgG) as 
compared with that of anti-IL-6R-treated mice (red bar) at Day 14 in recall responses to second skin allografts. Also, in vitro 
treatment of bone marrow cells from the no treatment mice with anti-IL-6R antibody significantly reduced IgG alloantibodies (blue 
bar).  
B: Representative histograms demonstrating antibody binding to HLA-A2-expressing target cells detected in 96-hr culture supernatants of 
(1) no treatment bone marrow (green bar); (2) anti-IL-6R-treated mouse bone marrow (red bar); (3) no treatment mouse bone 
marrow treated with anti-IL-6R in culture (blue bar) and the isotype control (gray line).  
 
*p < 0.05; **p < 0.01. 
Source:  Kim et al, 2014, Figure 6. 
 
4.2.1.2 
Non-Human Primate Lung Allograft Survival Is Prolonged by Anti-IL-6R 
Antibody and Anti-Thymocyte Globulin Treatment Possibly Through 
Expansion of Peripheral Regulatory T Cells 
Aoyama et al. examined the effect of anti-IL-6R mAb (TCZ) and / or anti-thymocyte 
globulin (ATG) treatment in cynomolgus monkeys before and after transplantation with 
equine lung [Aoyama et al, 2016]. Tocilizumab treatment in combination with ATG was 
associated with an increase in peripheral Treg cells (see Figure 13) that was not observed in 
animals treated with ATG alone. As shown in Figure 14, graft survival was prolonged in 
animals who received TCZ + ATG in addition to SOC treatment with tacrolimus + steroids + 
mycophenolate mofetil (MMF) compared to animals who received SOC alone or SOC + 
ATG. Briefly, all animals treated with SOC alone lost their grafts by Day 100 with 20% 
survival at Day 60, and all animals in this group were also DSA+. Animals receiving SOC + 
ATG had 60% survival at Day 120 and were also DSA+. However, those that received TCZ 
in addition to SOC + ATG had 100% survival at Day 120 and were DSA–.  
In summary, treatment with an IL-6 blocking antibody in combination with ATG was 
associated with an increase in peripheral Treg cells, inhibition of DSA generation 


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post-transplant, and graft survival. The observed increase in Treg cells is likely responsible 
for the improved graft survival and lack of DSA development post-transplant. 
Figure 13 
Flow Cytometry Analysis of Blood from Non-human Primates Before and 
After Treatment with TCZ and ATG (Before Transplant) 
 
ATG = anti-thymocyte globulin; TCZ = tocilizumab. 
Notes: Flow cytometry analysis of blood from cynomolgus monkeys before and after treatment with TCZ plus ATG 
showing increase in peripheral Treg cells. 
Source: Aoyama et al, 2016. 
 


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Figure 14 
Graft Survival in Non-Human Primates Treated with ATG Plus or Minus 
TCZ 
 
ATG = anti-thymocyte globulin; DSA = donor-specific antibody; IL6 = interleukin 6; MMF = mycophenolate mofetil; N.S. = not 
significant; SOC = Standard of Care; TCZ = tocilizumab.  
Notes: Survival of lung transplants in cynomolgus monkeys who received standard treatment with tacrolimus + steroids + MMF (ie, SOC), 
or SOC + ATG, or SOC +ATG + TCZ. 
Source: Aoyama et al, 2016. 
 
4.2.2 
Additional Nonclinical Studies Supporting the Role of IL-6 in ABMR 
4.2.2.1 
Anti-IL-6R Induced Suppression of TNFα Production by Human Monocytes 
in an In Vitro Model of Anti-HLA Antibody-Induced ADCC 
Shin et al. investigated if natural killer (NK) cells, primary cells for ADCC, and other CD16+ 
(ie, FcγR IIIA+) cells, primarily monocytes and CD8+ T cells, are capable of alloantibody-
mediated cell activation, resulting in cytokine production in the in vitro ADCC model, and if 
TCZ is capable of suppressing these activation events and cytotoxicity in ADCC [Shin et al, 
2017]. Whole blood from a normal individual was incubated overnight with irradiated 
allo-peripheral blood mononuclear cells (PBMCs) pretreated with anti-HLA antibody 
positive (in vitro ADCC) or negative sera (mixed lymphocyte reaction [MLR]), with or 
without TCZ or control IgG. Intracellular cytokine production was analyzed by cytokine flow 
cytometry.  
Results showed that IFN-γ+ and / or tumor necrosis factor alpha (TNFα)+ cell% in NK cells, 
monocytes and CD8+ T cells were elevated in the ADCC compared to the MLR condition 
(see Figure 15). IL-6+ cells were significantly increased in ADCC versus MLR (10.2 ± 4.8% 


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versus 2.7 ± 1.5%, p=0.0003), but only in monocytes. Treatment with TCZ significantly 
reduced TNFα+ cell% in monocytes in ADCC, but had no effect on other cytokine+ cells 
(see Figure 16) and showed no effect on cytotoxicity in ADCC. Thus, IFN-γ, TNFα, and IL-6 
production induced by HLA antibody-mediated CD16 bearing cell activation in NK cells, 
monocytes, and CD8+ T cells suggests a potential role for ADCC and these inflammatory 
cytokines in mediation of ABMR. Tocilizumab suppression of TNFα production in 
monocytes in the ADCC condition suggests a role of the IL-6 / IL-6R pathway in monocyte 
activation. Inhibition of this pathway could reduce the inflammatory cascade induced by 
alloantibody, although the inhibitory effect on cytotoxicity was minimal in vitro. 
Figure 15 
Cytokine Production in NK cells, Monocytes and CD8+ T Cells in the 
In Vitro ADCC and MLR Cultures as Detected by CFC 
 
ADCC = antibody-dependent cellular cytotoxicity; CFC = cytokine flow cytometry; HS = human leukocyte antigen (HLA) 
sensitized; IFNγ = interferon-gamma; IL-6 = interleukin 6; MLR = mixed lymphocyte reaction; NK = natural killer; 
NS = non-sensitized; PBMC=Peripheral blood mononuclear cells; TNFα=Tumor necrosis factor alpha. 
Source:  Shin et al, 2017, Figure 2. 
 


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Figure 16 
The Effect of TCZ on IFNγ, TNFα, and IL-6 Production in NK Cells, 
Monocytes and CD8+ T Cells in In Vitro ADCC 
 
ADCC = antibody-dependent cellular cytotoxicity; IFNγ = interferon-gamma; IgG = immunoglobulin G; IL-6 = interleukin 
6; NK = natural killer; TCZ = tocilizumab; TNFα = tumor necrosis factor alpha. 
Notes: 
# p < 0.05 vs control IgG at each concentration. 
* p < 0.05 vs ADCC condition without additives. 
Source:  Shin et al, 2017, Figure 4. 
 
4.2.2.2 
IL-6 Blockade (in Combination with CD28-B7 Blockade) Promotes Long-
Term Allograft Acceptance and Tolerance in Mice 
Zhao et al.  investigated the role of IL-6 in mediation of experimental cardiac allograft 
rejection. BALB/c cardiac allografts were transplanted into wild-type or IL-6-deficient (ie, 
IL-6 -/- knock-out) C57BL/6 mice [Zhao et al, 2012]. In wild-type mice, IL-6 and IFN-γ 
production were upregulated during rejection. In IL-6 deficient mice, IFN-γ production was 
greater than that observed in wild-type controls (Figure 17C) suggesting that IL-6 production 
affects Th1 / Th2 balance during allograft rejection. CD28-B7 blockade by treatment with 


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CTLA4-Ig (a fusion protein blocking the CD28-B7 pathway) inhibited IFN-γ production but 
did not affect IL-6. Although wild-type C57BL/6 recipients treated with CTLA4-Ig rejected 
fully major histocompatibility complex (MHC)-mismatched BALB/c heart transplants, 
treatment of IL-6 deficient mice with CTLA4-Ig resulted in graft acceptance (see Figure 17A 
and Figure 17B). 
Figure 17 
Effect of IL-6 Deficiency on Allograft Tolerance 
A
C
B


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IFN-γ = interferon-gamma; IL-6 = interleukin 6; KO = knock-out; MHC = major histocompatibility complex; NT = no 
treatment; WT = Wild type. 
Notes: 
A. Survival (%) of fully MHC-mismatched BALB/c cardiac allografts in wildtype C57BL/6 and IL-6 -/- knock-out mice
with and without treatment with CTLA4Ig (n = 4 to 7 per group). 
B. Representative example of allograft pathology at 3 weeks after transplantation showing relatively normal myocardium
and vasculature in the IL-6 -/- recipient. C. IFN-γ production (mean ± standard deviation) by splenocytes. 
Source:  Zhao et al, 2012, Figure 4. 
Long-term allograft acceptance was also seen in wildtype mice treated with combined 
CTLA4 immunoglobulin and anti-IL-6 antibody (see Figure 18). The investigators also noted 
an increase in Treg cells in animals receiving anti-IL-6 therapy that was not seen in isotype 
controls. The authors concluded that blocking the effects of IL-6 in combination with 
costimulatory blockade may be an important strategy to promote long-term allograft 
acceptance and tolerance. 
Figure 18 
Neutralization of IL-6 In Vivo Promotes Allograft Survival with 
Costimulation Blockade 
IgG = immunoglobulin G; IL-6 = interleukin 6; mAb = monoclonal antibody; MHC = major histocompatibility complex. 
Notes: Survival of fully MHC-mismatched BALB/c cardiac allografts in wildtype C57BL/6 recipients treated with 
CTLA4Ig and either anti-IL-6 mAb (n = 5) or control IgG (n = 8). 
Source:  Zhao et al, 2012, Figure 6. 
4.2.2.3 
Neutralizing IL-6 Reduces Human Arterial Allograft Rejection by Allowing 
Expansion of CD161+ CD4+ Treg Cells 
Fogal et al.  investigated the effect of neutralizing IL-6 on human arterial segments 
transplanted into immunodeficient mice [Fogal et al, 2011]. IL-6 transcripts in transplanted 
tissue were shown to rapidly increase post-transplantation compared to before transplant 


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specimens and fall dramatically by 30 days post-transplant. Adoptive transfer of human 
PBMCs with allospecificity to the arterial alloantigens resulted in T cell infiltrates and 
intimal expansion 4 weeks later. Neutralization of human IL-6 using a mAb significantly 
reduced the magnitude of intimal expansion and total T cell infiltration but increased the 
relative expression of CD161+ Treg cells while decreasing other Th17 markers. In other 
experiments, culturing of MHC Class II expressing human endothelial cells with allogeneic 
CD4+ memory T cells resulted in T cell activation and endothelial cell secretion of IL-6. In 
primary allogeneic T cell endothelial cell cocultures, neutralization of IL-6 with a mouse 
antihuman IL-6 mAb resulted in enhanced proliferation of CD161+ / CD4+ Treg cells. The 
authors concluded that IL-6 released from injured allograft vessels appears to enhance 
allogeneic T cell infiltration and intimal expansion in a model of human allograft rejection by 
inhibiting an increase in CD161+ Treg cells. 
4.2.2.4 
Intrarenal B Cell Cytokines Promote Transplant Fibrosis and Tubular 
Atrophy in a Mouse Model of Kidney Transplant Rejection 
Tse et al recently showed that chronic allograft damage in a mouse model of kidney 
transplant rejection, specifically interstitial fibrosis / tubular atrophy, was mediated by B cells 
producing intra-graft chemokines and IL-6 [Tse et al, 2015]. B cell depletion with anti-CD20 
antibody given after the initiation of chronic allograft damage was able to reduce intra-graft 
B cells, chemokines, IL-6 levels, and interstitial fibrosis / tubular atrophy. These findings 
suggest that persistent B cell activation and IL-6 production may be important in mediation 
of chronic allograft nephropathy and could possibly be important in human CABMR. 
4.2.2.5 
Antibodies from Donor B Cells Perpetuate Cutaneous Chronic GVHD in 
Mice 
Using a mouse model of chronic graft-versus-host disease (GVHD), Jin et al showed that 
donor antibodies were responsible for damage to the thymus and skin that was also 
associated with IgG-induced Th17 infiltration into the skin of affected animals 
[Jin et al, 2016]. Thus, B cell antibodies appeared to augment cutaneous chronic GVHD. 
Srinivasan et al reported that donor B cell–derived antibodies also enhance development of 
bronchiolitis obliterans in a murine model of chronic GVHD [Srinivasan et al, 2012]. In this 
model, recipient germinal centers were enlarged, and blockade of germinal center formation 
prevented induction of chronic GVHD. Both studies suggest a potential role for IL-6 in 
induction of the Th17 and plasmablast pathway for progression of chronic GVHD. 


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4.3 
Evidence from Clinical Studies Supporting the Role of IL-6 in 
ABMR - Studies with Anti-IL-6R (TCZ) 
4.3.1 
TCZ Treatment Resulted in Reduction of DSA and Improved Graft 
Survival in HLA-Sensitized Renal Allograft Recipients with CABMR 
and TG 
Choi et al investigated the effect of TCZ treatment in 36 HLA-sensitized renal allograft 
recipients with CABMR and TG, each of whom had failed treatment with IVIG + 
rituximab ± PLEX [Choi et al, 2017a]. These patients were treated with monthly intravenous 
(IV) infusions of TCZ (8 mg/kg, maximum dose 800 mg) as rescue therapy for 6 to
25 months and monitored for DSA and long-term outcomes for up to 8 years. Baseline 
features of these 36 patients are shown in Table 3.
All patients had evidence of significant pathological injury at initiation of TCZ treatment, 
and 17 of 36 (47%) patients were re-transplants. Twenty-five of 36 (69%) patients had more 
than 2 prior ABMR episodes and 33 of 36 (92%) had received more than 2 rounds of ABMR 
treatment with pulse steroids, IVIG, rituximab, ± eculizumab and ± PLEX for 
treatment-resistant ABMR before initiation of TCZ. At the time of CABMR diagnosis, 
31/36 (86%) patients had demonstrable HLA-DSA with Class II DSA predominating. Three 
patients did not demonstrate HLA-DSA but showed elevated levels of anti-angiotensin 
Type 1 receptor antibodies. 
Table 3 
Baseline Characteristics of CABMR Patients Treated with TCZ 
N 
Patients 
Recipient characteristics 
Age (yrs), mean (SD) 
36 
45.86 (16.64) 
Gender male, n (%) 
36 
19 (52.78) 
Graft rank > 1, n (%) 
36 
17 (47.22) 
Donor characteristics 
Decreased donor, n (%) 
36 
20 (55.56) 
Extended-criteria donor, n (%) 
36 
1 (2.78) 
Cold ischemia time > 24 h, n (%) 
36 
2 (5.56) 
Delayed graft function(a), n (%) 
36 
6 (16.67) 
Immunology at the time of transplantation 
HLA mismatches, mean (SD) 
28(b) 
4.07 (1.46) 
Anti-HLA DSA-positive, n (%) 
28(b) 
18 (64.29) 
Time from transplantation to treatment (yrs), mean (SD) 
36 
6.72 (4.63) 


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Immunology at the time of ABMR 
 
 
Anti-HLA DSA+, n (%) 
36 
33 (91.67) 
Anti-angiotensin Type 1 receptor antibody+ / DSA-, n (%) 
36 
3 (8.33) 
Number of anti-HLA DSA, mean (SD) 
33(c) 
1.91 (1.26) 
Number of Class 1, mean (SD) 
33(c) 
0.43 (0.66) 
Number of Class 2, mean (SD) 
33(c) 
1.45 (0.94) 
Renal function at the time of ABMR 
 
 
eGFR (mL/min/1.73 m2), mean (SD)  
36 
48.43 (34.56) 
eGFR (mL/min/1.73 m2) for adult patients, mean (SD) 
32 
38.82 (10.37) 
eGFR (mL/min/1.73 m2) for pediatric patients, mean (SD) 
4 
77.63 (25.86) 
Follow-up (yrs), mean (SD) 
36 
3.26 (2.04) 
Graft loss, n (%) 
36 
4 (11.11) 
Received > 2 ABMR treatment sessions before TCZ, n (%) 
36 
33 (91.67) 
ABMR = antibody-mediated rejection; CABMR = chronic active antibody-mediated rejection; DSA = donor-specific 
antibody; eGFR = estimated glomerular filtration rate; HLA = human leukocyte antigen; SD = standard deviation; 
TCZ = tocilizumab; yrs = years.  
Notes: 
a Delayed graft function was defined as the use of dialysis in the first postoperative week. 
b Information available for 28 of 36 patients. 
c Among the patients with anti-HLA DSAs. 
Source:  Choi et al, 2017a, Table 1. 
 
Tocilizumab-treated patients demonstrated graft survival and patient survival rates of 80% 
and 91% at 6 years, respectively (Figure 19). Statistically significant reductions in DSA were 
seen at 2 years (see Figure 20). Notably, stabilization of renal function (ie, eGFR) was seen 
over 36 months (see Figure 21), a clinically important finding given that renal function 
would be expected to decline over time in patients with ABMR and DSA [Fotheringham 
et al, 2011; Eskandary et al, 2014; Wiebe et al, 2015]. 
Nine patients also underwent repeat biopsies 1 year after initiation of TCZ treatment to assess 
the impact of therapy on pathologic features of CABMR (Banff 2013 criteria [Haas et al, 
2014]) and to determine if continuation of therapy was advisable. As shown Figure 22, 
statistically significant improvements in the scores of complement staining (C4d scores) and 
microvascular inflammation (glomerulitis (g) + peritubular capillaritis (ptc) scores) were 
observed. These parameters have been shown to be associated with the development of TG 
and graft loss [Haas and Mirocha, 2011; De Serres et al, 2016]. 


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Figure 19 
Kaplan-Meier Analysis of Graft and Patient Survival Over Time Post 
Treatment with TCZ 
 
cABMR = chronic active antibody-mediated rejection; TCZ = tocilizumab. 
Source:  Choi et al, 2017a, Figure 2. 
 
Figure 20 
Mean Immunodominant DSA Values for TCZ-Treated Patients 
 
DSA = donor-specific antibodies; MFI = mean fluorescence intensity; TCZ = tocilizumab. 
Source:  Choi et al, 2017a, Figure 4. 


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Figure 21 
Mean eGFR Value of TCZ-Treated Adult CABMR Patients 
 
ABMR = antibody-mediated rejection; CABMR = chronic active antibody-mediated rejection; eGFR = estimated 
glomerular filtration rate; MDRD = Modification of Diet in Renal Disease; TCZ = tocilizumab.  
Notes:  
Mean eGFR value of TCZ-treated adult CABMR patients (N = 32, > 18 years). eGFR values were maintained over the 
course of TCZ treatment after CABMR biopsy (36 months). 4 adult patients with graft loss were excluded. eGFR 
values were calculated by the MDRD equation for all adult patients. 
Source:  Choi et al, 2017a, Figure 3. 


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Figure 22 
Allograft Phenotype Pre- and Post-TCZ Treatment 
 
C4d = complement component 4d; g = glomerulitis; IFTA = interstitial fibrosis and tubular atrophy; ptc = peritubular 
capillaritis; TCZ = tocilizumab; TG = transplant glomerulopathy. 
Notes:  
This figure shows kidney allograft biopsy phenotypes (Banff 13 scoring) before and after TCZ treatment. Allograft biopsies 
were obtained 1 year post-TCZ treatment and compared with pre-TCZ CABMR biopsies in 9 patients. Significant 
reductions in g + ptc scores and C4d deposition were seen with TCZ treatment. Other parameters were stable. 
Source: Choi et al, 2017b, Figure 1B. 
 
Choi et al recently reported extended experience with a larger cohort of 65 kidney transplant 
recipients with CABMR and TG, treated monthly with TCZ 4 to 8 mg/kg IV for 3 to 
37 doses and followed up to 6 years from TCZ initiation [Choi et al, 2017b]. The mean time 
from transplant to TCZ treatment and from CABMR diagnosis to treatment was 
5.39 ± 4.3 years and 1.37 ± 1.62 years, respectively. Immunodominant DSA levels tended to 
decrease after therapy. Mean eGFR decreased from 53.18 ± 34.61 mL/min/1.73 m2 at 
Month 0 to 50.43 ± 36.37 mL/min/1.73 m2 at Month 24. At 6 years, 92.6% of TCZ-treated 
patients had functioning grafts compared to 53.3% of patients in a SOC group (p = 0.0005) 
that consisted of 39 non-concurrent CABMR patients treated with IVIG + rituximab ± PLEX. 
Post-TCZ biopsies taken at a mean of 29.5 ± 18.7 months from pre-TCZ, showed significant 


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reductions in g + ptc scores compared to biopsy at diagnosis. Two deaths occurred in the 
TCZ group. 
Together, these results indicate that inhibition of the IL-6 / IL-6R pathway may represent a 
novel approach to stabilize renal allograft function and extend patient lives.   
4.3.2 
Stabilization of Severe CABMR Progression Following TCZ Treatment 
in Pediatric Renal Transplant Patients Refractory to B Cell 
Immunotherapy 
Puliyanda et al investigated the effect of TCZ on ABMR progression in 6 pediatric kidney 
transplant recipients with severe CABMR, refractory to treatment with IVIG and rituximab 
[Puliyanda et al, 2017]. Patients were treated with TCZ 4 to 8 mg/kg IV monthly for 4 to 
12 doses and monitored for immunodominant DSA, renal function, and patient and graft 
survival. At initiation of TCZ treatment, the mean of patients was 14.2 years. The mean time 
to CABMR from transplant was 2177 days and the mean time to TCZ treatment from 
CABMR diagnosis was 457 days. Prior to TCZ treatment, all patients had developed strong 
(mean fluorescence intensity (MFI) > 10,000) dnDSA and continued to have biopsy-proven 
CABMR despite B cell immunotherapy. 
At a median follow-up of 15 months post TCZ, there was no decline in renal function and no 
change in the immunodominant DSA. Patient and graft survival were 100% and in 4 patients’ 
renal biopsy 3 months after TCZ there was mild to moderate reduction in C4d staining with 
no worsening of CABMR. Thus, treatment with TCZ was shown to stabilize the progression 
of ABMR, resulting in no graft loss and no decline in renal function. 
4.3.3 
Improved Renal Function and Reduced DSAs Following TCZ Treatment 
in HLA-Sensitized Patients with Acute ABMR 
Venkatachalam et al. examined the efficacy of addition of TCZ to treatment of acute ABMR 
in 5 highly HLA-sensitized kidney transplant recipients [Venkatachalam et al, 2017]. All 
5 patients had evidence of high DSA MFIs at the time of biopsy. During an acute rejection 
episode, monthly infusions of TCZ 8 mg/kg (for 3 to 6 months) was added to background 
treatment with solumedrol, IVIG and tacrolimus. In addition, 1 patient also received 
rituximab, 2 patients received thymoglobulin, and 1 patient received a dose of eculizumab for 
thrombotic microangiopathy-like features on kidney biopsy.  
Renal function improved in all 5 patients; DSA remained stable in 1 patient and decreased 
significantly in 4 patients (see Table 4). Thus, addition of TCZ to standard acute ABMR 
treatment appeared to be effective. 


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Table 4 
DSA and Creatinine Levels Before and After Treatment with TCZ for 
Acute ABMR 
Patient 
Age 
Race 
iDSA 
Pre-TCZ 
iDSA 
MFI 
Post-
TCZ 
iDSA 
MFI 
Cr at 
Time 
of 
ABMR 
Cr 3 
months 
Post 
Rejection 
1 
42 
African American 
DQB5*01:01 
23,477 
11,580 
2.92 
1.70 
2 
67 
Caucasian 
DQA1* 06:01/ 
DQB1*01:01 
21,663 
6,344 
1.8 
1.2 
3 
35 
Caucasian 
DRB5*01:01 
5,346 
1,089 
1.49 
0.7 
4 
35 
Asian 
B*51:02 
16,864 
5,013 
5.69 
2.02 
5 
39 
African American 
DRB1*13:03 
22,923 
5,515 
2.1 
1.5 
ABMR = antibody-mediated rejection; Cr= creatinine; DSA = donor-specific antibodies; iDSA = immunodominant DSA; 
MFI = mean fluorescence intensity; TCZ = tocilizumab. 
Source: Venkatachalam et al, 2017. 
 
4.3.4 
Increased Treg Cells, Decreased CD4+ T Cell Cytokine Production and 
Decreased Graft Inflammation Following TCZ Treatment in Kidney 
Transplant Recipients  
Chandran et al. examined the effects of TCZ treatment in a small randomized controlled 
study in stable (eGFR > 30 mL/min/1.73 m2) kidney transplant recipients with biopsy 
evidence of subclinical inflammation within 1 year of their transplant and on treatment with 
tacrolimus + MMF ± prednisone [Chandran et al, 2017]. Subjects received TCZ 8 mg/kg IV 
monthly for 6 months (n = 11) or no additional treatment (n = 11). PBMCs were collected at 
baseline, 3 and 6 months after initiation of TCZ treatment and kidney biopsies were 
performed at baseline and 6 months after initiation of TCZ.  
As shown in Figure 23, circulating Treg cells increased over 6 months in the TCZ group 
(+ 50%) and decreased in the control group (-22.5% [p = 0.012]). Conversely, phorbol 
myristate acetate / ionomycin stimulated production of interleukin 17 (IL-17) by CD4+ 
T cells decreased in the TCZ group and increased in the control group. At 6 months, the 
mean Banff total cortical inflammation score declined 39.5% in the TCZ group and increased 
21.9% in the control group. There were no cases of death or graft loss. 
In conclusion, TCZ was well tolerated and was associated with a significant increase in 
circulating Treg cells, a significant decrease in CD4+ T cell cytokine (IL-17) production, and 
a trend towards decreased graft inflammation. 


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Figure 23 
Increased Circulating Treg Cells and Decreased Graft Inflammation 
Following TCZ Treatment in Kidney Transplant Recipients 
TCZ = tocilizumab; ti-score = total cortical inflammation score; Treg = regulatory T cell. 
Source: Chandran et al, 2017. 
4.3.5 
Stabilization of Renal Function Following TCZ Treatment in Kidney 
Transplant Recipients with Refractory CABMR 
Patel et al investigated the efficacy of the addition of monthly TCZ 8 mg/kg IV to a regimen 
of tacrolimus, mycophenolate and prednisone in 20 kidney transplant recipients with 
refractory CABMR [Patel et al, 2017]. All patients had prior ABMR with persistent HLA 
DSA despite treatment with PLEX (n = 9), IVIG (n = 11), or rituximab (n = 5). TCZ 
treatment was initiated a mean of 1,648 ± 1,420 days after transplant and was administered 
for a mean of 323 ± 281 days, and all patients in the study had > 3 months follow-up. 
Following treatment with TCZ, the rate of eGFR decline decreased to 
0.05 mL/min/1.73 m2/month from 3.9 mL/min/1.73 m2/month in the 3 months prior to TCZ 
treatment (see Figure 24). Proteinuria also stabilized with a urine protein creatine ratio of 
0.80 at follow-up compared to 1.01 at baseline. No significant changes in DSA were 
observed. Two graft failures (1 noncompliance and 1 progressive rejection) were reported. 
There were few infectious complications. 
Thus, the addition of TCZ 8 mg/kg IV monthly to a regimen of tacrolimus, mycophenolate 
and prednisone was shown to stabilize eGFR, despite persistent DSA. 


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Figure 24 
Rate of eGFR Decline Before and After TCZ Treatment 
 
CKD Epi = Chronic Kidney Disease Epidemiology Collaboration; eGFR = estimated glomerular filtration rate; 
TCZ = tocilizumab. 
Source:  Patel et al, 2017. 
 
4.3.6 
Improved Renal Transplant Rates Following TCZ Treatment in 
HLA-Sensitized Patients (Resistant to Desensitization with IVIG + 
Rituximab Therapy ± PLEX) Awaiting Kidney Transplant 
Vo et al. investigated the efficacy of TCZ for reduction of DSA (to a level permissible for 
renal transplant) in 10 highly-HLA sensitized patients awaiting kidney transplants (see 
Figure 25) [Vo et al, 2015]. All patients had received previous renal transplants and were 
resistant to SOC for desensitization (ie, IVIG + rituximab ± PLEX). Two subjects were 
withdrawn from the study due to non-compliance with the protocol. Of the 8 patients 
remaining in the study, 5 received transplants during the study. Of note, an additional patient 
had frequent offers with negative crossmatches, but allocation was not favorable. 


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Significant reductions in immunodominant DSA were seen in all transplanted patients, with 
the most significant reduction at 12 months post-transplant. Figure 26A shows the course of 
immunodominant DSA before treatment, at transplant, and 12 months after transplant, and 
Figure 26B shows the mean DSA levels. 
It is important to note that all patients received additional monthly doses of TCZ for 
6 months after transplant. Protocol biopsies at 6 months showed no evidence of CABMR or 
TG in any of these patients. 
Although this study was conducted in a different clinical setting, results of this study show 
that IL-6 antagonism can reduce the strength and number of immunodominant DSA 
supporting the potential treatment benefit of IL-6 / IL-6R blockade in the treatment of 
CABMR in kidney transplant recipients. 


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Figure 25 
Study Design: TCZ Protocol for Desensitization Before- and After 
Transplant 
 
CFC = cytokine flow cytometry; CMV = cytomegalovirus; CRP = C-reactive protein; DSA = donor-specific antibodies; 
EBV = Epstein-Barr virus; IFNγ = interferon-gamma; IVIG = intravenous immunoglobulin; NK = natural killer; 
PCR = polymerase chain reaction; SC = subcutaneous; TCZ = tocilizumab; Th17= T helper cell 17. 
Notes: 
Patients entered into this study received desensitization with IVIG + TCZ for up to 6 months. If renal transplantation was 
accomplished, patients received an additional 6 months of TCZ after initial induction with Campath 1-H 
(alemtuzumab) 30 mg SC and IVIG post-transplant. DSA and other immune parameters were measured. Importantly, 
DSA present before transplant were reduced by TCZ + IVIG treatment.  
a 
Before transplant de-sensitization schema. 
b 
Post-transplant treatment schema. 
Source: Vo et al, 2015; Figure 4. 


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Figure 26 
Reduction in Immunodominant DSA Following TCZ Treatment 
 
ABMR = antibody-mediated rejection; AT1R = angiotensin II receptor Type 1; DSA = donor-specific antibodies; MFI = mean 
fluorescence intensity; RIS = relative intensity scale; TCZ = tocilizumab. 
Notes: 
This figure shows the course of immunodominant DSA before treatment, at transplant, and 12 months after transplantation. 
A. The course of immunodominant DSA before treatment, at transplant and 12 months after transplant. DSA levels are 
shown for the 5 individual patients who received a transplant during the study (TCZ02, TCZ03, TCZ06, TCZ07, and 
TCZ08). The DSA were eliminated in all but 1 patient (TCZ08) who had 2 weak DSA at 12 months without evidence 
of ABMR on protocol biopsy. Patient TCZ03 had mild ABMR at 12 months without evidence of DSA although AT1R 
antibody was positive.  
B. Mean immunodominant DSA scores for TCZ-treated and transplanted patients shown before treatment, at transplant and 
12 months post-transplant. Significant reductions in DSA number and strength were seen at transplant* and 12 months 
after transplantation†. The DSA values were calculated based on number and strength of DSA present at timepoints 
indicated. Strong DSA (> 10,000 MFI) were given a score of 10, moderate DSA (5000-10,000 MFI) were given a score 
of 5, weak DSA (<5000 MFI) were given a score of 2 whereas no DSA received a score of 0. 
Source:  Vo et al, 2015, Figure 2. 


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5. CONCLUSIONS 
Active ABMR, especially CABMR, is now recognized as the most common cause of 
allograft failure after a successful kidney transplant. Active ABMR and CABMR are part of 
a continuum of injury which, left untreated, results in the loss of the transplanted allograft. 
ABMR in kidney transplant recipients is a rare condition, and currently, there are no 
approved or effective treatments for active ABMR, including CABMR. 
Based on evidence from both nonclinical and clinical studies, IL-6 appears to be a critical 
cytokine involved in CABMR. Notably, Kim et al. [Kim et al, 2014] demonstrated that 
blockade of IL-6 /I L-6R interactions in an animal model of alloimmunity resulted in a 
significant reduction of alloantibodies, reduction of antibody production by splenic and bone 
marrow plasma cells, direct inhibition of plasma cell anti-HLA antibody production, and 
induction of Treg cells with inhibition of Tfh cells. Jordan et al (unpublished) have shown a 
significant increase in IL-6 expression in kidney biopsies with ABMR. Several small studies 
have shown stabilization and / or improvement of renal function in ABMR and CABMR 
following treatment with TCZ [Choi et al, 2017a; Choi et al, 2017b; Patel et al, 2017; 
Puliyanda et al, 2017; Venkatachalam et al, 2017]. In the largest of these studies, Choi et al. 
[Choi et al, 2017a; Choi et al, 2017b] demonstrated that treatment with anti-IL-6R mAb 
(TCZ) resulted in reduction of DSAs, stabilized graft function, and improved graft survival in 
HLA-sensitized renal allograft recipients with CABMR and TG. Chandran et al. showed that 
treatment of kidney transplant recipients with TCZ was associated with a significant increase 
in circulating Treg cells, a significant decrease in CD4+ T cell cytokine (IL-17) production, 
and a trend toward decreased graft inflammation [Chandran et al, 2017]. Vo et al. showed 
that renal transplant rates in HLA-sensitized patients (resistant to desensitization SOC) were 
improved following treatment with TCZ [Vo et al, 2015]. These data, together with additional 
studies summarized in Section 4, provide scientific evidence that a sound rationale exists for 
the treatment of CABMR with an anti-IL-6 mAb. 
In summary, the current treatments commonly being used for the treatment of CABMR are 
not evidenced-based. Considering the costs and potential for serious toxicity with the current 
treatments, this highlights the need for well-designed randomized controlled studies to 
investigate the safety and efficacy of any new drugs for the treatment of CABMR – a serious 
and rare condition with an unmet clinical need. Blocking the activity of IL-6 in kidney 
transplant recipients with ABMR has been investigated in a number of small uncontrolled 
clinical trials. Promising signals of efficacy have been seen with this anti-IL-6 approach. 


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Wu G, Chai N, Kim I, Klein AS, Jordan SC. Monoclonal anti-interleukin-6 receptor antibody 
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APPENDIX 4 
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TABLE OF CONTENTS 
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LIST OF TABLES 
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LIST OF FIGURES 
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7.
REFERENCES
Actemra® (tocilizumab) injection (20 mg/mL) vials; tocilizumab injection (162 mg/ 0.9 mL) 
pre-filled syringe and autoinjector. Product Monograph. Hoffmann-La Roche Limited. 
Canada. 2017 Aug. Date of Approval: 28 November 2018. 
Actemra® (tocilizumab) injection, for intravenous or subcutaneous use. Prescribing 
Information. Genentech, Inc.: South San Francisco, CA. 2017 Aug. 
Chandran S, Leung J, Laszik ZS, Tang Q, Hu C, Sarwal M, et al. IL-6 Inhibition With 
Tocilizumab To Promote Tregs and Control Renal Graft Inflammation: A Prospective 
Randomized Controlled Trial. Am J Transplant. 2017;17(Suppl 3). 
Choi J, Aubert O, Vo A, Loupy A, Haas M, Puliyanda D, et al. Assessment of tocilizumab 
(anti-interleukin-6 receptor monoclonal) as a potential treatment for chronic antibody-
mediated rejection and transplant glomerulopathy in HLA-sensitized renal allograft 
recipients. Am J Transplant. 2017;17:2381-9.  
Choi J, Aubert O, Louie S, Ammerman N, Vo A, Peng A, et al. Extended experience using 
tocilizumab (anti-IL6R, TCZ) for the treatment of chronic antibody mediated rejection 
(CABMR). Am J Transplant. 2017;17(Suppl 3). 
Eskandary F, Dürr M, Budde K, Doberer K, Reindl-Schwaighofer R, Waiser J, et al. 
Clazakizumab in late antibody-mediated  rejection: study protocol of a randomized 
controlled pilot trial. Trials. 2019;20(37):1-13.  
Hoffmann-La Roche Inc. Tocilizumab Arthritis Advisory Committee. 2008 Jul 29. 
Investigator's Brochure Clazakizumab. Version 4.0. Final report. Victoria (BC): Vitaeris Inc.; 
2018 May 1. 
Jordan S, Choi J, Kim I, Wu G, Toyoda M, Shin B, et al. Interleukin-6, a cytokine critical to 
mediation of inflammation, autoimmunity and allograft rejection: therapeutic implications of 
IL-6 receptor blockade. Transplantation. 2017;101(1):32-44. 
Kevzara® (sarilumab) injection. Prescribing Information. Regeneron Pharmaceuticals, Inc. / 
sanofi-aventis U.S. LLC, USA. 2017 May. 
Kevzara® 150 mg solution for injection in pre-filled syringe. Summary of Product 
Characteristics. Genzyme, UK. 2017 Dec 13. 
Patel S, Mohan S, Fernanez H, Batal I, Ratner L, Crew J. Tocilizumab stabilizes renal 
function in kidney transplant recipients with chronic active antibody mediated rejection 
(CAAMR). Am J Transplant. 2017;17(Suppl 3).  
Puliyanda D, Kim I, Choi J, Haas M, Zhang X, Vo A, et al. Safety and efficacy of 
tocilizumab (anti-IL6R, TCZ) therapy in the treatment of Chronic Antibody Mediated 
Rejection (cABMR) in pediatric renal transplant recipients. Am J Transplant. 2017;
17(Suppl 3). 


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Study Product: 
CSL300, clazakizumab 
 
 
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RoActemra® 20 mg/ml concentrate for solution for infusion. Summary of Product 
Characteristics. Roche Products Limited, Garden City, Herfordshire, UK. 2018 Apr 12. 
Venkatachalam K, Reem D, Andrew M, Delos Santos R, Alhamad T. Efficacy and safety of 
tocilizumab in treatment of acute antibody mediated rejection. Am J Transplant. 
2017;17(Suppl 3). 
Vo AA, Choi J, Kim I, Louie S, Cisneros K, Kahwaji J, et al. A phase I/II trial of the 
interleukin 6 receptor specific humanized monoclonal (tocilizumab) + intravenous 
immunoglobulin in difficult to desensitize patients. Transplantation. 2015;99(11):2356-63. 
Zhao Q, Pang J, Shuster D, Hung C, Baglino S, Dodge R, et al. Anti-IL-6 antibody 
clazakizumab is more potent than tocilizumab in blocking in vitro and in vivo IL-6-induced 
functions. ACR/ARHP Annual Meeting; 2013 Oct 25-30; San Diego, CA. Poster 2385. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SAP_001.pdf: 
SAP version: 0.9
Page 1 of 54
Date: 15 SEP 2022
Confidential
STATISTICAL ANALYSIS PLAN FOR INTERIM ANALYSES
(SAP FOR IA #1 & IA #2)
A Pivotal Phase 3 Trial to Evaluate the Safety and Efficacy of Clazakizumab for the 
Treatment of Chronic Active Antibody-Mediated Rejection in Kidney Transplant 
Recipients
Study Number:
CSL300_3001
Study Product:
Clazakizumab
Development Phase:
Phase 3
Sponsor:
CSL Behring, LLC
1020 First Avenue
King of Prussia, PA 19406
Version:
1.0
Version Date:
16 August 2023
Compliance:
This study will be conducted in accordance with standards of 
Good Clinical Practice (as defined by the International Council 
for Harmonization) and all applicable national and local 
regulations. 
COMMERCIAL IN CONFIDENCE
This document and the information contained herein are proprietary and confidential. This document 
and the contained information are intended for disclosure to and use by those personnel who are under 
an obligation of confidentiality by a signed agreement with the Sponsor CSL Behring. This document 
and the contained information may be disclosed and used only to the extent necessary to conduct the 
clinical study. Reproduction or disclosure of this document or its contained information is forbidden 
unless at the express request or with the written consent of CSL Behring.


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
2
TABLE OF CONTENTS
1.
MODIFICATION HISTORY ...................................................................................6
2.
LIST OF ABBREVIATIONS...................................................................................7
3.
PURPOSE ................................................................................................................8
4.
STUDY DESIGN.....................................................................................................9
4.1.
Objectives and Endpoints .......................................................................................10
4.1.1.
Hypothesis for Efficacy Analysis at IA #2 ..............................................................11
4.2.
Study Treatments....................................................................................................11
4.3.
Randomization Procedures and Blinding.................................................................11
4.4.
Planned Sample Size...............................................................................................12
4.5.
Planned Interim Analyses and Reviews...................................................................12
4.5.1.
Subject Trigger for Interim Analyses ......................................................................13
4.5.2.
Sample size Re-estimation in IA #1 ........................................................................13
4.5.2.1.
Operating Characteristics of Sample Size Re-Estimation at IA#1............................14
4.5.2.2.
Efficacy Results Presentation to DSMB at IA #1 ....................................................17
4.5.3.
Efficacy Results Presentation to DSMB at IA #2 ....................................................17
4.5.4.
DSMB Safety Reviews ...........................................................................................18
5.
CHANGES FROM THE PROTOCOL PLANNED ANALYSES ...........................19
6.
STUDY ANALYSIS SETS ....................................................................................20
6.1.
Screened Analysis Set.............................................................................................20
6.2.
Intention-to-Treat (ITT) Analysis Set......................................................................20
6.2.1.
Efficacy Analysis Set..............................................................................................20
6.3.
Per-protocol (PP) Analysis Set................................................................................20
6.4.
Safety Analysis Set.................................................................................................20
6.5.
Pharmacokinetic (PK) Analysis Set ........................................................................21
6.6.
Pharmacodynamic (PD) Analysis Set......................................................................21
6.7.
PK/PD Substudy Analysis Set.................................................................................21
7.
GENERAL CONSIDERATIONS...........................................................................22
8.
DATA HANDLING CONVENTIONS...................................................................23
8.1.
Database Lock (DBL).............................................................................................23
8.1.1.
Data Included in the Analysis .................................................................................23
8.2.
Missing Data ..........................................................................................................24


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
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8.3.
General Derived Variables......................................................................................24
8.3.1.
Reference Dates and Study Days ............................................................................24
8.3.2.
Durations and Time to Event Data..........................................................................25
8.3.3.
Baseline Definition.................................................................................................25
8.3.4.
Change from Baseline.............................................................................................25
8.3.5.
Multiple Assessments .............................................................................................25
8.3.6.
Actual Treatment....................................................................................................26
9.
STUDY POPULATION.........................................................................................27
9.1.
Subject Disposition.................................................................................................27
9.2.
Demographic and Baseline Characteristics..............................................................27
9.3.
Prior/Concomitant Medications ..............................................................................28
9.4.
Study Population - Derived Variables.....................................................................28
10.
INTERIM EFFICACY ANALYSES ......................................................................29
10.1.
Primary Estimand ...................................................................................................29
10.1.1.
Primary Analysis of the Primary Estimand..............................................................29
10.2.
Sensitivity Analyses for IA #2 ................................................................................31
10.2.1.
Analysis Based on Imputation of Missing Data.......................................................31
10.2.2.
Nonparametric Analysis..........................................................................................32
10.3.
Supplementary Analyses for IA #2 .........................................................................32
10.4.
Exploratory analysis of Primary Endpoint of All-Cause Allograft Loss or 
Irreversible loss of allograft function at IA #2.........................................................33
10.5.
Additional Efficacy Analyses..................................................................................34
10.5.1.
Subgroup Analysis for IA #2 ..................................................................................35
10.6.
Multiple Comparisons and Multiplicity...................................................................35
11.
SAFETY ANALYSES ...........................................................................................36
11.1.
Adverse Events (AEs).............................................................................................36
11.2.
OVERVIEW OF COVID-19 IMPACT...................................................................38
11.3.
Clinical Laboratory Evaluations..............................................................................38
11.3.1.
Analysis of Immunoglobulin G (IgG) .....................................................................40
11.4.
Other Safety Measures............................................................................................40
11.4.1.
Viral PCR Assay.....................................................................................................40
11.4.2.
Calcineurin Inhibitor (CNI) levels...........................................................................41


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
4
12.
ADDITIONAL ANALYSIS TO SUPPORT REGULATORY 
SUBMISSION FOR EXPEDITED MARKETING APPROVAL............................42
13.
REFERENCES.......................................................................................................46
14.
APPENDICES........................................................................................................47
14.1.
Figures for DSMB at IA #1.....................................................................................47
14.2.
R Code for Simulated Overall Power at IA #2 Using rpact R Package ....................50
14.3.
SAS Code for MMRM Analysis Using PROC MIXED ..........................................50
14.4.
Tipping Point Analysis Using Delta Adjustment Method........................................50
14.5.
Analysis Under Each Analysis Set..........................................................................54
LIST OF TABLES
Table 1:
Interim Analyses Efficacy Endpoints......................................................................10
Table 2:
Safety Endpoints for DSMB Safety Reviews ..........................................................11
Table 3:
Operating Characteristics for Overall Power at IA #2..............................................16
Table 4:
Data to be included for each interim analysis and DSMB........................................24
Table 5:
TEAE Assignment in Case of Missing AE Start Date Elements..............................36
Table 6:
List of laboratory tests summarized for DSMB Safety Reviews ..............................38
Table 7:
Laboratory Values of Potential Clinical Importance................................................40
Table 8:
Categories for BKV, CMV and EBV viral PCR assays ...........................................41


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
5
LIST OF FIGURES
Figure 1: Study Flow Chart
....................................................................................................10
Figure 2:
Number of Additional Subjects Needed ..................................................................15
Figure 3:
Sample figure for DSMB based on hypothetical observed effect size 0.45 at 
IA #1 ......................................................................................................................47
Figure 4:
Sample figure for DSMB based on hypothetical observed effect size 0.35 at 
stage 1 (IA #1) and assumed effect size of 0.30 to 0.54 in stage 2 ...........................48
Figure 5:
Sample figure for DSMB based on hypothetical observed effect size 0.25 at 
stage 1 (IA #1) and assumed effect size of 0.30 to 0.54 in stage 2 ...........................49


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
6
1.
MODIFICATION HISTORY
Version
Effective Date 
Author of 
Modification
Summary of Change
1.0
16 August 2023
First Version


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
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2.
LIST OF ABBREVIATIONS
Abbreviation
Term
AE
Adverse event
AESI
Adverse event of special interest
ANCOVA
Analysis of covariance
CABMR
chronic active antibody mediated rejection
CP
Conditional power
CSR
Clinical study report
DSA
Donor-specific antibodies
DSMB
Data Safety Monitoring Board
EOS
End of study
eCRF
Electronic case report form
GBM
Glomerular basement membrane
IP
Investigational product
ITT
Intention-to-Treat
LLN
Lower limit of normal
LLOQ
Lower limit of quantification
MAR
Missing at random
MedDRA
Medical Dictionary for Regulatory Activities
MFI
Mean fluorescence intensity
MI
Multiple imputations
MMRM
Mixed model repeated measures
MNAR
Missing not at random
SAE
Serious adverse event
SAP
Statistical analysis plan
SAP for IA
Statistical Analysis Plan for interim analyses
SAS
Statistical Analysis System
SD
Standard deviation
SE
Standard error
SOC
System organ class
TEAE
Treatment-emergent adverse event
ULN
Upper limit of normal


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
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3.
PURPOSE
This Statistical Analysis Plan for interim analyses (SAP for IA) provides a detailed description of 
the statistical methods to be used for the efficacy data and data derivations to be conducted at the 
first and the second interim analyses (IA #1 and IA #2) for study CSL300_3001 for review by 
DSMB. The analyses to be performed in case of regulatory submission based on IA #2 are also 
described here.
This SAP for IA complies with the International Council for Harmonization (ICH) E9 ‘Statistical 
Principles for Clinical Trials’ and E9(R1) ‘Statistical Principles for Clinical Trials: Addendum on 
Estimands and Sensitivity Analysis in Clinical Trials’, and is based upon the following study 
documents:

Clinical Study Protocol Amendment 9 dated 3 July 2023

electronic Case Report Form (eCRF), Version 12 dated 26 April 2023
A separate statistical analysis plan (SAP) will be prepared for the final analysis.


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
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4.
STUDY DESIGN
This study is a Phase 3, interventional, multi-site, randomized, double-blind, placebo-controlled, 
parallel-group study, consisting of 3 periods:

Screening period (up to 6 weeks; Day -42 to Day -1)

Double-blind treatment period (approximately 5 years on average; from Day 1 until the 
subject permanently discontinues treatment with IP, withdraws from the study,
experiences allograft loss, dies, or reaches the common treatment end date, whichever
occurs first). The common treatment end date is the date when the primary efficacy 
endpoint (all-cause composite allograft loss) is achieved, ie, the date the prescribed 
target number of primary allograft loss events (221) has been reached.

Follow-up period for safety (monthly telephone calls for 5 months after last dose of 
investigational drug)
The average study duration for an individual subject will not be expected to be more than 5.5 years.
Adult kidney transplant recipients with chronic active antibody mediated rejection (CABMR) will 
be enrolled in this study. Across sites in North America, South America, Europe, Asia and 
Australia, approximately 350 subjects (175 per treatment group) will be randomized into the 
double-blind treatment period.
The Study Flow Chart


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
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Figure 1: Study Flow Chart
4.1.
Objectives and Endpoints
The objective of IA #1 is:
1. To re-estimate the sample size for IA #2 based on the observed effect size for the change 
from baseline to Week 52 in eGFR
The objectives of IA #2 are:
1. To evaluate the efficacy of clazakizumab in slowing/preventing the progressive loss of 
kidney function (as measured by eGFR using the Modification of Diet in Renal Disease 4 
[MDRD4] equation)
2. To summarize the incidence of all-cause allograft loss or irreversible loss of allograft 
function due to chronic active antibody-mediated rejection (CABMR, defined as return to 
dialysis*, allograft nephrectomy, re-transplantation, estimated glomerular filtration rate
[eGFR] <15 mL/min/1.73 m2*, 40% decline in eGFR from Baseline that is sustained for at 
least 60 days, or death from any cause [*total cumulative duration of eGFR < 15 
mL/min/1.73 m2 AND / OR dialysis ≥ 60 days])
Table 1:
Interim Analyses Efficacy Endpoints
Interim Analysis
Endpoints
Summary Measure(s)
IA #1 and 
IA# 2
Change from Baseline to Week 52 
in eGFR (in mL/min/1.73 m2) 
Mean change from Baseline to 
Week 52 in eGFR (in 
mL/min/1.73 m2)
Effect size for the change from 
Baseline to Week 52 in eGFR
IA #2 only
All-cause allograft loss or 
irreversible loss of allograft 
function (defined as return to 
dialysis*, allograft nephrectomy, 
re-transplantation, estimated 
glomerular filtration rate [eGFR] 
<15 mL/min/1.73 m2*,40% 
decline in eGFR from Baseline 
that is sustained for at least 60 
days, or death from any cause 
[*total cumulative duration of 
eGFR < 15 mL/min/1.73 m2 AND 
/ OR dialysis ≥ 60 days])
Proportion of subjects who met 
the primary composite endpoint of 
All-cause Allograft Loss or 
irreversible loss of allograft 
function.
Proportion of subjects with 40% 
decline in eGFR from Baseline 
sustained for at least 60 days.
Proportion of subjects with 40% 
decline in eGFR from Baseline 
that is sustained for at least 60 
days and accompanied by 
investigator’s decision to 
supplement the therapy by 
additional treatment.
Proportion of subjects who 
returned to dialysis.
Proportion of subjects with 
allograft nephrectomy


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
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Interim Analysis
Endpoints
Summary Measure(s)
Proportion of subjects who had re-
transplantation.
Proportion of subjects with eGFR 
<15 mL/min/1.73 m2
Proportion of subjects who died
Table 2:
Safety Endpoints for DSMB Safety Reviews
Endpoints
Summary Measure(s)
Treatment-emergent adverse events (TEAEs), 
serious TEAEs
Proportion of subjects with TEAEs and serious 
TEAEs and the number of events
Adverse Events of Special Interest (AESIs)
Proportion of subjects with Adverse Events of 
Special Interest (AESIs) and the number of events
Viral infection monitoring (BKV, CMV, and EBV 
by PCR)
Proportion of subjects tested positive for BKV, 
CMV, and EBV
Clinical laboratory data (serum chemistry, urine 
chemistry, lipids and hematology)
Mean change from baseline in laboratory parameters 
by visit
4.1.1.
Hypothesis for Efficacy Analysis at IA #2
The study is designed to test the null (H0) versus the alternative (HA) hypothesis for the mean 
change from baseline in eGFR at week 52.
H0: µclaza - µplacebo = 0
HA: µclaza - µplacebo≠ 0
Where µclaza is the mean change from baseline to week 52 in eGFR (in mL/min/1.73 m2) in the 
clazakizumab group and µplacebo is the mean change from baseline to week 52 in eGFR (in 
mL/min/1.73 m2) in the placebo group.
4.2.
Study Treatments
All subjects eligible for study participation will be randomized to treatment with either 1 mL (12.5 
mg) clazakizumab or 1 mL placebo administered by SC injection, Q4W.
4.3.
Randomization Procedures and Blinding
Eligible subjects will be randomized by means of Interactive Response Technology (IRT). The 
IRT will assign the investigational product (IP) to each subject. Randomization will be done 
centrally. Randomization will be stratified by 


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
12

dichotomized screening eGFR (25–45 mL/min/1.73 m2 versus >45–65 mL/min/1.73 
m2) 

baseline proteinuria (urine albumin creatinine ratio (UACR) <300 mg/g (<30 
mg/mmol) or UACR ≥300 mg/g (≥30 mg/mmol))

treatment for early (within 6 months of transplant) antibody-mediated rejection 
(ABMR) rejection episodes (yes/no)

treatment for late (greater than 6 months post-transplant) ABMR rejection episodes 
(yes/no).
Two formal unblinded interim analyses (IA #1 and IA #2) will be performed by the Unblinded 
Independent Statistician for the Data Safety Monitoring Board (DSMB) review. DSMB charter 
describes the roles and responsibilities of the Unblinded Independent Statistician and the DSMB.
Unless there is a medical emergency, study unblinding for the final composite primary endpoint
(all-cause allograft loss) analysis will be done after the final database lock. The study blind may 
only be broken for an individual patient in the case of an emergency and when the knowledge of 
the investigational product is essential for the clinical management of the patient. A record will be 
kept at each study center (and in the electronic case report form [eCRF]) of all broken treatment 
codes, of the person who broke the treatment code, and of the reasons for breaking the treatment 
code.
4.4.
Planned Sample Size
IA #1
The IA #1 is planned to be performed when 100 subjects have been randomized and completed 52 
weeks of study participation (refer to Section 4.5.1 for subject trigger for interim analysis).
The planned sample size for IA#1 maybe higher than 100 randomized subjects to allow for 
withdrawals such that approximately 100 randomized subjects with 52 weeks of follow-up are 
included in the analysis.
IA #2
The fixed sample size for IA #2 was determined to be 180 randomized subjects (90 per group)
based on a fixed design with 90% power, a two-sided alpha of 0.05, a common standard 
deviation (SD) of 9.252 mL/min/1.73 m2 for the mean eGFR change from Baseline to Week 52, 
a minimum difference of 4.515 mL/min/1.73 m2 between the treatment groups (assuming eGFR 
declines at a rate of 0.753 mL/min/1.73 m2/month in the placebo group and that clazakizumab 
reduces the rate of decline by 50%; effect size = 4.515/9.252 = 0.488).
The planned sample size has been increased to approximately 200 randomized subjects to allow 
for 10% withdrawals such that at least 180 randomized subjects with 52 weeks of follow-up are 
included in the analysis.
4.5.
Planned Interim Analyses and Reviews
The trigger for the two interim analyses (IA #1 and IA #2) is defined in the section below. 


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
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The results from IA #2 may be used for a regulatory submission. At the IA #2, the DSMB will, 
following a review of the interim data, make recommendations for continuing or stopping the study 
based on the observed risk-benefit of clazakizumab, and for increasing the sample size if required. 
Detailed procedures for maintaining the blind will be specified in the Data Access Plan (DAP) to 
ensure that the interim data remain blinded to maintain clinical trial integrity until trial completion.
4.5.1.
Subject Trigger for Interim Analyses
IA #1 will be based on 100 randomized subjects completing 52 weeks of study participation and 
IA #2 will be based on at least 180 randomized subjects (or more as per the re-estimated sample 
size determined at IA #1) completing 52 weeks of study participation. Additional subjects may be 
included in IA #1 and IA #2 to account for the discontinuations prior to week 52. 
Randomization will continue until the target number of subjects are randomized in the study. At 
IA#1 and IA#2, subjects randomized beyond the required number of subjects (i.e., 100 for IA#1, 
180 for IA#2) will not be included with an exception for BLA submission package and 
confirmation from regulatory agencies at pre-submission meetings following IA#2 (details are in 
Section 8.1).
4.5.2.
Sample size Re-estimation in IA #1
The primary analysis of change from baseline to week 52 in eGFR has been based on a 2-stage 
design where the subjects included in the 2 stages are defined as follows:

Stage 1 consists of randomized subjects who are included in IA#1

Stage 2 consists of randomized subjects who are randomized post the randomization of 
the subjects included in IA#1.
Sample size re-estimation has been planned to estimate the number of additional subjects to be 
randomized and followed up for 52 weeks (stage 2) for IA#2.
Sample size re-estimation will be conducted using the inverse normal method for a 2-stage design 
with pre-specified cumulative information fractions of [0.5556, 1] to control the type I error rate
where 0.5556 = 100/180 is the ratio of the planned size of stage 1 to the total planned sample size. 
Following steps will be implemented to re-estimate the sample size for IA #2:
Set a pair of weights to the square root of the information fraction at each stage. In this case, _1 =
√(100/180) = 0.7454 is based on the number of subjects planned for stage 1 and _2 =
√(80/180) = 0.6667 is based on the number of subjects planned for stage 2. These weights are 
based on the originally planned design.
The estimate of sample size at stage 2 ( ̃_2) is derived as per equation (1), derivation is based on
Bauer and Koenig (2006). For a general discussion on conditional power and sample size re-
estimation, see Lan and Wittes (1988), Proschan et al. (2006, Chapters 3, 11), and Wassmer and 
Brannath (2016, Chapter 7). Estimate of sample size at stage 2 ( ̃_2) is,


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
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 =

∆
 
/√ √
√
+ !"#

(1)
where,
Z1 = Estimated treatment difference at Week 52 divided by its standard error
$1 = observed effect size at Stage 1 
$2 = assumed effect size at Stage 2 
_1= planned total sample size at Stage 1 i.e. 100
_2= planned total increment in sample size at Stage 2 i.e. 80
 = planned total sample size at IA #2 i.e. 180 (_1 + _2)
CP = target conditional power

Total sample size for IA #2 will be selected as follows:

If _1 +  ̃_2 ≤180 then sample size for IA #2 will remain as planned sample size 
of 180 randomized subjects with 52 weeks of study participation. DSMB is 
expected to recommend that the IA #2 should be conducted with 180 randomized 
subjects with 52 weeks of study participation as planned.

If 180 < _1 +  ̃_2 ≤250 then sample size for IA #2 should be close to _1 +
 ̃_2 such that the sample size of IA #2 could be a maximum of 250 randomized 
subjects with 52 weeks of study participation. DSMB is expected to make a 
recommendation about the number of randomized subjects with 52 weeks of study 
participation required for IA #2 (a maximum of 250 randomized subjects with 52 
weeks of follow-up).

If _1 +  ̃_2 > 250 then sample size for IA #2 could increase to a maximum of 
250 randomized subjects with 52 weeks of study participation. DSMB is expected 
to make a recommendation about IA #2 based on the review of the data package.

The sample size for the interim efficacy analysis surrogate endpoint (IA #2) will 
not exceed a total of 250 subjects with 52 weeks of study participation
(approximately 280 subjects will be randomized to account for 10% withdrawal 
before week 52).
4.5.2.1.
Operating Characteristics of Sample Size Re-Estimation at IA#1
Effect Size at Stage 1 and Stage 2
The following figure is an example that shows the number of subjects needed at stage 2 to ensure 
90% conditional power for five different scenarios of observed effect size at IA #1 and various 
assumed effect size for the stage 2.


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Study Number:             CSL300_3001    
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The black open circles in each line represents the number of subjects needed at stage 2 when the 
assumed effect size at stage 2 is identical to the observed effect size at stage 1. 
Figure 2:
Number of Additional Subjects Needed 
The green line represents the observed effect size of 0.488 at IA #1 (effect size assumed in study 
design). Fewer than 50 subjects would need to be randomized in stage 2 to ensure 90% conditional 
power for analysis at IA #2 (black open circle on the green line) assuming effect size of 0.488 at 
stage 1 will remain unchanged in stage 2. In this case, the sample size at IA #2 would remain at 
the planned sample size of 180 randomized subjects as it cannot decrease below 180 randomized 
subjects with 52 weeks of study participation.
If the observed effect size at IA #1 is 0.36 (represented by blue line) then the sample size at IA #2 
would need to be at the maximum of 250 randomized subjects (150 additional subjects required at 
stage 2) to ensure 90% conditional power (black open circle on the blue line) assuming same effect 
size will be seen at stage 2.
If the observed effect size at IA #1 is 0.30 (represented by solid purple line) then the total sample 
size at IA #2 would need to be close to 400 randomized subjects (approximately 300 additional 
randomized subjects at IA #2 if the same effect size is assumed for stage 2). In this case, as the 
maximum sample size cannot exceed 250 randomized subjects, the DSMB recommendation to 
continue the study at IA #2 implies DSMB assumes an increase of effect size of at least 0.42 at 
stage 2 at 90% conditional power.
Overall Power at IA #2
Overall power for the IA #2 is summarized in Table 3 for a range of hypothetical scenarios of 
effect size, conditional power and maximum total sample size at IA #2. Overall power is obtained 
from simulations with 100 randomized subjects in Stage 1 and information rates [0.5556, 1]. 
Simulations were performed using rpact R package (rpact 2021). The R codes are provided in the 
Appendix 0 including the seed used for simulation. 


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Study Number:             CSL300_3001    
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Table 3:
Operating Characteristics for Overall Power at IA #2
eGFR Effect 
Size
Conditional 
Power
Maximum Total 
Sample Size at IA 
#2
Expected Total 
Sample Size at IA 
#2
Overall 
Power
0.488
90%
180
180
90%
250
202
96%
0.46
90%
180
180
87%
250
205
93%
0.43
90%
250
209
90%
0.40
85%
250
210
85%
90%
250
213
85%
0.37
85%
250
214
79%
90%
250
218
80%
0.33
85%
250
220
70%
90%
250
223
71%
0.30
85%
250
224
62%
90%
250
227
63%
If the effect size is 0.488 (the assumed effect size used for the original study design), then there is 
no increase in sample size required for IA #2, (ie, the maximum sample size for IA #2 was specified 
as 180 randomized subjects). In this case, the expected total sample size of 180 randomized 
subjects will ensure overall 90% power. When simulation is performed with the maximum allowed 
samples size of 250 randomized, overall power increased to 96% with the expected total sample 
size of 202 randomized subjects.
Overall power is around 85% when the effect size is 0.40, with expected total sample size of 210 
randomized subjects for conditional power of 85% and expected total sample size of 213 


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Study Number:             CSL300_3001    
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randomized subjects for conditional power of 90%. These simulations were done with the 
maximum allowed samples size of 250 randomized subjects at IA #2.
Overall power drops below 80% with the maximum allowed samples size of 250 randomized 
subjects when the effect size is less than 0.37. 
Simulation results show that the study design with the sample size re-estimation procedure 
provides 80% or higher overall power for various plausible scenarios.
4.5.2.2.
Efficacy Results Presentation to DSMB at IA #1
The observed effect size ($1) based on the 100 randomized subjects with 52 weeks of study 
participation will be presented to the DSMB. The effect size is calculated as the ratio of the 
difference in mean change from baseline to Week 52 in eGFR between clazakizumab and placebo 
to the SD. The difference in mean change from baseline to Week 52 in eGFR between 
clazakizumab and placebo and the SD will be estimated from the MMRM model (refer to Section 
10.1.1). 
Estimates of sample sizes at stage 2 ( ̃_2) will be calculated based on the observed effect size at 
IA #1 using equation (1) for a range of assumed effect sizes at stage 2 ($2), for e.g. $2 could be 
five values ranging approximately from $1 – 0.12 to $1 + 0.12, with one value same as $1.
A figure of  ̃_2 vs $2 for the above range will be also presented to DSMB. This figure will include 
lines corresponding to conditional power of 90%, 85% and 80% (refer to Appendix 14.1 for sample 
figures). A table may also be created to present the numbers in the figure along with the conditional 
power for the minimum and the maximum allowed sample size increase at stage 2 i.e. 80 and 150, 
respectively.
Any decision to stop the study in the event of unacceptable effect size of eGFR or to increase the 
sample size for the IA #2 beyond the protocol specified maximum of 280 randomized subjects 
would be made by CSL Behring based on the recommendation of the DSMB.
4.5.3.
Efficacy Results Presentation to DSMB at IA #2
The number of subjects required for IA#2 is approximately 180 randomized subjects with 52 
weeks of study participation (if the sample size re-estimation at IA #1 remains at this planned 
number). If the sample size re-estimation at IA #2 increases the sample size for IA #2 then the IA 
# will be done when the re-estimated number of subjects are randomized and followed for 52 
weeks. Since the re-estimated sample size for IA #2 is unknown, this document will refer to IA #2 
to be based on 200 randomized subjects (to have approximately 180 randomized subjects with 52 
weeks of study participation). 
Change from baseline to Week 52 in eGFR will be analyzed at IA #2. The details of efficacy 
analyses of change from baseline in eGFR is described in Section 10. 
Any decision to stop the study in the event of non-significant effect on eGFR or to increase the 
sample size for the primary efficacy endpoint (time to all-cause composite allograft loss or 
irreversible loss of allograft function) would be made by CSL Behring based on the 
recommendation of the DSMB after review of the totality of the data, ie, observed effect on eGFR, 
updated predicted all-cause allograft survival based on the model using data observed in the study, 
and safety data.


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4.5.4.
DSMB Safety Reviews
DSMB will receive the safety outputs outlined in the charter which are delivered to DSMB for 
each safety review (approximately every 9 months as specified in the DSMB Charter) including 
those during IA #1 and IA #2. The DSMB can recommend stopping the study for safety reasons 
at any time.


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5.
CHANGES FROM THE PROTOCOL PLANNED ANALYSES
There are no changes to the analyses planned in the study protocol.


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6.
STUDY ANALYSIS SETS
6.1.
Screened Analysis Set
The Screened analysis set consists of all subjects who provided written informed consent. 
6.2.
Intention-to-Treat (ITT) Analysis Set
The ITT set will consist of all randomized subjects who took at least one dose of investigational 
drug and who had a baseline assessment and at least one post-baseline assessment of eGFR. Refer 
to Section 8.1.1 for details on data to be included in the analysis.
Subjects will be analyzed according to the treatment to which they were randomized.
6.2.1.
Efficacy Analysis Set
Efficacy analysis set for IA #1: This will be a subset of ITT analysis set. This subset will include 
first 100 randomized subjects who meet the subject trigger definition (refer to Section 4.5.1).
Subjects who discontinue the study prior to the subject trigger will also be included in this analysis 
set.
Efficacy analysis set for IA #2: This will be a subset of ITT analysis set. This subset will include 
number of subjects as per the re-estimated sample size who meet the trigger definition (refer to 
Section 4.5.1).
Subjects who discontinue the study prior to the subject trigger will also be included in this analysis 
set. 
Efficacy analysis set for Stage 2: This set will include subjects in the Efficacy analysis set for IA 
#2 but not in the Efficacy analysis set for IA #1. 
6.3.
Per-protocol (PP) Analysis Set
The PP set will consist of all randomized subjects who satisfy the ITT analysis set criteria and who 
complied with the protocol requirements (i.e., no major protocol deviations that impact the primary 
efficacy endpoint for the interim or the final analysis). PP analysis set will be used for IA #2 only. 
Protocol deviations resulting in exclusion from the PP set will be documented in the data review 
meeting (DRM) minutes before the study data unblinding for IA #2.
Subjects will be analyzed according to the treatment to which they were randomized.
6.4.
Safety Analysis Set
The Safety set will consist of all randomized subjects who took at least one dose of investigational 
drug.
Refer to Section 8.1.1 for details on data to be included in the IA#1 and IA#2 interim analysis.
Subjects will be included in the analysis according to the actual treatment received ie, in cases 
where information is available indicating that a subject received a different treatment for the entire 
course of his/her participation in the study, the subject will be analyzed according to the treatment 
actually received rather than the treatment to which he/she was randomized. If a subject receives 


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Study Number:             CSL300_3001    
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both clazakizumab and placebo, the safety information of the subject will be summarized under 
the clazakizumab arm.
6.5.
Pharmacokinetic (PK) Analysis Set
The pharmacokinetic analysis set consists of all subjects in the safety analysis set with at least one 
quantifiable PK concentration after investigational drug administration.
6.6.
Pharmacodynamic (PD) Analysis Set
The pharmacodynamic analysis set consists of all subjects in the Safety Analysis Set with at least 
one PD measurement obtained after investigational drug administration.
6.7.
PK/PD Sub-study Analysis Set
The PK/PD sub-study analysis set consists of all subjects in the Safety Analysis Set who consented 
to be part of the PK/PD Sub-study and have at least 1 quantifiable PK concentration of 
investigational drug after administration.


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Study Number:             CSL300_3001    
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7.
GENERAL CONSIDERATIONS
Datasets will be created according to Clinical Data Interchange Standards Consortium (CDISC) 
standards. Study data will be provided in Study Data Tabulation Model (SDTM) format. Analysis 
data will be provided in Analysis Data Model (ADaM) format.
SAS version 9.4 or higher will be used to perform all data analyses. 
Summaries of continuous variables will be in terms of the number of observations, mean, standard 
deviation, median, first quartile (Q1), third quartile (Q3), minimum and maximum. Other 
descriptive statistics (eg, standard error, coefficient of variation) may be reported when 
appropriate. Categorical variables will be summarized using frequency counts and percentages. 
Analyses that use other descriptive statistics will have the specific descriptive statistics identified 
with the analysis in the applicable SAP for IA section.
Unless otherwise stated, all statistical testing will be two-sided and will be performed using a 
significance (alpha) level of 0.05. Two-sided 95% confidence intervals will be provided when 
relevant.


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Study Number:             CSL300_3001    
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8.
DATA HANDLING CONVENTIONS
8.1.
Database Lock (DBL)
There will be a DBL for each interim analysis. BLA submission following IA#2 will be based on 
the analysis datasets generated from the locked database for IA#2. The analysis datasets will 
include the target number of subjects in IA#2.
DBL for IA #1 will occur when the 100 randomized subjects meet the subject trigger definition 
(see Section 4.5.1 Subjects randomized beyond the last randomized subject required for IA#1 will 
not be included in the IA#1 analysis. 
DBL for IA #2 will occur when 180 randomized subjects or more (as re-estimated during IA #1) 
meet the subject trigger definition (see Section 4.5.1). 
The trigger definition (see Section 4.5.1) will be used to include data for all additional subjects 
randomized beyond the target number of subjects required for IA#2.  
8.1.1.
Data Included in the Analysis
The study will continue to randomize subjects after the DBLs for IA #1 and IA #2 until the target 
number of subjects required in the study are randomized. Randomization will continue during the 
interim analyses. Therefore, number of subjects required for each IA will be selected 
programmatically from the source data as per the subject trigger defined in Section 4.5.1.
At the time of IA #1, subjects who discontinue the study prior to the subject trigger will also be 
included in the respective IA. These subjects will have less than 52 weeks of follow-up.
All available data from the DBLs will be included in the regular DSMB safety reviews 
(Section 4.5.4). 


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Study Number:             CSL300_3001    
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Table 4:
Data to be included for each interim analysis and DSMB Safety Reviews
Analysis
Study Milestones
IA #1
IA #2
DSMB Safety Reviews
BLA Submission
Primary analysis of 
eGFR using MMRM
Subjects in Efficacy analysis 
set for IA #1 with data up to 
52 weeks. Visits beyond 52 
weeks will be excluded 
Subjects in Efficacy analysis set 
for IA #2 with data up to 52 
weeks. Visits beyond 52 weeks 
will be excluded
NA
Same as IA #2
Sensitivity analysis of 
eGFR
NA
Subjects in Efficacy analysis set 
for IA #2 with data up to 52 
weeks. Visits beyond 52 weeks 
will be excluded
NA
Same as IA #2 
Supplementary 
analysis of eGFR 
using ANCOVA and 
MMRM
NA
Subjects in Efficacy analysis set 
for IA #2 with data up to 52 
weeks. Visits beyond 52 weeks 
will be excluded
NA
Same as IA #2 
Summary of eGFR over time 
based on all subjects included 
in the DBL for IA #2
Summary statistics of 
eGFR
Subjects in Efficacy analysis 
set for IA #1 with visits up to 
52 weeks
Subjects in Efficacy analysis set 
for IA #2 with all visits
All subjects and all visits 
from the DSMB data cut
Same as IA #2
Summary of 
proportions of subjects 
with all-cause allograft 
loss or irreversible loss 
of allograft function
NA
Subjects in Efficacy analysis set
for IA#2
All subjects from the 
DSMB data cut
Subjects in Efficacy analysis 
set for IA#2
All randomized subjects from 
the DBL for IA#2
Safety analyses
NA
Subjects in Efficacy analysis set 
for IA #2 with all visits
All subjects and all visits 
from the DSMB data cut
Same as IA #2
Safety package based on all 
randomized subjects included 
in the DBL for IA#2
HRQoL
NA
NA
NA
Subjects in Efficacy analysis 
set for IA #2 with all visits
PK and PD
NA
NA
NA
Subjects in respective PK or 
PD or PK/PD analysis sets
8.2.
Missing Data
Missing data occurs when any requested data are not provided, leading to blank fields on the 
collection instrument. These data will be indicated by the use of a “blank” (empty field) in subject 
listing displays. Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
The details of handling missing data are presented in the corresponding sections of this SAP for 
IA for respective analyses (eg, primary and secondary efficacy analyses, safety analyses).
8.3.
General Derived Variables
8.3.1.
Reference Dates and Study Days
Reference dates are used to assign study periods relative to treatment.

The safety reference date is the treatment start date and will be used to calculate study 
day for safety measures.


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Study Number:             CSL300_3001    
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
The efficacy reference date is the date of randomization and will be used to calculate 
study day for efficacy measures.
The respective study day will be calculated as (date of interest - reference date) + 1 if the date of 
interest occurs on or after the reference date. If the date of interest occurs before the reference date,
then the study day will be calculated as (date of interest – reference date). There will be no study 
day zero. Study week will be calculated by dividing study day by 7.
8.3.2.
Durations and Time to Event Data
Durations (eg, the duration of an adverse event [AE]) are calculated in days as:

event end date – event start date + 1; if end time or start time not available.

event end date / time – event start date / time; if both end time and start time available.
Thus, there will be no duration of 0 if end time or start time are not available. If an AE has missing 
or partially missing start or end date, no duration will be calculated.
For elapsed time (eg, the time to event), use:

event date / time – reference date /time, (if time available).
Thus, an event which happens on the same date as the reference date will have an elapsed time of 
0, if event time or reference time are not available.
To transform durations or elapsed times, which are calculated in days into weeks, divide the 
number of days by 7; to report in months, divide the number of days by 30.4375; to report in years,
divide the number of days by 365.25. These algorithms return decimal numbers and ignore the 
actual numbers of days in the months or years (the calendar days) between start date and stop date. 
The "year" used in these algorithms is 365.25 days long, and the "month" is one twelfth of that 
year.
8.3.3.
Baseline Definition
Baseline is defined as the most recent, non-missing value before the first IP administration 
(including unscheduled visits) for all assessments unless otherwise stated.
Baseline eGFR is defined as an average of 2 pre-treatment measurements up to 8 weeks apart.
8.3.4.
Change from Baseline
Change from baseline is calculated as:

visit value – baseline value.
If either the baseline or visit value is missing which, will result in missing change from baseline.
8.3.5.
Multiple Assessments
All data will be reported according to the nominal visit date for which they were reported. If the 
actual visit date deviates from the planned date according to the visit schedule in the protocol (i.e., 
outside the visit window) then no visit re-allocation will be done. Unscheduled data will not be 


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Study Number:             CSL300_3001    
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included in by-visit summaries but may contribute to the End of Study (EOS) value, or best/worst 
case value (eg, shift tables) and will appear in listings. 
If multiple assessments are reported on the same date for the same scheduled time, then the worst-
case result will be analyzed. 
Data from all assessments (scheduled and unscheduled), including multiple assessments, will be 
included in listings.
8.3.6.
Actual Treatment
The subjects’ actual treatment will be derived by reconciling the kit numbers. The actual treatment 
may be different from the randomized treatment assigned to the subject.


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Study Number:             CSL300_3001    
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9.
STUDY POPULATION
Unless otherwise stated, all tables and listings in this section will be based on the Efficacy or Safety 
analysis set. Analysis sets to be used for each analysis are summarized in Section 14.5.
9.1.
Subject Disposition
The following summaries will be provided by treatment group and total population using the 
Screened Analysis Set:

Subjects in each of the analysis sets are described in Section 6.

Subject study status, including subjects screened, screen failures, subjects randomized, 
completed the study, completed Week 52 visit, and discontinuation from the study by 
primary reasons for study discontinuation.

Study treatment status, including completed study treatment, ongoing study treatment, 
treatment withheld, or dose reduced, discontinued subjects by primary reasons for 
discontinuation.

Completed study treatment and discontinued subjects at each dosing visit.
Reasons for study withdrawal and study treatment discontinuation will be presented in the order 
they are displayed in the eCRF. The number of subjects randomized will be used as the 
denominator for the percentage calculation.
The following listings will be provided:

Reasons for study withdrawal including the date of withdrawal.

Reasons for study treatment discontinuation. The listing will include last dose date, and 
reasons for study treatment discontinuation.
9.2.
Demographic and Baseline Characteristics
The following summaries will be provided by treatment group and total population using the 
Efficacy Analysis Sets:

Demographic characteristics (age, race, ethnicity, sex, baseline height, baseline body 
weight and Body Mass Index (BMI)). In addition to summarization as a continuous 
variable, age will also be categorized and summarized by 18-64 and > 64.

Randomization stratification factors (dichotomized
screening eGFR [25–45 
mL/min/1.73 m2 versus >45–65 mL/min/1.73 m2], baseline proteinuria (UACR <300 
mg/g [<30 mg/mmol] or UACR ≥300 mg/g [≥30 mg/mmol]), treatment for early 
ABMR rejection episodes [yes/no], and treatment for late ABMR rejection episodes 
[yes/no]).

Baseline disease characteristics (time since kidney transplant in months, eGFR, eGFR 
categories UACR, DSA titers and DSA MFI scores and Renal Biopsy parameters).


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9.3.
Prior/Concomitant Medications
Prior/concomitant medications will not be summarized at the time of interim analyses (IA #1 and
IA #2).
9.4.
Study Population - Derived Variables
Derivation of Body Mass Index (BMI)
BMI will be calculated using the following formula:
BMI (kg/m2) = Weight (kg) / [Height (m)]2
using the height measured at Screening and the weight measured at Day 1 (if available). If weight 
at Day 1 is not available, the assessment at Screening will be used.


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Study Number:             CSL300_3001    
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10.
INTERIM EFFICACY ANALYSES
All efficacy analyses will be based on Efficacy Analysis Sets as defined in Section 6.2.1.
Baseline eGFR is defined as an average of 2 pre-treatment measurements up to 8 weeks apart.
For IA #1and IA #2, data beyond nominal Week 52 visit will be excluded from the primary and 
sensitivity analyses of change from baseline in eGFR, unless specified otherwise. However, eGFR 
data beyond 52 weeks of follow-up will be included in the descriptive summary statistics.
The randomized treatment will be used for the interim efficacy analyses described in this section.
10.1.
Primary Estimand
The estimand quantifies the treatment effect of clazakizumab vs placebo in adult patients with 
CABMR on the difference in mean change from baseline to Week 52 in eGFR (in mL/min/1.73 
m2) regardless of the missed doses or discontinuation of study treatment, as if the allograft loss 
events did not occur. 
Specific elements of the estimand are as follows:
Population: adult patients with CABMR
Variable: change from baseline to Week 52 in eGFR (in mL/min/1.73 m2)
Intercurrent events: eGFR data collected after the following allograft loss events is not relevant to 
the clinical question of interest:

Onset of allograft nephrectomy or re-transplantation

Date of confirmed eGFR < 15 ml/min/1.73m2

Onset of permanent return to dialysis
Population level summary: Difference in mean change from baseline
10.1.1.
Primary Analysis of the Primary Estimand 
A Mixed Model for Repeated Measures (MMRM) will be used to test the difference between 
clazakizumab and placebo for change from baseline to week 52 in eGFR. eGFR data collected 
after the occurrence of the intercurrent events will be excluded from the analysis. The SAS 
procedure PROC MIXED will be used. Missing data will not be imputed. Under the assumption 
of missing at random (MAR), the missing data will be accounted for through correlation of 
repeated measures in the model. The model will include a response variable of change from 
baseline in eGFR (in mL/min/1.73 m2) with the following terms:

Treatment (categorical variable for clazakizumab or placebo)

Visit (nominal visits through Week 52, categorical variable)

Treatment by visit interaction term

baseline eGFR 

Randomization stratification factor of dichotomized
baseline eGFR (25–45 
mL/min/1.73 m2 versus >45–65 mL/min/1.73 m2)


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Study Number:             CSL300_3001    
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
Randomization stratification factor of baseline proteinuria (UACR <300 mg/g
[<30 mg/mmol] or UACR ≥300 mg/g [≥30 mg/mmol])

Randomization stratification factor of treatment for early (within 6 months of 
transplant) ABMR rejection episodes (yes/no)

Randomization stratification factor of treatment for late (within 6 months of transplant) 
ABMR rejection episodes (yes/no)
An unstructured covariance structure will be used to model the within-subject errors. If this 
analysis fails to converge, the following covariance structures will be tested and the one 
converging to the best fit, as determined by Akaike’s information criterion (AIC), will be used as 
the primary analysis:

compound symmetry 

Toeplitz, 
The Kenward-Roger approximation will be used to estimate denominator degrees of freedom if 
the unstructured covariance structure is used; otherwise, the default method of the between-within 
(in SAS Proc Mixed) will be used to estimate denominator degrees of freedom.
Analysis for IA #1
Primary analysis of change from baseline in eGFR at IA #1 will be based on the Efficacy Analysis 
Set for IA #1 and will only include nominal visits up to 52 weeks. Treatment effect size will be 
estimated from the MMRM model.
Details of sample size re-estimation for IA #2 are included in Section 4.5.2 .
Also, the guidance for the outputs for DSMB are provided in Section 14.1.
Analysis for IA #2
At IA #2, primary analysis of change from baseline in eGFR is based on the combination statistics 
from stage 1 and stage 2 and will only include nominal visits up to 52 weeks. Therefore, MMRM 
analysis will be performed separately for change from baseline in eGFR for stage 1 subjects (ie, 
Efficacy Analysis Set for IA #1) and stage 2 subjects (ie, Efficacy Analysis Set for Stage 2). The 
number of subjects in the Efficacy Analysis Set for Stage 2 will be,

at least 80 randomized subjects if the sample size re-estimation at IA #1 does not 
require any increase in sample size for IA #2, or

if the sample size re-estimation increases the sample size for IA #2 then the number of 
subjects for stage 2 will include all the subjects eligible for IA #2 except those who 
were already included in IA #1.
The effect size and test statistics will be obtained from MMRM. The inverse normal combination 
test will be used for testing the hypothesis at IA #2 as follows:

7_1 and 7_2 are z-statistics, at stage 1 (based on Efficacy Analysis Set for IA #1) and 
at stage 2 (based on Efficacy Analysis Set for Stage 2), respectively and corresponding 
one-sided p-values 8_1 and 8_2 will be estimated from the MMRM. The 7 statistic for 


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the primary analysis for change from baseline to week 52 in eGFR is a combination 
test-statistic based on the test statistics at stage 1 and stage 2: 
7_1 = Φ^(−1) (1 −8_1 ) and 7_2 = Φ^(−1) (1 −8_2 )

The overall combination test statistic (7) will be:
7 = ├_1 7_1 + _2 7_2 ┤
Note that _1 = √(100/180) = 0.7454 and _2 = √(80/180) = 0.6667 have been specified 
in the design of the study. 

Two-sided p-value for the combination test will be: 8 = 2 ∗(1 −Φ(7))

Reject ?_0 at a 2-sided level @ if 8 < @
P-value for the combination test will be provided to the DSMB, along with the effect size at stage 
1 and stage 2.
The details of SAS codes are provided in the Section 14.3.
10.2.
Sensitivity Analyses for IA #2
To assess the robustness of the analysis of change from baseline to week 52 in eGFR, the primary 
analysis will be repeated using the PP Analysis Set.
Additional sensitivity analyses will be conducted as described in the following subsections. All 
sensitivity analyses described below will be based on the Efficacy Analysis Set for IA #2. 
10.2.1.
Analysis Based on Imputation of Missing Data
Missing data will be imputed using following approaches:
Single Imputation will be performed as follows and analyzed using the MMRM model specified 
in Section 10.1.1:
1. Missing values at all visits through week 52 that are not preceded by an all-cause composite 
allograft event will be imputed by the mean of the observed values at that time point within 
the same treatment group.
2. Missing values at all visits through week 52 following an all-cause composite allograft
event will be imputed by an eGFR value of 15 mL/min/1.73m2. 
Multiple Imputation:
The delta adjustment method, assuming missingness not at random (MNAR), will be used to 
estimate the tipping point beyond which the active treatment would have an unfavorable effect. 
The delta adjustment method, based on multiple imputations (MI) under the MNAR assumption 
assumes that subjects from the active treatment group who discontinue at a given time point would 
have, on average, an eGFR value that is worse by a specific amount δ compared with the observed 
values from subjects in the active treatment group who continue to the next time point. This general 
model can be estimated with a progression of values of δ until the treatment difference moves to a 


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significantly worse outcome for active subjects than for controls. This analysis is conducted to 
show the value of delta that would reverse the study conclusion in favor of the control arm. The 
values of δ that lead to a negative study conclusion can then be evaluated from a clinical 
perspective as to their plausibility. 
Regression imputation for monotone missing data patterns will be implemented using SAS PROC 
MI. Analysis results from the multiple imputed datasets will be combined using SAS PROC 
MIANALYZE. A forest plot will be provided to summarize the point estimates and confidence 
intervals for the treatment effect under each value of δ.
The details of SAS codes including number of imputations and seed are provided in 
Appendix 14.4.
10.2.2.
Nonparametric Analysis 
A nonparametric rank-based analysis will be conducted based on the Efficacy Analysis Set for IA 
#2 without complex multiple imputation methodology. Wilcoxon rank sum test will be used for 
the treatment comparison (Ouyang et al., 2017) using the change from baseline eGFR value at 
Week 52 or at last visit prior to Week 52 if subject discontinued.
In the rank-based analysis, subjects will first be ranked on the time point when they last provided
data and then by the value of eGFR change from baseline at that visit (with lower ranks for larger 
eGFR decline). The ranking of change from baseline in eGFR will be from smallest to largest, so 
that the smallest change from baseline in eGFR values will appear first within the subset of subjects 
with the same discontinuation visit.
Once all the rankings are assigned, the change from baseline in eGFR data are converted to a set 
of ranks in which the lower the rank is, the worse the outcome is. In this approach, subjects 
completing Week 52 will be assigned higher ranking than subjects who discontinued the study at 
earlier visit. For example, a subject with a change from baseline at Week 44 visit (last visit before 
discontinuation) which shows improvement in eGFR from baseline will be assigned lower rank 
than subjects who completed Week 52 with a decline in eGFR.
A Wilcoxon rank sum test will then be applied to compare treatment groups using the ranks. If the 
treatment comparison in this rank-based analysis supports the results obtained based on the 
primary analysis of the surrogate efficacy endpoint described in Section 10.1.1, then the 
interpretation is that earlier discontinuation did not introduce substantial bias into the primary 
analysis of the efficacy surrogate endpoint of change from baseline to week 52 in eGFR.
10.3.
Supplementary Analyses for IA #2
The Analysis of covariance (ANCOVA) approach will be used to explore a model with linear 
decline in the slope of eGFR over time as a fixed effect, rather than a categorical mean at each 
visit. This model will replace the categorical nominal visit with the continuous numeric study week 
as defined in Section 8.3.1. Response variable in the model will be eGFR (instead of change from 
baseline in eGFR as in the primary analysis). This analysis will be based on the Efficacy Analysis 
Set for IA #2 and will only include nominal visits up to 52 weeks. In addition to study week, 
following other terms will be included in the model:

Treatment (categorical variable for clazakizumab or placebo)


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
Treatment by study week interaction term

baseline eGFR 

Randomization stratification factor of dichotomized
baseline eGFR (25–45 
mL/min/1.73 m2 versus >45–65 mL/min/1.73 m2)

Randomization stratification factor of baseline proteinuria (UACR <300 mg/g
[<30 mg/mmol] or UACR ≥300 mg/g [≥30 mg/mmol])

Randomization stratification factor of treatment for early (within 6 months of 
transplant) ABMR rejection episodes (yes/no)

Randomization stratification factor of treatment for late (within 6 months of transplant) 
ABMR rejection episodes (yes/no)
The estimated slopes for each treatment, difference of slopes between the treatments and 
corresponding CIs will be presented.
In addition, an analysis will also be conducted using the MMRM (model specified in 
Section 10.1.1) based on the Efficacy Analysis Set for IA #2 (combination of subjects from stage 
1 and stage 2) and will only include nominal visits up to 52 weeks. Missing data will not be 
imputed.
Summary statistics for the mean difference between the treatment groups for change from baseline 
to Week 52 based on the mixed model will be presented along with two-sided 95% confidence 
intervals. Estimated effect size from the model will be also presented.
10.4.
Exploratory analysis of Primary Endpoint of All-Cause Allograft 
Loss or Irreversible loss of allograft function at IA #2
The relationship between eGFR and long-term allograft survival will be further explored by 
extending the results of the joint modelling study to data from the current study. These data will 
be provided to the DSMB at the time of the IA #2 and help inform recommendations for continuing 
or stopping the study and increasing the sample size for the final analysis of all-cause composite 
allograft loss.
Parameter estimates from the joint modeling study will be applied to predict the hazard function 
for all-cause composite allograft loss or irreversible loss of allograft function based on the serial 
eGFR measurements and other independent variables collected during the present study. To reflect 
the uncertainty inherent in the modeling process, several sets of predictions can be generated and 
combined to create an empirical distribution of the hazard ratio.
For a given patient, the survival sub-model from the joint modeling study has the following form:
ℎ_B (C) = ℎ_0 (C) exp[FG + H]
where FG and H are linear predictors based on baseline characteristics and eGFR trajectory 
features, respectively, and ℎ_0 (C) is a piecewise constant baseline hazard function as described 
by Rizopoulos (2012).


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For each prediction set, a random draw from the distribution of parameter estimates in G and 
from the joint modeling study will be taken. The randomly drawn parameter vector will be used to 
calculate the projected hazard rate for each subject as a function of their baseline characteristics 
and observed trajectory of eGFR values. Survival times based on the parameters from the joint 
modeling study can then be compared to the observed time to all-cause composite allograft loss in 
an exploratory manner. 
Using the actual treatment group assignments, the estimates of the log hazard rate will be averaged 
across subjects within a treatment group. Then an estimate of the hazard ratio for clazakizumab 
versus controls will be computed as
ℎ̂(C) = ℎ_0 (C) exp[F ̅_ G ̂ + H ̅_  ̂ −(F ̅_ G ̂ + H ̅_  ̂ )]
where F ̅_ and H ̅_ are averages for the clazakizumab group and F ̅_ and H ̅_ are means from 
the control group. An estimated confidence interval for the hazard ratio using this method can be 
constructed from the empirical distribution of hazard ratios across the set of predictions.
10.5.
Additional Efficacy Analyses
Analysis of eGFR beyond week 52:
Change from baseline to week 52 and week 104 in eGFR, will be conducted using the available 
data at the time of the IA # 2.
A Mixed Model for Repeated Measures (MMRM) analysis will be conducted based on the subjects 
who completed 2 years (104 weeks) in the study. Change from baseline in eGFR through week 
104 will be included. The difference between clazakizumab and placebo for change from baseline 
to week 52 in eGFR will be estimated. The MMRM will include terms specified in Section 10.1.1.
All available eGFR data (through week 52 and beyond) from the subjects in the Efficacy Analysis 
Sets will be summarized by using descriptive statistics at IA #1 and IA #2
Additional Analyses:
In addition, proportion of subjects for individual components of the all-cause composite allograft 
loss will be presented for IA #2 based on all data from Efficacy Analysis Set for IA #2, 

40% decline in eGFR from Baseline that is sustained for at least 60 days.

40% decline in eGFR from Baseline that is sustained for at least 60 days and 
accompanied by investigator’s decision to supplement the therapy by additional 
treatment.

Proportion of subjects who returned to dialysis for at least 60 days.

Proportion of subjects with allograft nephrectomy.

Proportion of subjects who had re-transplantation.

Proportion of subjects with eGFR <15 mL/min/1.73 m2 for at least 60 days.

Proportion of subjects who died.
Proportion of subjects who received any prohibited therapy and medications (Protocol section 
7.6.1) will also be presented.


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10.5.1.
Subgroup Analysis for IA #2
Additional subgroup analyses will be performed for Change from Baseline to Week 52 in eGFR 
to determine whether significant differences exist between subgroups.
These subgroup analyses will be carried out using the subjects from the Efficacy Analysis Set for 
IA #2.
Summary of observed change from Baseline to Week 52 in eGFR will be presented for the 
subgroups. The list of potential subgroups (with applicable definitions in parentheses) includes, 
but is not necessarily limited to, the following:

Age (<65 years vs. ≥65 years)

Sex (Female vs. Male)

Race (white vs. non-white)

Geographic region (North America vs. rest of the world)

eGFR category at Baseline (low [<45 mL/min/1.73 m2] vs. high [≥45 mL/min/1.73 
m2])

Baseline proteinuria (UACR < 300 mg/g [< 30 mg/mmol] or UACR ≥300 mg/g [≥30 
mg/mmol])

Treatment for early (within 6 months of transplant) ABMR rejection episodes 
(yes/no)

Treatment for late (greater than 6 months post-transplant) ABMR rejection episodes 
(yes/no)

Biopsy score categories and DSA will be summarized if the data is available at the 
time of IA # 1 and IA # 2
10.6.
Multiple Comparisons and Multiplicity
The overall type 1 error of 5% for hypothesis testing of change from baseline to week 52 is 
preserved by the two-stage weighted inverse normal test. Test statistics will be calculated from the 
subjects in each of the two stages and combined using the weighted inverse normal method in a 
prespecified way for the testing at IA #2 (refer to Section 4.5 for details on combination test).


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11.
SAFETY ANALYSES
All safety analyses will be based on the safety analysis set as defined in Section 6.4 and summaries 
will include safety assessments specified below.
For by-visit summaries of events, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each visit. For worst post 
baseline summaries of events, the denominator in percentage calculation will be based on the 
number of subjects with at least one non-missing value post baseline.
No formal statistical test on the treatment difference will be performed for any safety analyses.
11.1.
Adverse Events (AEs)
AEs will be coded using the MedDRA dictionary version 25.0 or higher and will be presented 
according to SOC and PT. Treatment-emergent AEs (TEAEs), defined as AEs starting on or after 
the date of the first dose of IP, will be summarized. All AEs regardless of whether they were 
treatment-emergent or not will be listed.
Where AE start dates are missing or partially missing, AEs will be assumed to be treatment-
emergent, except if the partial start dates or the AE end date indicate that the AE started before the 
first administration of IP (Table 5).
Table 5:
TEAE Assignment in Case of Missing AE Start Date Elements
Missing elements of 
AE start
Rule
Regardless of any missing information for AE start:
AE end date < IP start date
non-TEAE
Otherwise (ie, if AE end date ≥ IP start date)
All
TEAE
day and month
AE start year ≥ IP start year
TEAE
AE start year < IP start year
non-TEAE
Day
AE start month / year ≥ IP start month / year
TEAE
AE start month / year < IP start month / year
non-TEAE
If AE start dates or end dates are missing or partially missing for an AE, no duration will be 
calculated. If for a TEAE the relationship to study treatment is missing the worst case will be 
assumed for summarizing analysis (ie, the relationship to study treatment will be assumed to be 
“Yes”). No imputation will be done in case of missing study treatment relationship for non-
treatment emergent AEs. No other imputations for missing AE information will be done.
The Adverse events of special interest (AESIs) are defined in section 10.1.4 of the protocol.


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An overview summary of all AEs, including number and percentages of subjects as well as the 
number of events will be provided including the following:

Any AE

SAE

Fatal AEs

AEs leading to discontinuation of study treatment
Similarly, an overview summary of TEAEs, including number and percentages of subjects as well 
as the number of events will be provided including the following:

Any TEAE

TEAEs related to study treatment

TEAEs leading to discontinuation of study treatment

TEAEs leading to dose interruptions

TEAEs leading to modification to background immunosuppression

TEAE of Severity Grade 3 or Higher

Serious TEAEs

Fatal TEAEs
Following descriptive tables will be generated for AEs including number and percentages of 
subjects and the number of events: 

TEAEs by PT

TEAEs by SOC and PT

Related TEAEs by SOC and PT

AESIs by SOC and PT

Serious TEAEs by PT

Serious TEAEs by SOC and PT

SAEs by SOC and PT
Additionally, number of subjects, exposure-adjusted subject incidence rate per 100 subject-years 
and the number of events will be summarized for TEAEs by PT and Serious TEAEs by PT. 
The exposure-adjusted subject incidence rate per 100 subject-years is calculated as
(Total number of subjects with AE)/(Total treatment exposure in years) * 100
Total treatment exposure in years is the sum of treatment exposure for all subjects where treatment 
exposure is the difference between last dose date and first dose date + 1.


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The following listings will be provided:

All AEs

SAEs

AESIs
11.2.
OVERVIEW OF COVID-19 IMPACT
Number and percentages of subjects with at least one of the following due to COVID-19 will be 
summarized in an overview table:

Subjects with Any COVID-19 Impact,

Protocol Deviations,

Missing Visit,

Alternate Visit Modality,

Study Treatment Discontinuation,

Study Discontinuation,

Any TEAEs,

Any Serious TEAEs.
11.3.
Clinical Laboratory Evaluations
Laboratory data will be presented in SI units. Laboratory values and changes from baseline will 
be summarized descriptively by visit using only values from scheduled visits for following 
laboratory tests (Table 6). Box plots will be produced for change from baseline at each scheduled 
visit. Definition of the baseline assessment is in Section 8.3.3.
Table 6:
List of laboratory tests summarized for DSMB Safety Reviews
Hematology

Hb

Hematocrit

White blood cell count

White blood cell differential (absolute)

Platelet count

RBC
Clinical Chemistry

BUN

Creatinine


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Study Number:             CSL300_3001    
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Hematology

Hb

Hematocrit

White blood cell count

White blood cell differential (absolute)

Platelet count

RBC

Liver function tests (AST, ALT, alkaline 
phosphatase, total bilirubin, indirect bilirubin, 
direct bilirubin, GGT, INR)

Potassium

Sodium

Fasting glucose
Urinalysis

UACR spot urine test

Albumin / Creatinine Ratio
Lipids (serum)

Cholesterol (total, HDL, and LDL)

Triglycerides
Number and percentage of subjects with post baseline laboratory abnormalities (defined in 
Table 7) will be summarized. 


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Study Number:             CSL300_3001    
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Table 7:
Laboratory Values of Potential Clinical Importance
Laboratory Parameter
Abnormality
Unit
Alanine aminotransferase (ALT)
>ULN to 3xULN
>3xULN to 5xULN
>5xULN
U/L
Aspartate aminotransferase (AST)
>ULN to 3xULN
>3xULN to 5xULN
>5xULN
U/L
Bilirubin
>ULN to 2xULN
>2xULN
umol/L
Neutrophils
<2.5 to 1.5
<1.5 to 1
<1
10^9/L
Platelets
<LLN to 75
<75 to 50
<50
10^9/L
11.3.1.
Analysis of Immunoglobulin G (IgG)
Number and percentage of subjects with worst post baseline IgG (400 mg/dl) levels will be 
summarized for following categories. 

< 4.0

≥ 4.0
The denominator in percentage calculation will be based on the number of subjects with at least 
one non-missing value post baseline.
11.4.
Other Safety Measures
11.4.1.
Viral PCR Assay
Subjects with post baseline viral PCR assays for BKV, CMV and EBV greater than the lower limit 
of quantification (LLOQ) will be considered to have an active infection and counted as “positive”. 
The number and percentage of subjects positive for each virus by visit will be summarized.
Number and percentage of subjects with worst post baseline results for following viral load 
categories (


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Study Number:             CSL300_3001    
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Table 8) will be summarized.


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Study Number:             CSL300_3001    
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Table 8:
Categories for BKV, CMV and EBV viral PCR assays
Parameter
Category
BKV (IU/mL)
>LLOQ to <320
≥320 to <3,200
≥3,200*
CMV (IU/mL)
>LLOQ to <1,000
≥1,000 to <5,000
≥5,000
EBV (IU/mL)
>LLOQ to <10,200
≥10,200 to <20,400
≥20,400
* This is ≥ 10,000 copies/mL
11.4.2.
Calcineurin Inhibitor (CNI) levels
CNI trough levels above detectable threshold (>=20 ng/mL for Cyclosporine and >=2 ng/mL for 
Tacrolimus) will be summarized for baseline and post-baseline assessments for Tacrolimus and 
Cyclosporine using descriptive statistics.


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12.
ADDITIONAL ANALYSIS TO SUPPORT REGULATORY 
SUBMISSION FOR EXPEDITED MARKETING APPROVAL
DSMB may recommend for submission to regulatory authorities for expedited marketing approval 
based on the review of results of efficacy analysis at IA #2.
In such a scenario, CSLB regulatory submission team (RST) will initiate submission related 
activities which includes production of planned tables, figures, listings to support regulatory 
submission.
Analyses based on all randomized subjects in DBL for IA #2 
Only summary tables will be provided for the following analyses. No subject level listings will be 
provided for the following summaries.  

Summary (table and figure) of eGFR over time (and change from baseline) for all 
randomized subjects in the DBL for IA#2.

Summary of proportions of subjects with all-cause allograft loss or irreversible loss of 
allograft function (and components) for all randomized subjects in DBL for IA#2.

Safety package based on all randomized subjects included in the DBL for IA#2.

Additional analysis requested by regulatory agencies at pre-submission meetings.
Following analysis will be performed to support submission based on the appropriate analysis set.  
Subject level listings will be provided.

Medical History will be coded using MedDRA dictionary version 25.0 or higher and 
will be summarized by SOC and PT. Summary of medical history will be based on the 
Efficacy Analysis Set for IA #2. 

Prior and Concomitant Medications will be coded using WHO Drug Dictionary 
(March 2022 or later). Prior medications are defined as any therapy used before the day 
of first dose (partial or complete) of IP. Concomitant medications are defined as any 
therapy used on or after the same day as the first dose of IP, including those that started 
before and continue after the first dose of IP. Prior and Concomitant medications will 
be summarized by Anatomical Therapeutic Chemical (ATC) classification level 4 and 
PT. If the ATC level 4 coding is not available for a PT, the next available lower level 
ATC code will be used. Summary of prior and concomitant medications will be based 
on the Efficacy Analysis Set for IA #2.

Exposure to IP will be calculated in months as (last dose date – first dose date + 1 + 
150 days)/30.4375. Exposure will be summarized by treatment group. The total actual 
dose and the total planned dose of IP will be calculated for each subject and 
summarized by treatment group. Treatment compliance will be calculated as (the total 
number of doses received/number of planned doses) x 100% and summarized by 
treatment group. Exposure summaries will be based on the Safety Analysis Set. 


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
Change in Banff lesion grading score of pre-treatment to post-treatment (Week 52) 
kidney biopsies will be summarized by treatment group and will be based on the 
Efficacy Analysis Set for IA #2.

AE summaries in addition to those specified in Section 11.1 may be generated based 
on Safety Analysis Set.

Laboratory parameters in addition to those specified in Table 6 may be summarized. 
Laboratory abnormalities in addition to those specified in Table 7 may be summarized. 
All laboratory data summaries will be based on the Safety Analysis Set.

Health Related Quality of Life (HRQoL) data will be summarized for the following 
scales based on the Efficacy Analysis Set for IA #2: 

EuroQol 5 dimensions questionnaire (EQ-5D-5L): Number and proportion of 
subjects at each response level for each of the 5 domains will be presented by 
treatment group and visit. Mean visual analogue scale (VAS) scores at each time 
point and change from baseline will be summarized by treatment group and visit. 
A comparison of change from baseline in mean VAS scores will be conducted using 
mixed model repeated measures as described in Section 10.1.1 with contrasts for 
the mean change from baseline to Week 24 and from baseline to Week 52. A graph 
should also be provided with a frequency distribution of the percent improvement 
in VAS scores to week 24 and week 52. Health states in the EQ-5D-5L will be 
converted into a single index value using EQ-5D-5L values based on the crosswalk 
[van Hout, 2012] for the UK value set. Index values can also be converted to e 
country specific utility scores using other value sets. The same analyses conducted 
for the VAS scores should also be conducted for the mean utility scores. Mean 
utility scores at each time point and change from baseline will be summarized by 
treatment group and visit. A comparison of change from baseline in mean Index 
scores will be conducted using mixed model repeated measures as described in 
Section 10.1.1 with contrasts for the mean change from baseline to Week 24 and 
from baseline to Week 52. A graph should also be provided with a frequency 
distribution of the percent improvement in Index scores to week 24 and week 52.

Kidney Disease Quality of Life 36 (KDQoL-36): Change from baseline in KDQoL-
36 subscale scores at all visits will be summarized descriptively by treatment group 
and visit. KDQoL-36 Summary Score (KSS), which is a composite of items from 
the KDQoL-36’s kidney targeted scales will also be derived and summarized 
descriptively by treatment group and visit (Peipert et al. 2019). A comparison of 
change from baseline in mean KSS and domain scores will be conducted using 
mixed model repeated measures as described in Section 10.1.1 with contrasts for 
the mean change from baseline to Week 24 and from baseline to Week 52. A graph
should also be provided with a frequency distribution of the percent improvement 
in KSS and domain scores to week 24 and week 52. The domain scores for the 
KDQoL-36 include the physical component score, the mental health component 
score, the burden of kidney disease, symptoms/problems of kidney disease, and 
effects of kidney disease.


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
45

Functional Assessment of Chronic Illness Therapy (FACIT) – Fatigue Scale: Change 
from baseline in FACIT Fatigue score at all visits will be summarized descriptively by 
treatment group and visit. Number and proportion of subjects achieving a minimum 
clinically important difference (MCID) of 3 will be presented by treatment group and 
visit (Cella D. et al 2002) Subject achieves MCID of 3 if the change from baseline in 
the FACIT Fatigue score is ≥ 3. A comparison of change from baseline in mean FACIT 
Fatigue scores as well as a comparison of the proportion of subjects achieving an 
improvement of at least 3 points will be conducted using mixed model repeated 
measures as described in Section 10.1.1 with contrasts for the mean change from 
baseline to Week 24 and from baseline to Week 52.In addition, please provide the 
number of subjects with any HRQoL data and the mean as well as the range of EQ-5D-
5L VAS scores, EQ-5D-5L Index scores, FACIT Fatigue scores, KSS and KDQoL-36 
domain scores at baseline for each of the following GFR categories G2 (60-89), G3a 
(45-59), and G3b (30-44).

PK Concentrations of clazakizumab in serum will be listed and summarized by 
treatment group and nominal timepoints. Standard summary statistics will be 
calculated, including n, arithmetic mean, SD, CV%, median, geometric mean, 
minimum, and maximum. The lower limit of quantification of the clazakizumab PK 
assay is 20 ng/mL. Any pre-dose BLQ and/ or BLQ occurring post-dose but before the 
first quantifiable value will be set to zero. Any BLQ present in the profile or at the end 
of the profile will be treated as missing. If two or more BLQs occur in succession, then 
the profile will be considered to have been terminated at the previous quantifiable 
concentration and all further values will be treated as missing. The mean concentrations 
at any individual time point will be calculated if at least 50% of the individual values 
are available (i.e. are quantifiable and not missing) at given time point otherwise the 
mean value will be reported as ’not calculated (NC). All PK concentration analysis will 
be based on the PK Analysis Set. 

PK Parameters will be determined for subjects in the clazakizumab treatment group 
participating in the PK/PD Substudy. For all derived parameters, except Tmax, the 
following summary statistics will be calculated for the clazakizumab treatment group: 
n, mean, standard deviation [SD], coefficient of variation (CV) defined as STD / 
mean*100%, median, minimum, and maximum, along with geometric mean, geometric 
mean SD, geometric percent coefficient of variation [%CV], and 95% CIs around the 
geometric mean. For Tmax, only n, median, minimum and maximum will be presented.
All PK parameter analysis will be based on the PK/PD Sub-study Analysis Set. The PK 
parameters will be calculated by standard noncompartmental analysis, using 
WinNonlin® versions 5.2 or higher.

PD markers to be evaluated include IL-6 (both total and free levels) and hsCRP. These 
parameters will be summarized by treatment group and visit based on the 
Pharmacodynamic Analysis Set. Additional Biomarkers may be evaluated and reported 
separately.

PK/PD modelling will be explored, as feasible, for further time-dependent 
characterization of PK versus PD endpoints and/or safety/efficacy and reported 


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
46
separately. Additional information on PK/PD analyses will be provided separately in a 
modeling and simulation analysis plan.

Immunogenicity data will be summarized and listed based on the PK analysis set. 
Anti-drug antibody incidence will be calculated and summarized. 


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
47
13.
REFERENCES
Bauer P, Koenig F. The reassessment of trial perspectives from interim data--a critical view. Stat 
Med. 2006; 25(1): 23-36
Cella D, Eton DT, Lai JS, Peterman AH, Merkel DE. Combining Anchor and Distribution-Based 
Methods to Derive Minimal Clinically Important Differences on the Functional Assessment of 
Cancer Therapy (FACT) Anemia and Fatigue Scales; JPSM, 2002; 24:6: 547-561
Lan KK, Wittes J. The B-value: a tool for monitoring data. Biometrics, 1988; 44(2):579–585
Ouyang J, Carroll KJ, Koch G, Li J. Coping with missing data in phase III pivotal registration 
trials: Tolvaptan in subjects with kidney disease, a case study. Pharm Stat. 2017; 16(4):250-266
Peipert J, Nair D, Klicko K, Schatell D, Hays R. Kidney Disease Quality of Life 36-ItemShort 
Form Survey (KDQOL-36) normative values for the United States dialysis population and new 
single summary score. J Am Soc Nephrol. 2019;30(4):654-663
Proschan MA, Lan KK, Wittes JT. Statistical Monitoring of Clinical Trials. A Unified Approach. 
New York: Springer, 2006
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharmaceutical Statisitics, 2013; 12:337
Rizopoulos D. Joint Models for Longitudinal and Time-to-Event Data with Applications in R. Boca 
Raton, FL: CRC Press, 2012.
rpact (2021), “rpact: Confirmatory Adaptive Clinical Trial Design and Analysis,” available at 
https://www.rpact.org/
van Hout B, Janssen MF, Feng YS, Kohlmann T, Busschbach J, Golicki D, Lloyd A, Scalone L, Kind 
P, Pickard AS. Interim scoring for the EQ-5D-5L: mapping the EQ-5D-5L to EQ-5D-3L value sets. 
Value Health. 2012 Jul-Aug;15(5):708-15. 
Wassmer G, Brannath W. Group Sequential and Confirmatory Adaptive Designs in Clinical Trials. 
Switzerland: Springer Series in Biopharmaceutical Statistics, 2016


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
48
14.
APPENDICES
14.1.
Figures for DSMB at IA #1
The following figures show examples of figures for DSMB review based on observed effect size 
at stage 1 (IA #1) and a range of possible effect size at stage 2. The two horizontal reference lines 
have been provided corresponding to the planned (N2 = 80) and the maximum number of 
randomized subjects (N2 = 250, as stated in protocol) required from stage 2
Example 1: 
Figure 3 shows the proposed figure if the observed effect size estimated from the MMRM at IA 
#1 is 0.45. The following figure has been generated using this observed effect size at stage 1 and 
assumed effect size in stage 2 (range 0.30 to 0.54). The three lines represent additional subjects to 
be randomized at stage 2 for conditional powers 90%, 85% and 80% for testing the efficacy 
endpoint at IA #2.
Figure 3:
Sample figure for DSMB based on hypothetical observed effect size 0.45 at 
IA #1
Please note that if effect size at stage 2 is similar to the effect size observed at stage 1 (0.45), then 
there is no need to increase from planned sample size of 180 randomized subjects with 52 weeks 
of follow-up at IA #2. All three curves corresponding to the conditional powers are below the 
horizontal line of N2 = 80 around the effect size of 0.45.


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
49
In this case, DSMB is expected to recommend continuing the study as planned without increasing 
the sample size for IA #2.
Example 2:
Figure 4:
Sample figure for DSMB based on hypothetical observed effect size 0.35 at 
stage 1 (IA #1) and assumed effect size of 0.30 to 0.54 in stage 2 
In this case, it appears from the figure that more than 150 additional randomized subjects will be 
needed at stage 2 if the effect size at stage 2 remains similar to the observed effect size at stage 1 
with conditional power of 90%. DSMB recommendation of whether to continue the study is based 
on the review of totality of information presented at IA #1. It appears from the figure that the study 
could continue with the planned maximum number of randomizations (150) at stage 2, assuming
similar effect size at stage 1 and stage 2 and conditional power is approximately 85% 
more optimistic effect size from the subjects at stage 2 and conditional power remains at 90%.
In this case, if DSMB is making a recommendation to continue the study based on the totality of 
data then a recommendation about the sample size for IA #2 is also needed. The recommended 
sample size for IA #2 could be the maximum allowed sample size of 250 randomized subjects or 
lower.


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
50
Example 3:
Figure 5:
Sample figure for DSMB based on hypothetical observed effect size 0.25 at 
stage 1 (IA #1) and assumed effect size of 0.30 to 0.54 in stage 2
In this case, it appears that IA #2 with the planned maximum sample size of 250 randomized 
subjects with 52 weeks of follow-up is not adequate with reasonable conditional power or 
assumption of effect size at stage 2 (all the curves corresponding to conditional power are above 
the reference line of N2 = 150, even for the assumed effect size of 0.35 for IA #2). DSMB is 
expected to recommend stopping further randomization. The final decision to stop the study will 
be confirmed by CSLB senior management.


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Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
51
14.2.
R Code for Simulated Overall Power at IA #2 Using rpact R Package
# Specify inverse normal design
designIN <- getDesignInverseNormal(typeOfDesign = "asUser", beta=0.1, 
informationRates = c(0.5556, 1), userAlphaSpending = c(0.00, 0.025))
# Simulation for overall power
n1 = 100    # Size of Stage 1, both arms
n2 = 80     # Size of Stage 2, planned, both arms
N = n1 + n2 # Total planned sample size
Nmax = 250  # Total maximum sample size
simCpower <- getSimulationMeans(designIN, thetaH0 = 0, 
             alternative = 0.488, # "True" value used for simulating data
             plannedSubjects = c(n1, N), # Cumulative overall sample size
             conditionalPower = 0.9,
             minNumberOfSubjectsPerStage = c(n1, n2), #stage-wise min overall 
sample size
             maxNumberOfSubjectsPerStage = c(n1, Nmax-n1), # stage-wise max 
overall sample size
                maxNumberOfIterations = 10000,   # Number of simulations
                                seed = 12347)    # Random seed
14.3.
SAS Code for MMRM Analysis Using PROC MIXED
proc mixed data=egfr2 order=data;
  where visit ne 'Visit 2'; *remove baseline visit;
  class subjid treatdesc visit randbegfr randbprot randearlytrt    
  randlatetrt;
  model change = treatdesc visit randbegfr randbprot randearlytrt   
  randlatetrt treatdesc*visit base/s DDFM=KR;
  repeated visit / type= UN subject=subjid;
  lsmeans treatdesc*visit / diff cl ;
  ods output Estimates=est;
run;
Where, response variable ‘change’ is change from baseline in eGFR; treatdesc = Clazakizumab or 
Placebo; visit=nominal post baseline visits; ‘randbegfr’, ‘randbprot’, ‘randearlytrt’, ‘randlatetrt’ 
are the stratification factors; DDFM=KR requests the Kenward-Roger method for the covariance 
matrix if unstructured covariance structure is used. 
DDFM option should not be specified if other covariance structure is used.
14.4.
Tipping Point Analysis Using Delta Adjustment Method
The delta adjustment method described by Ratitch et al (2013) will be implemented using the 
following steps:
1. Create a dataset with one record per subject, containing values of AVAL for all weeks 
(Baseline and Weeks 4–52) on one record, where AVALx represents the analysis value of 
eGFR at month X (where month = week/4, ranging from 1 to 13). 
2. Run 25 Markov Chain Monte Carlo (MCMC) imputations to make the missing values in 
the dataset have a monotone missingness pattern. This will produce a dataset with an index 


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
52
variable _Imputation_ and otherwise the same variables as the input dataset. It will 
have one record per imputation per subject. 
3. Run a pattern mixture model regression imputation using MNAR statement in SAS on each 
imputed dataset from step 2. Apply delta penalty (by subtracting eGFR values) using 
SHIFT option to all post baseline visits in clazakizumab arm. This will generate a dataset 
with the same structure as the input dataset for each delta but will have the missing values 
filled in and delta penalty applied. 
4. Transpose data in longitudinal format.
5. Run the primary MMRM analysis on the imputed datasets, once for each imputation. This 
will create 25 estimates of the output statistics. 
6. Combine the 25 estimates to generate the test statistic and p-value. 
7. Repeat steps 1–6 for a range of eGFR values. eGFR values will start from 0 in the increment 
of -0.5 until the p-value is >=0.05. For example, from 0 to –4 by –0.5. 
Steps 2–7 may be implemented using SAS code similar to the following. 
%macro miparms( data=, smin=, smax=, sinc=, outparms=);
data &outparms;
  set _null_;
run;
/*# of shift values*/
%let ncase= %sysevalf( (&smax-&smin)/&sinc, ceil );
/*Multiple imputation analysis for each shift*/
%do jc=0 %to &ncase;
%let sj= %sysevalf( &smin + &jc * &sinc);
/* step 2: Impute intermitent missing variables to create monotone 
missingness with MCMC */
proc mi data=&data seed=81431864 nimpute=25 out=outdata1; 
  by trtp; 
  mcmc impute=monotone; 
  var AVAL1- AVAL4; 
run;
proc sort data=outdata1;
  by _Imputation_; 
run;  
/* step 3: Impute all visits under MNAR first, then apply delta adjustments 
at each visit */
proc mi data=outdata1 seed=74358221 nimpute=1 out=outdata2; 
  by _Imputation_; 
  class treatdesc; 


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
53
  monotone reg(AVAL2-AVAL4 / details); 
  mnar ADJUST(AVAL2 / SHIFT=-&sj ADJUSTOBS=(TREATDESC =' Clazakizumab ')); 
  mnar ADJUST(AVAL3 / SHIFT=-&sj ADJUSTOBS=(TREATDESC =' Clazakizumab ')); 
  mnar ADJUST(AVAL4 / SHIFT=-&sj ADJUSTOBS=(TREATDESC =' Clazakizumab ')); 
  var treatdesc AVAL2-AVAL4; 
run;
/* step 4: convert data in log and skinny format, calculate change from 
baseline */
proc sort data=outdata2;
  by _Imputation_ subjid treatdesc;
run;
proc transpose data=outdata2 out=outdata3;
  by _Imputation_ subjid treatdesc;
  var AVAL1-AVAL4;
run; 
data outdata4;
  set outdata3;
  visit=input(compress(_name_, "y"),best.);
  aval=col1;
  drop _name_ col1;
run;
data base;
set outdata4;
where visit=1;
base=aval;
keep _Imputation_ subjid base;
run;
proc sort data=base;
by _Imputation_ subjid;
proc sort data=outdata4;
by _Imputation_ subjid;
run;
data outdata5;
merge outdata4 base;
by _Imputation_ subjid;
change=aval-base;
run;
proc sort data=outdata5;
  by _Imputation treatdesc visit subjid;
run;
/* step 4: Analyze data for imputation using MMRM */
proc mixed data=outdata5 order=data;
  by _Imputation_;
  where visit ne 'Visit 2'; *remove baseline visit;
  class subjid treatdesc visit randbegfr randbprot randearlytrt    
  randlatetrt;


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
54
  model change = treatdesc visit randbegfr randbprot randearlytrt   
  randlatetrt treatdesc*visit base/s DDFM=KR;
  repeated visit / type= UN subject=subjid;
  lsmeans treatdesc*visit / diff cl ;
  estimate 'Visit 6 (Claza-pbo)' treatdesc -1 1 treatdesc*visit 0 0 -1 0 0 
  1/cl;
  ods output Estimates=est;
run;
/* step 5: Combine estimates for inference */
proc mianalyze data=est;
  modeleffects estimate;
  stderr;
  ods output parameterestimates=miparm;
run;
data miparm;
  set miparm;
  shift= -&sj;
run;
/*Output multiple imputation results*/
data &outparms;
  set &outparms miparm;
run;
%end;
%mend miparms;
/*Assume that the tipping point for the shift parameter that reverses the
study conclusion is between 0 and 4. The following statement performs
multiple imputation analysis for each of the shift parameters 0,-0.5, -1,  -
1.5,…,-4*/
ods listing close;
%miparms(data=pr_trans, smin=0, smax=4, sinc=0.5, outparms=parms1);


CSL 
Study Number:             CSL300_3001    
Study Product: CSL300, clazakizumab
55
14.5.
Analysis Under Each Analysis Set
Analysis Set
Baseline and 
Demography
All 
Interim 
Effiacy
Safety 
Analyses
PK 
Concentration
PK 
Parameters
PD
Efficacy
X
X
Per-protocol
X*
Safety
X
PK
X
PD
X
PK/PD Sub-
study
X
X
*Sensitivity analysis only


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CSL300_3001 - Statistical Analysis Plan -
Statistical Analysis Plan for Interim Analysis
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Approved-
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16-Aug-2023 18:16:03
Approved-
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17-Aug-2023 10:44:59
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