Clinical trial NCT02547220
Conditions: Acute Antibody-Mediated Rejection (AMR)
Sponsor: Shire
Start date: 2016-05-20; Completion date: 2019-05-31
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of the study is to evaluate the efficacy of CINRYZE administered with plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free immunoglobulin (IVIg) for the treatment of acute antibody-mediated rejection (AMR) of renal allograft in kidney transplant recipients as measured by the proportion of participants with new or worsening transplant glomerulopathy (TG) at 6 months after treatment initiation.

Detailed description:

Arms: arm 1: Participants will receive 5000 Units of CINRYZE (50 millilitre \[mL\] of CINRYZE/ 50 mL of normal saline) on Day 1 and 2500 Units of CINRYZE (25 mL of CINRYZE/ 75 mL of normal saline) on Day 3, 5, 7, 9, 11, and 13 respectively. arm 2: Participants will receive 7 doses of matched placebo over 13 days of treatment.
Interventions: intervention 1: Cinryze® intervention 2: Placebo
Intervention descriptions: intervention 1: Participants will receive 5000 Units of CINRYZE (50 millilitre \[mL\] of CINRYZE/ 50 mL of normal saline) on Day 1 and 2500 Units of CINRYZE (25 mL of CINRYZE/ 75 mL of normal saline) on Day 3, 5, 7, 9, 11, and 13 respectively. intervention 2: Participants will receive 7 doses of matched placebo over 13 days of treatment.

Protocol documents:
Prot_000.pdf: 
PROTOCOL:  SHP616-302
TITLE:
A randomized double-blind placebo-controlled study to evaluate the 
efficacy and safety of CINRYZE® (C1 esterase inhibitor [human]) for the 
treatment of acute antibody-mediated rejection in kidney transplant 
patients
DRUG:
SHP616, C1 esterase inhibitor [human]
IND:
IND 16417
EUDRACT NO.:
2015-000726-11
SPONSOR:
Shire ViroPharma, Inc.
300 Shire Way, Lexington, MA  02421 USA
INVESTIGATORS:
Multicenter
PROTOCOL 
HISTORY:
Amendment 4: 22 Nov 2017
Amendment 3: 01 Sep 2016
Amendment 2:  25 Jun 2015
Amendment 1:  28 May 2015
Original Protocol:  01 Apr 2015
This document contains confidential and proprietary information of Shire ViroPharma, Inc. and is disclosed 
pursuant to confidentiality and non-disclosure obligations.  This information should be used solely for the purposes 
for which it was provided and should not be copied, shared with, or disclosed to any third party without the express 
written consent of Shire ViroPharma, Inc.


PROTOCOL SIGNATURE PAGE 
Sponsor's (Shire ViroPharma, Inc.) Approval 
---
-
--
Investigator's Acknowledgement 
---,
--
I have read this protocol for Shire ViroPharma Study SHP616-302. 
Title: A randomized double-blind placebo-controlled study to evaluate the efficacy and safety of 
CINRYZE® (Cl esterase inhibitor [human]) for the treatment of acute antibody-mediated rejection 
in kidney transplant patients. 
I have fully discussed the objective(s) of this study and the contents of this protocol with the 
sponsor's representative. 
I understand that the infonnation in this protocol is confidential and should not be disclosed, 
other than to those directly involved in the execution or the scientific/ethical review of the study, 
without written authorization from the sponsor. It is, however, permissible to provide the 
information contained herein to a subject in order to obtain their consent to participate. 
I agree to conduct this study according to this protocol and to comply with its requirements, 
subject to ethical and safety considerations and guidelines, and to conduct the study in 
accordance with International Conference on Harmonisation guidelines on Good Clinical 
Practice and with the applicable regulatory requirements. 
I understand that failure to comply with the requirements of the protocol may lead to the 
termination of my participation as an investigator for this study. 
I understand that the sponsor may decide to suspend or prematurely terminate the study at any 
time for whatever reason; such a decision will be communicated to me in writing. Conversely, 
should I decide to withdraw from execution of the study I will communicate my intention 
immediately in writing to the sponsor. 
Investigator Name and Address: 
(please hand print or type) 
Signature: ---------------------------- Date: 
Shire ViroPharma, Inc. 
CONFIDENTIAL 
Page 2  
Protocol SHP616-302 
C1 inhibitor, human 
 
22 Nov 2017 
 
 


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C1 inhibitor, human
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AMENDMENT SUMMARY AND RATIONALE
Clinical protocol SHP616-302 has been amended to provide increased clarity and guidance to 
investigational sites on the exclusion of subjects with a medical history that would render them 
ineligible for study participation. Exclusion criteria on history of thrombotic/thromboembolic 
events have been clarified to better define the patient population. Guidance to provide additional 
clarity on study procedures has been included without actual change to those procedures. 
Changes include clarification of laboratory testing requirements and other study testing. 
Clarification regarding treatment discontinuation and implementation of the stopping rules has 
been provided. 
Changes in grammar, spelling, punctuation, format, minor editorial changes, and updates to the 
list of abbreviations and cross-references have been made for consistency and clarity and are not 
reflected in the summary of changes.
SUMMARY OF CHANGES FROM PREVIOUS VERSION
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
22 Nov 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
Updated the high-level amendment summary and rationale to provide a general 
overview and justification of amendment revisions
Amendment Summary and 
Rationale
Updated the emergency contact information
Emergency Contact 
Information
Section 8.2.2
Updated the planned study period and provided rationale for extension.
Rationale: Study period will be longer than expected due to slow enrollment in this 
rare disease
Synopsis
Section 3.1
Updated/clarified as follows:

“Randomization via IV/WRS" changed to "Screening Registration / 
Randomization via IV/WRS (IRT) and added to rescreening visit

Central and local lab requirements clarified 

BUN and Serum Cr updated to Serum Cr, BUN and eGFR

BUN and serum creatinine to be tested at all visits, including recurrent 
AMR, Day 1 and Day 13 and clarification provided on the purpose of the 
first Serum Cr after biopsy

“Proteinuria Spot Urine Protein to Cr Ratio” updated to “Urine Protein, 
Urine Creatinine and Urine Protein/Urine Creatinine Ratio”

Renal allograft assessment procedure added to screening visit
Rationale: IRT and lab description term changes for consistency in terminology 
used in the IRT system and by Central lab, respectively; clarifications of Central vs 
Local labs to make it consistent and clear throughout the protocol
Synopsis
Study Schedules, Table 1
Section 7
Section 9.8.2.2


Shire ViroPharma, Inc.
CONFIDENTIAL
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Protocol SHP616-302
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22 Nov 2017
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
22 Nov 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
Updated/clarified as follows:

Central and local lab requirements clarified 

BUN and Serum Cr updated to Serum Cr, BUN and eGFR

“Proteinuria Spot Urine Protein to Cr Ratio” updated to “Urine Protein, 
Urine Creatinine and Urine Protein/Urine Creatinine Ratio”

Anti-C1 INH antibody testing updated for Month 3 to be performed without 
regard to positivity of previous result
Rationale: For consistency in terminology between lab and protocol; Month 3 Anti-
C1 INH not dependent on previous result as it is needed for proper detection and 
monitoring of immunogenic response
Synopsis
Study Schedules, Table 2
Section 7
Clarified the Study Design as follows:

Retreatment of recurrent AMR episodes may occur  “during the first 180 
days after the qualifying biopsy for AMR”, which was updated from 
“during the first 6 months of the study”
Rationale: To avoid confusion with the window of the Month 6 visit, the time to 
allow retreatment was set to 180 days
Synopsis
Section 3.1
Section 6.2.3
Section 7.2.2.2
Section 7.2.2.4
Section 7.2.3.5.2
Schedule of Assessments, 
Table 1
Updated exclusion criteria as follows:

Exclusion criterion #3: clarified that double kidney transplant procedure is 
considered to be one procedure
Rationale: frequently asked clarification from clinical sites.

Exclusion criterion #7: removed transient ischemic attack (TIA) to be 
included in exclusion criterion #8, clarified exclusion criteria of myocardial 
infarction and treatment with anticoagulants

Exclusion criterion #8: clarified and detailed exclusion criterion of history 
of abnormal bleeding, clotting events or disorders, and coagulopathy
Rationale: request from DMC to clarify criteria to ensure exclusion of subjects with 
the above thrombotic/thromboembolic events

Exclusion criterion #12: time frame for exclusionary range of platelet was 
updated to 24 hours
Rationale: To make window consistent with WBC in order to assess eligibility from 
one hematology time point
Synopsis
Section 4.2
Section 7.2.3.1
Stopping rules provided in more detail:

Listed events leading to stop of enrollment of new subjects

Specified process for DMC safety review of such events
Rationale: To specify the clinically significant events, consistently with Section 
8.2.4 in the protocol that trigger the stopping rule
Synopsis
Section 3.1
Section 4.5.3
Section 9.5.2


Shire ViroPharma, Inc.
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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
4
Amendment Date
22 Nov 2017
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
Updated definition of Pharmacokinetic (PK) and Pharmacodynamic (PD) Analysis 
Set.
Rationale: The definition was updated as the previous wording raised questions 
regarding the interpretation of the measured PK/PD concentrations or levels. 
Synopsis
Section 9.7
Clarified procedure for subjects discontinuing from treatment, but not from the study.
Rationale: To maintain sequence of visits if subjects discontinue from treatment only, 
and to allow for safety data collection shortly after discontinuation
Section 3.2
Section 4.5
Clarified what new findings identified during the physical examination at screening 
should be considered adverse events as opposed to medical history
Rationale: To clarify what adverse events may fall within the adverse event 
collection window between consent and the physical examination at screening, and 
are not considered medical history.
Section 7.2.3.2
Section 7.2.3.3.
Reporting of events of special interest updated
Rationale: To clarify how to report non-serious events of special interest via the SAE 
form
Section 8.1.4
Serious Adverse Event procedure for thrombotic and thromboembolic events updated 
Rationale: To clarify that superficial thrombophlebitis, dialysis access clotting, or 
catheter-related thrombotic events can be reported as serious via SAE form if they 
meet SAE definition
Section 8.2.4
Correction of typographical error: Units for eGFR MDRD value updated from 
mL/min/1.72m2 to mL/min/1.73m2)
Throughout protocol
See Appendix 1 for protocol history, including all amendments.


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22 Nov 2017
EMERGENCY CONTACT INFORMATION
Please refer to Section 8.2.2 for additional information on serious adverse event reporting.  
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Trial Serious 
Adverse Event Form within 24 hours to the Shire Pharmacovigilance Department and the PPD 
Clinical Study mailbox. Applicable fax numbers and e-mail address can be found on the form 
(sent under separate cover) and are provided below. 
US and Canadian Sites
Fax: 
Email: 
AND
 (email should include 
both addresses)
EU/ROW Sites
Fax: 
Email:
AND
 (email should include 
both addresses)
For protocol- or safety-related issues, the investigator must contact the Shire / PPD 
Medical Monitor (please refer to the study-specific contact list):
 (Shire Medical Monitor)
Email:


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire ViroPharma 
product (marketed or investigational) does not meet expectations (eg, inadequate or faulty 
closure, product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please report all Product Quality Complaints to:
300 Shire Way, Lexington, MA 02421 USA


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
AMENDMENT SUMMARY AND RATIONALE ........................................................................3
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................6
PRODUCT QUALITY COMPLAINTS..........................................................................................7
TABLE OF CONTENTS.................................................................................................................8
LIST OF TABLES.........................................................................................................................13
LIST OF FIGURES .......................................................................................................................13
ABBREVIATIONS .......................................................................................................................14
STUDY SYNOPSIS ......................................................................................................................16
STUDY SCHEDULES..................................................................................................................26
1.
BACKGROUND INFORMATION.......................................................................................32
1.1
Preclinical Experience..............................................................................................32
1.2
Indication and Current Treatment Options...............................................................33
1.3
Product Background and Clinical Information ........................................................34
1.3.1
Clinical Experience with Hereditary Angioedema ................................................35
1.3.2
Clinical Experience with Antibody-mediated Rejection .......................................35
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................37
2.1
Rationale...................................................................................................................37
2.1.1
Rationale for the Study ..........................................................................................37
2.1.2
Rationale for Dose Selection .................................................................................37
2.2
Study Objectives ......................................................................................................39
2.2.1
Primary Objective..................................................................................................39
2.2.2
Secondary Objectives.............................................................................................39
2.2.3
Exploratory Objectives ..........................................................................................39
3.
STUDY DESIGN ...................................................................................................................40
3.1
Study Design and Flow Chart ..................................................................................40
3.2
Duration and Study Completion Definition .............................................................44
3.3
Sites and Regions .....................................................................................................45
4.
STUDY POPULATION.........................................................................................................46
4.1
Inclusion Criteria......................................................................................................46
4.2
Exclusion Criteria.....................................................................................................47
4.3
Restrictions...............................................................................................................48
4.4
Reproductive Potential .............................................................................................48
4.4.1
Female Contraception............................................................................................48
4.4.2
Male Contraception................................................................................................49


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4.5
Discontinuation or Withdrawal of Subjects .............................................................49
4.5.1
Reasons for Discontinuation and/or Withdrawal...................................................50
4.5.2
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit..................................50
4.5.3
Stopping Rules.......................................................................................................50
5.
CONCOMITANT AND POST-TREATMENT MEDICATIONS ........................................52
5.1
Concomitant Medications ........................................................................................52
5.2
Concomitant Blood Products ...................................................................................52
5.3
Immunosuppressive Agents or Treatments..............................................................52
5.4
Prohibited Medications ............................................................................................53
5.5
Other Medications....................................................................................................53
6.
INVESTIGATIONAL PRODUCT ........................................................................................54
6.1
Identity of Investigational Product...........................................................................54
6.1.1
Blinding the Treatment Assignment......................................................................54
6.1.2
Commercially Obtained Investigational Product...................................................54
6.2
Administration of Investigational Product(s)...........................................................54
6.2.1
Interactive Voice/Web Response System Technology for Investigational 
Product Management .............................................................................................55
6.2.2
Allocation of Subjects to Treatment ......................................................................55
6.2.3
Dosing....................................................................................................................55
6.2.4
Unblinding the Treatment Assignment..................................................................56
6.3
Labeling, Packaging, Storage, and Handling ...........................................................56
6.3.1
Labeling .................................................................................................................56
6.3.2
Packaging...............................................................................................................57
6.3.3
Storage ...................................................................................................................57
6.4
Drug Accountability.................................................................................................58
6.5
Subject Compliance..................................................................................................58
7.
STUDY PROCEDURES........................................................................................................59
7.1
Study Schedule.........................................................................................................59
7.1.1
Screening Period....................................................................................................59
7.1.2
Investigational Product Administration Period......................................................60
7.1.2.1
Day 1 ......................................................................................................60
7.1.2.2
Days 3, 5, 7, 9, and 11............................................................................61
7.1.2.3
Day 13 ....................................................................................................62
7.1.3
Post-Treatment Follow-Up Period.........................................................................63
7.1.3.1
Day 25 (±48 hours).................................................................................63
7.1.3.2
Month 3 (±21 days)................................................................................63
7.1.3.3
Month 6 (±21 days)................................................................................64
7.1.3.4
Months 12 (±21 days), Months 18, 24, 30, 36, 42 (all ±28 days)..........64


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7.1.3.5
EOS Visit/Month 48 [±28 days] or at patient discontinuation if after 
Month 6 Visit .........................................................................................65
7.1.3.6
Early Discontinuation Visit: Discontinuation between End of 
Investigational Product Dosing (Day 13) and Month 6 (not 
applicable if discontinuation is from treatment only) ............................65
7.1.4
Additional Care of Subjects After the Study .........................................................65
7.2
Study Evaluations and Procedures ...........................................................................66
7.2.1
Demographic and Other Baseline Characteristics .................................................66
7.2.2
Efficacy..................................................................................................................66
7.2.2.1
Donor-specific Antibody Identification .................................................66
7.2.2.2
Renal Allograft Biopsies ........................................................................66
7.2.2.3
Resolution of Qualifying and Recurrent AMR Episodes.......................68
7.2.2.4
Recurrence of AMR During the First 180 days of the Study.................69
7.2.2.5
Allograft Failure.....................................................................................69
7.2.2.6
Splenectomy...........................................................................................69
7.2.2.7
Subject Survival Status...........................................................................69
7.2.2.8
Donor-specific Antibody Reduction Treatments and Intravenous 
Immunoglobulin.....................................................................................70
7.2.3
Safety .....................................................................................................................70
7.2.3.1
Medical History......................................................................................70
7.2.3.2
Physical Examination (Including Height and Weight) ..........................71
7.2.3.3
Adverse Event Collection.......................................................................72
7.2.3.4
Vital Signs..............................................................................................72
7.2.3.5
Clinical Laboratory Evaluations.............................................................73
7.2.3.6
Pregnancy Test .......................................................................................75
7.2.3.7
Electrocardiogram ..................................................................................76
7.2.4
Others.....................................................................................................................76
7.2.4.1
Pharmacokinetic/Pharmacodynamic Assessments.................................76
7.2.4.2
Health Outcomes and Outcomes Research Assessments.......................76
7.2.4.3
Healthcare Resource Utilization.............................................................76
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................77
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................77
8.1.1
Severity Categorization..........................................................................................77
8.1.2
Relationship Categorization...................................................................................78
8.1.3
Outcome Categorization ........................................................................................78
8.1.4
Adverse Events of Special Interest ........................................................................79
8.1.5
Symptoms of the Disease Under Study .................................................................79
8.1.6
Clinical Laboratory and Other Safety Evaluations................................................79


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8.1.7
Pregnancy...............................................................................................................80
8.1.8
Abuse, Misuse, Overdose, and Medication Error..................................................80
8.2
Serious Adverse Event Procedures ..........................................................................81
8.2.1
Reference Safety Information................................................................................81
8.2.2
Reporting Procedures.............................................................................................81
8.2.3
Serious Adverse Event Definition .........................................................................82
8.2.4
Thrombotic or Thromboembolic Events................................................................82
8.2.5
Serious Adverse Event Collection Time Frame.....................................................83
8.2.6
Serious Adverse Event Onset and Resolution Dates .............................................83
8.2.7
Fatal Outcome........................................................................................................83
8.2.8
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................84
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................85
9.1
Data Collection.........................................................................................................85
9.2
Clinical Data Management.......................................................................................85
9.3
Data Handling Considerations .................................................................................85
9.4
Statistical Analysis Process......................................................................................85
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......86
9.5.1
Interim Analysis and Adaptive Design..................................................................86
9.5.2
Data Monitoring Committee..................................................................................87
9.5.3
Endpoint Adjudication Committee ........................................................................88
9.5.3.1
Pathology Endpoint Adjudication Committee .......................................88
9.5.3.2
Nephrology Endpoint Adjudication Committee ....................................88
9.6
Sample Size Calculation and Power Considerations................................................88
9.7
Study Population ......................................................................................................89
9.8
Efficacy Analyses.....................................................................................................90
9.8.1
Primary Efficacy Endpoint ....................................................................................90
9.8.2
Secondary Efficacy Endpoints...............................................................................91
9.8.2.1
Key Secondary Efficacy Endpoint .........................................................91
9.8.2.2
Secondary Efficacy Endpoints ...............................................................91
9.8.2.3
Secondary efficacy endpoints from study entry to 4 years are 
defined as: ..............................................................................................92
9.8.3
Exploratory Efficacy Endpoints.............................................................................92
9.9
Safety Analyses........................................................................................................93
9.10
Pharmacokinetic/Pharmacodynamic Endpoints.......................................................93
9.11
Health Economics and Outcomes Endpoints ...........................................................94
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...........................................95
10.1
Sponsor’s Responsibilities .......................................................................................95


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10.1.1 Good Clinical Practice Compliance.......................................................................95
10.1.2 Indemnity/Liability and Insurance.........................................................................95
10.1.3 Public Posting of Study Information......................................................................95
10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................95
10.1.5 Study Suspension, Termination, and Completion..................................................96
10.2
Investigator’s Responsibilities .................................................................................96
10.2.1 Good Clinical Practice Compliance.......................................................................96
10.2.2 Protocol Adherence and Investigator Agreement..................................................96
10.2.3 Documentation and Retention of Records.............................................................97
10.2.3.1
Case Report Forms.................................................................................97
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................97
10.2.3.3
Audit/Inspection.....................................................................................98
10.2.3.4
Financial Disclosure...............................................................................98
10.3
Ethical Considerations..............................................................................................98
10.3.1 Informed Consent...................................................................................................98
10.3.2 Institutional Review Board or Ethics Committee..................................................99
10.4
Privacy and Confidentiality......................................................................................99
10.5
Study Results / Publication Policy .........................................................................100
11. REFERENCES .....................................................................................................................102
12. APPENDICES ......................................................................................................................105
Appendix 1
Protocol History ...................................................................................106
Appendix 2
Banff Classification of Renal Allograf Biopsy (2013 Update)............114
Appendix 3
Scales and Assessments .......................................................................116
Appendix 4
Recommended Procedures for Suspected Thrombotic or 
Thromboembolic Events .....................................................................117


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LIST OF TABLES
Table 1
Schedule of Assessments (Screening through Day 25).................................26
Table 2
Schedule of Assessments (Month 3 through Month 48 [End of Study])a .....29
Table 3
Blood Sample Collection Time Points for Pharmacokinetic/   
Pharmacodynamic Testing (All Subjects).....................................................31
Table 4
Investigational Product Dosing Day, Volume and Amount.........................55
LIST OF FIGURES
Figure 1
Study Design Flow Chart ..............................................................................44


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ABBREVIATIONS
ABO
blood type
ADR
expected adverse reaction
AE
adverse event
AESI
adverse event of special interest
AMR
antibody-mediated rejection (of renal allograft)
beta-HCG
beta human chorionic gonadotropin
BMI
body mass index
BUN
blood urea nitrogen
C1 INH
C1 inhibitor
C3a
anaphylatoxin split product of C3 activation important in chemotaxis
C4d
4th complement protein degradation product
C5a
anaphylatoxin split product of C5 activation important for histamine release 
and chemotaxis
CBC
complete blood count
cg
chronic glomerulopathy (cg score is based on published Banff criteria)
CL
clearance
Cmax
maximum concentration
Cmin
minimum concentration
CP
conditional power
Cr
creatinine
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
DMC
data monitoring committee
DSA
donor-specific antibody
DVT
deep vein thrombosis
EAC
Endpoint Adjudication Committee
EC
ethics committee
ECG
electrocardiogram
eGFR
estimated glomerular filtration rate
EM
electron microscopy
EMA
European Medicines Agency
EOS
end of study (visit)
EQ-5D-5L
EuroQoL Group 5-Dimension 5-Level Self-Report Questionnaire
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
g
glomerulitis
GBM
glomerular basement membrane
GCP
Good Clinical Practice
HAE
hereditary angioedema
HIPAA
Health Insurance Portability and Accountability Act
HLA
human leukocyte antigen


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HRU
healthcare resource utilization
HSCT
hematopoietic stem cell transplant
ICH
International Conference on Harmonisation
IRB
Institutional Review Board
IV
intravenous
IVIg
intravenous immunoglobulin
IV/WRS
Interactive Voice/Web Response System
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities Terminology
MI
myocardial infarction
PRA
panel reactive antibody
PTC
peritubular capillaries
PVRM
pharmacovigilance and risk management
rhC1INH
recombinant human C1 inhibitor
RSI
reference safety information
SAE
serious adverse event
SAP
statistical analysis plan
SC
subcutaneous
TEAE
treatment-emergent adverse event
TG
transplant glomerulopathy
TIA
transient ischemic attack
t1/2
terminal half-life
tmax
time of maximum observed concentration sampled during a dosing interval
US
United States
WBC
white blood cell (count)


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Protocol SHP616-302
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22 Nov 2017
STUDY SYNOPSIS
Protocol number: SHP616-302
Drug: C1 esterase inhibitor 
[human]
Title of the study: A randomized double-blind placebo-controlled study to evaluate the efficacy and safety of 
CINRYZE® (C1 esterase inhibitor [human]) for the treatment of acute antibody-mediated rejection in kidney 
transplant patients.
Number of subjects (total and for each treatment arm):
Approximately 112 subjects are planned for randomization (56 for each treatment arm) to ensure 100 subjects 
complete; sample size may be increased based on the interim analysis for sample size re-estimation.
Investigator(s): Multicenter study
Site(s) and Region(s): 
Approximately 40 sites planned in North America and the European Union 
Study period (planned):
Enrollment was originally expected to occur from 2015 through 2017; however, 
it will be extended since enrollment was found to be slower than expected and 
the sample size may increase following the first interim analysis for sample size 
re-estimation. Subjects could be followed for up to a maximum of 4 years.
Clinical phase:
3
Objectives:
Primary: To evaluate the efficacy of CINRYZE administered with plasmapheresis, plasma exchange, or immune 
adsorption treatments and sucrose-free intravenous immunoglobulin (IVIg) for the treatment of acute antibody-
mediated rejection (AMR) of renal allograft in kidney transplant recipients as measured by the proportion of 
subjects with new or worsening transplant glomerulopathy (TG) at 6 months after treatment initiation.
Key Secondary: To evaluate the efficacy of CINRYZE administered with plasmapheresis, plasma exchange, or 
immune adsorption treatments and sucrose-free IVIg for the treatment of acute AMR of renal allograft in kidney 
transplant recipients as measured by the proportion of subjects with all-cause graft failure at 4 years following 
treatment initiation for the initial qualifying AMR episode.
Secondary:
Secondary objectives from study entry to 6 months:

To assess renal function

To assess proteinuria

To assess change in histopathology

To assess graft outcomes
Secondary objectives from study entry to graft failure or 4 years:

To assess renal function

To assess proteinuria

To assess graft outcomes

To assess resolution of AMR

To assess safety and tolerability of CINRYZE in kidney transplant recipients

To assess subject survival status 


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Exploratory:
Rationale:  Since AMR results in complement-mediated damage to a transplant, the sponsor hypothesized that a 
complement inhibitor such as plasma-derived C1 inhibitor (C1 INH) could effectively protect a renal allograft while 
reduction of DSA is achieved with standard-of-care plasmapheresis, plasma exchange, or immune adsorption 
treatments with sucrose-free IVIg, resulting in less long-term damage to the kidney and prolonged graft survival.
Investigational product, dose, and mode of administration:

CINRYZE: an initial intravenous (IV) infusion of 5000 U CINRYZE  on Day 1, followed by 2500 U of 
CINRYZE  IV on Days 3, 5, 7, 9, 11, and 13

Placebo (0.9% sodium chloride for infusion): an IV infusion on Days 1, 3, 5, 7, 9, 11, and 13 (100 mL)
Methodology:
This randomized, double-blind, placebo-controlled multicenter, multinational study will assess the efficacy and 
safety of CINRYZE with protocol-mandated DSA reduction treatment and sucrose-free IVIg for the treatment of acute 
AMR in kidney transplant recipients. Eligible study subjects will have had a kidney transplant with adequate 
function defined as having a pre-AMR baseline eGFRMDRD ≥20 mL/min/1.73m2 if the qualifying AMR episode 
occurs ≤21 days after transplant or pre-AMR baseline eGFRMDRD ≥30 mL/min/1.73m2 if the qualifying AMR 
episode occurs >21 days after transplant. The pre-AMR baseline is the highest eGFRMDRD value obtained following 
the kidney transplant and within 30 days prior to the biopsy for the qualifying AMR episode. If more than 
1 eGFRMDRD value is available, a mean of the 2 highest values (at least 1 day apart and both prior to the AMR 
episode) will be used as the pre-AMR baseline value. If no eGFRMDRD was obtained within 30 days prior to the 
biopsy for the qualifying AMR episode, it can be evaluated within a 60-day period.
The qualifying episode of biopsy-proven AMR will be defined by 2013 Banff criteria and will have evidence of 
circulating DSA. Once the qualifying AMR episode is diagnosed through a biopsy, subjects will enter a screening 
period for additional eligibility assessments at the investigative site. During this screening period, the first 
eGFRMDRD value obtained after the qualifying biopsy should be used for the screening visit period. Biopsy slides 
and images (including, but not limited to EM) will be sent to an independent, blinded pathology Endpoint 
Adjudication Committee (EAC) for confirmation of AMR. Subjects will be stratified across centers for (1) living vs 
deceased donor and (2) severity of acute AMR as defined by screening period eGFRMDRD (≤15 mL/min/1.73m2 for 
severe, or >15 mL/min/1.73m2 for mild to moderate). CINRYZE or placebo treatment should be started as soon as 
possible and within 7 days after the biopsy procedure.
Approximately 112 eligible subjects with biopsy-proven AMR will be randomized (56 per treatment arm) to receive 
either CINRYZE or placebo in a 1:1 ratio after being stratified for (1) living vs deceased donor and (2) severity of 
acute AMR as described above. Additional eligible subjects may be enrolled and randomized based on the interim 
data analysis of the first 30 subjects who complete the Month 6 TG assessment for the re-estimation of sample size. 
During the study treatment period, subjects will receive a total of 7 doses of investigational product over 13 days in 
addition to protocol-mandated DSA reduction treatment and sucrose-free IVIg for each qualifying episode of AMR. 
To minimize variability, the use of DSA reduction treatments and sucrose-free IVIg for the treatment of AMR will 
be administered as mentioned below. 


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Protocol SHP616-302
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22 Nov 2017
Donor-specific Antibody Reduction Treatment: Subjects will be required to receive a minimum of 5 plasmapheresis, 
plasma exchange, or immune adsorption treatments from the time of diagnostic biopsy for qualifying episode of 
acute AMR through Study Day 13. Each DSA reduction treatment will be followed by sucrose-free IVIg (no less 
than 100 mg/kg). Additional DSA reduction treatments and sucrose-free IVIg may be administered at the discretion 
of the investigator as per local standard of care. NOTE: If plasmapheresis, plasma exchange, or immune adsorption 
treatment occurs on the same day as investigational product dosing, investigational product will be administered 
after completion of the DSA reduction therapy session and dosing of sucrose-free IVIg. Collection of blood samples 
for laboratory testing (other than those specified on Table 3) will be performed prior to each DSA reduction 
treatment, if performed. 
As shown in Table 2, in addition to the qualifying kidney biopsy, an additional kidney biopsy will be obtained at the 
Month 6 study visit. See Section 7.2.2.2 for details. Biopsy slides and pertinent micrographs (including, but not 
limited to EM images) for the qualifying and Month 6 biopsies will be provided to an independent, blinded 
pathology EAC for confirmation of AMR diagnosis and the assessment of the primary endpoint (new or worsening 
TG at 6 months of initiation of treatment). 
 
 
Subjects will remain in the study until the clinical confirmatory endpoint of all-cause graft failure is evaluated up to 
a maximum of 4 years. Graft failure is evaluated by the nephrology EAC. Graft failure, for the purpose of this study, 
will be defined as 1 or more of the following: (1) institution of permanent dialysis (defined as dialysis treatment 
>30 days), (2) current transplant nephrectomy, or (3) clinical determination of cessation of kidney graft function and 
eGRFMDRD ≤15 mL/min/1.73m2. If a subject is discontinued for any reason prior to the Month 6 follow-up Visit, 
every effort will be made to obtain adverse events (AEs), serum blood urea nitrogen (BUN) and creatinine (Cr) 
results, eGFRMDRD, and a biopsy to send slides and images to the pathology and nephrology EACs for 
determination of TG and graft function status respectively (see Table 2 for Early Discontinuation Visit procedures). 
If a subject is discontinued for any reason prior to the end of the study at 4 years, every effort will be made to obtain 
AEs, serum BUN and Cr and eGFRMDRD results to send to the nephrology EAC for determination of graft function 
status (see Table 2 for End of Study Visit procedures).
There will be 3 analyses (2 interim, 1 final) of proportions of subjects with all-cause graft failure, at approximately 
50% (~26 events), 75% (~39 events), and 100% (~51 events) of the study data. Following the Month 6 evaluation, 
subjects will enter a long-term follow-up stage of the protocol, which will include allograft function evaluations 
every 6 months up to a maximum of 4 years. The duration of the study will be event driven, and is based upon an 
assumption that there will be approximately 51 all-cause graft failures. The study will continue until 51 such events 
are accrued and adjudicated by the nephrology EAC. However the maximum amount of time each subject will be 
followed in the study will be 4 years post initial treatment with investigational product. See Section 9.5.2 for 
additional details.
Resolution: Resolution will be achieved when, after treatment, the local eGFRMDRD value increases to at least 
within 20% or above the eGFRMDRD value collected as a pre-AMR baseline. If an AMR episode is diagnosed, in 
absence of significant decline (≥20%) of eGFR from pre-AMR baseline, a follow-up biopsy within 3 months is 
recommended in order to assess resolution. Resolution is defined initially by the local pathologist according to 
histological findings, and later confirmed by the pathology EAC, and should be based on improvement from 
previous biopsy and characterized by Banff criteria as: glomerulitis (g + ptc) <2 if C4d-negative; (g + ptc) = 0 if 
C4d-positive. The investigator will record the applicable eGFRMDRD values and the date of resolution of the 
qualifying and recurrent AMR episodes in the CRF, when applicable, including the criteria used for determination of 
resolution (clinically and/or through histopathology). 
Recurrence: Recurrence is defined as biopsy-proven new evidence of AMR upon resolution of the previous AMR 
episode. Investigators will also be asked to record the date of recurrence of AMR, when applicable. During the first
180 days after the qualifying biopsy, if the qualifying AMR episode resolves and there is new biopsy-proven acute 
AMR per protocol definition in the inclusion criteria, the subject may be retreated at the investigative site with the 
same investigational product to which they were originally randomized as well as DSA reduction treatment and 
sucrose-free IVIg per protocol. 


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Protocol SHP616-302
C1 inhibitor, human
22 Nov 2017
Between the qualifying biopsy that is diagnostic for a recurrent episode of AMR and the first retreatment dose of 
investigational product, subjects will complete a subset of the screening procedures as indicated in Table 1. Subjects 
will follow the assessments noted in Table 1 and Table 2. For each new episode of AMR occurring during the first 
180 days after the qualifying biopsy. Retreatment should occur as soon as possible within 7 days of the biopsy that 
defined the new AMR episode. Retreatment may not occur for recurrent AMR episodes diagnosed through biopsies 
done after the first 180 days after the qualifying biopsy date. Biopsies at 6 months following retreatment are not 
required to be performed by the protocol. The only mandated follow-up biopsy will be at Month 6 after initial 
treatment. With the exception of the Month 6 biopsy, completion of follow-up biopsies after the qualifying AMR 
episode is at the discretion of the study sites per local standard of care. Biopsy slides and images for unscheduled 
standard of care biopsies will also be submitted to the EAC.
The effect on the quality of life will be measured by using the EuroQoL Group 5-Dimension 5-Level Self-Report 
Questionnaire (EQ-5D-5L). The effect on healthcare utilization will also be assessed.
Complement and C1 INH levels will be assessed at specified time points up to Day 13 for 
pharmacokinetic/pharmacodynamic evaluation (Table 2 and Table 3).
Safety will be monitored through the recording of AEs and changes in physical examinations, vital signs, antibodies 
to C1 INH, and clinical safety laboratory testing. Adverse events and serious adverse events (SAEs) will be recorded 
from the time the informed consent is signed through 30 days after the last dose of investigational product regardless 
of relationship to study treatment. Following the 30-day capture period for all AEs and SAEs, only those AEs/SAEs 
deemed related to investigational product or other protocol-mandated procedures will be collected during the 
long-term follow-up phase of the study. If the subject undergoes retreatment with investigational product for a new 
AMR episode, AEs and SAEs will also be captured as described above for the treatment of the initial occurrence of 
AMR. In addition, the following adverse events of special interest (AESI) will be closely monitored, both serious 
and non-serious, and reported throughout the study to Shire Pharmacovigilance and Risk Management (PVRM) via 
SAE form, regardless of relationship to investigational product: 

any thrombotic or thromboembolic event (Section 8.2.4)

any hypersensitivity reaction

any new episode of kidney allograft rejection (excluding AMR), even if the event does not qualify for 
retreatment with investigational product

any kidney allograft failure
Stopping rules: If clinically significant drug-related thrombotic or thromboembolic events (as defined in Section 
4.5.3) are reported as a study-drug-related SAE, enrollment will be halted (See Section 4.5.3). The DMC will review 
the case and will issue a recommendation to the Sponsor with regard to re-starting enrollment.
The schedules of study procedures are provided immediately following the synopsis:
Table 1: Schedule of Assessment (Screening though Day 25)
Table 2: Schedule of Assessments (Month 3 through Month 48 [End of Study] 
Table 3: Blood Sample Collection Time Points for Pharmacokinetic/Pharmacodynamic Testing (All Subjects)
See the study design flow chart below.


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Protocol SHP616-302
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Graft failure1 
up to 4 yearsn 
a: Biopsy-proven AMR 72 hours to 12m onths after current transplant. 
b: Subjects \vill havea minimwn of 5 DSAreduction treatments 
(plasm a pheresis, plasm a ex change, or im m wte adsorption treatm ents) 
each followed by sucrose-free IVIgfor each qualifyingAMR episode. 
DSA reduction treatm entsiiVIgm ay be pro>i ded as part of standard of 
care prior to study entry. 
c: first dose of i·tvestigational product (Day I) must be administered 
" ithin 7 daysafter qualifying biopsy. 
d: Additional new episodes of acute AMR may be retreated if subject is 
eligible after screeningforre-treatm ent and if the biopsy 
the new AMR occurs during the first ISO days after the qualifying 
biopsy date. Treatment must be \Vith the same investigational product 
assignm en! (CINRYZE or Placebo) to which the subject was originally 
randomized in addition to DSA reduction treatment and sucrose-free 
IVIgperprotocol. 
e: Day 25: (± 2 days) afterflli1 dose of investigational product. Renal 
fwtction \Vill.:>e assessed at this visit. 
f: Month 3: (± 21 days) afterflli1 dose of investigational product. 
g 6-Month Post-Treatm en! Biopsy: (± 2 1 days) relative to first dose of 
investigational product: Arena! allograft biopsy " ill be obtained. 
h: Subjects \vill be assessed every 6 m onthsup to 4 years. At these visits, 
renal fwtction \Vill be detenn ined as well as graft failure (yes/no). 


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Protocol SHP616-302
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Inclusion and exclusion criteria:
Inclusion Criteria:
To be eligible for this protocol, a subject must:
1.
Be 18 and ≤70 years of age.
2.
Weigh 45 kg with a body mass index (BMI) <35 kg/m2 at screening.
3.
Have HLA DSA identified at the time of diagnosis of AMR. If it is anticipated that the local DSA results 
will not be available within the screening period, previously obtained local DSA results can be used to 
assess eligibility, if obtained after kidney transplant and within 30 days prior to the qualifying AMR 
episode. In any instance, a local DSA test should still be performed at the time of AMR diagnosis.
4.
Have a first qualifying episode of AMR in the subject’s current renal allograft between 72 hours and 
12 months after transplant defined by a renal allograft biopsy demonstrating neutrophil and/or monocyte 
infiltration in the peritubular capillaries and/or glomeruli with or without evidence of C4d by 
immunohistopathology according to 2013 Banff criteria for AMR.
5.
Have achieved adequate renal function defined as: Pre-AMR baseline eGFRMDRD ≥20 mL/min/1.73m2 for a 
qualifying AMR episode occurring ≤21 days after transplant or pre-AMR baseline eGFRMDRD ≥30 
mL/min/1.73m2 for a qualifying AMR episode occurring >21 days after transplant. The pre-AMR baseline 
is the highest eGFRMDRD value obtained following the kidney transplant and within 30 days prior to the 
qualifying AMR episode. If more than one eGFRMDRD value is available, a mean of the 2 highest values (at 
least 1 day apart and both prior to the AMR episode) will be used as the pre-AMR baseline value. If no 
eGFRMDRD was obtained within 30 days prior to biopsy, it can be evaluated within a 60 day period. 
6.
Receive first dose of investigational product after 7 days after the kidney transplant procedure and within 
7 days after the qualifying renal allograft biopsy procedure that was positive for AMR.
7.
Be informed of the nature of the study and provide written informed consent before any study-specific 
procedures are performed.
8.
If female and of child-bearing potential, must have a negative urine pregnancy test confirmed by a negative 
serum beta human chorionic gonadotropin pregnancy test at the Screening Visit and must have a negative 
urine pregnancy test at the Day 1 visit.
9.
Agree to comply with any applicable contraceptive requirements of the protocol.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Have received pediatric en bloc kidney transplant.
2.
Have primary Focal Segmental Glomerulosclerosis, rapidly progressive glomerulonephritis, 
membrano-proliferative glomerulonephritis type 1 (including C3 Glomerulopathy), “dense deposit 
disease”, or thrombotic microangiopathy as the cause of native kidney failure. 
3.
Have prior or concurrent non-renal solid organ transplant or hematopoietic stem cell transplant (HSCT) or 
have more than 2 completed kidney transplant procedures (note: 1 double kidney transplant procedure is 
considered 1 procedure) .
4.
Have a known neoplastic lesion in the transplanted allograft.
5.
Have, any ongoing infection that causes hemodynamic compromise or as determined by the investigator, 
any surgical or medical condition that could interfere with the administration of investigational product, 
interpretation of study results, or could compromise patient safety, including (as determined by the 
transplanting surgeon and documented in the operative report) any major technical complications of the 
renal artery, renal vein, or ureteral anastomosis.


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6.
Have ongoing treatment for hepatitis C virus (HCV) infection.
7.
Have had a recent myocardial infarction (MI) within the past 6 months and/or at the time of screening are 
treated with anticoagulants and/or antiplatelet agents (excluding aspirin) for a previous myocardial 
infarction.
8.
Have a history of:

abnormal bleeding,

clotting events or disorders (excluding a history of clotted hemodialysis access or superficial 
thrombophlebitis in the absence of medically confirmed coagulopathy),

any coagulopathy (documented or clinically suspected)
For example patients should be excluded if they have a history of renal allograft arterial or venous 
thrombosis, deep vein thrombosis, pulmonary embolism, ischemic cerebrovascular accident (stroke) or 
transient ischemic attack (TIA), any large vessel thrombosis.
9.
Have a history of allergic reaction to CINRYZE or other blood products.
10. Have had any change in androgen therapy (eg, danazol, oxandrolone, stanozolol, testosterone), tranexamic 
acid, epsilon-aminocaproic acid, or other fibrinolytics within 3 months before the first dose of 
investigational product.
11. Have participated in the active dosing phase of any other investigational drug study within 30 days prior to 
dosing with investigational product.
12. Have any of the following local laboratory values reported prior to dosing with investigational product:

Within 24 hours prior to subject dosing, white blood cell count <0.5×109/L or >20×109/L (the value of 
>20 x 109/L should be excluded if obtained during steroid treatment)

Within 24 hours prior to dosing , platelet count <25×109/L or >600×109/L
13. Be pregnant or breastfeeding.
14. Have received any of the following agents within 1 month prior to the first dose of investigational product:

Sucrose-containing IVIg

Any C1 INH (plasma-derived [eg, CINRYZE®, Berinert®, Cetor®] or recombinant [eg, Rhucin®])

Eculizumab (Soliris®)

Ecallantide (Kalbitor®)
Maximum duration of subject involvement in the study:

Planned duration of screening period: up to 7 days

Planned duration of investigational product administration period: 13 days

Planned duration of post-treatment evaluations: up to 4 years
Endpoints and statistical analysis:
Subject Populations:
The All-enrolled Set will consist of subjects who have signed informed consent.
The Intent-to-Treat Population will consist of all subjects in the All-enrolled Set for whom a randomization 
number has been assigned. This set will be used for sensitivity analyses of efficacy endpoints.
The Full Analysis Set (FAS) will consist of all subjects who have taken at least 1 dose of investigational product. 
The FAS will be used for efficacy analysis according to assigned treatment.
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of investigational product. The 
Safety Analysis Set will be used for safety analysis according to actual treatment received.
The Per Protocol Analysis Set-1 will consist of all subjects in the FAS who have taken at least 5 of the 7 planned 


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doses, are assessed for TG at 6 months after initiation of treatment or have post-baseline biopsy-proven new or 
worsening TG within 6 months of initiation of treatment, and do not have predefined major protocol deviations that 
may affect the primary efficacy endpoint.
The Per Protocol Analysis Set-2 will consist of all subjects in the FAS who have taken at least 5 of the 7 planned 
doses, are assessed for graft failure at 4 years, or have shown graft failure within 4 years, or died, and do not have 
predefined major protocol deviations that may affect the key secondary endpoint.
The Pharmacokinetic (PK) and Pharmacodynamic (PD) Analysis Set is defined as all subjects who received at 
least 1 dose of CINRYZE and have at least 1 evaluable post-dose PK/PD concentration value.
Primary Efficacy Endpoint: 
Proportion of subjects with new or worsening TG at 6 months after treatment initiation as determined by Banff 
criteria.
Key Secondary Efficacy Endpoint: 
Proportion of subjects with all-cause graft failure (ie, return to permanent dialysis and/or removal of the transplanted 
kidney and/or clinical determination of cessation of graft function) at 4 years following treatment of the initial 
qualifying AMR episode.
Secondary Efficacy Endpoints from study entry to 6 months:

Measurement of renal function (eGFRMDRD) at 6 months

Change in renal function (eGFRMDRD) from pre-AMR to 6 months 

Change in renal function (eGFRMDRD) from screening to 6 months

Measurement of proteinuria (spot urine protein , urine creatinine, and urine protein/urine creatinine ratio) at 
6 months

Change in proteinuria (spot urine protein, urine creatinine, and urine protein/urine creatinine ratio) from 
screening to 6 months

Change in histopathology per Banff criteria from pre-AMR to 6 months

Proportion of subjects with  all-cause graft failure at 6 months
Secondary Efficacy Endpoints from study entry to 4 years:

Measurement of renal function (eGFRMDRD) and change from pre-AMR baseline and screening at 1, 2, 3, 
and 4 years following the qualifying AMR episode

Measurement of proteinuria (spot urine protein , urine creatinine, and urine protein/urine creatinine ratio) 
and change from screening at 1, 2, 3, and 4 years following the qualifying AMR episode

Proportion of subjects with graft failure due to AMR at 4 years

Time to all-cause graft failure

Time to graft failure due to AMR

Proportion of subjects with resolution of the qualifying AMR episodes

Time to resolution of AMR episodes

Proportion of subjects alive at 4 years 

Time to all-cause mortality


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Exploratory Endpoints:
Safety Endpoints:

Assessment of treatment-emergent adverse events (TEAEs), vital signs measurements, antibodies to C1 
INH, and clinical safety laboratory testing
Pharmacokinetic/Pharmacodynamic Endpoints:

Analysis of serum complement factors (anaphylatoxin split product of C3 activation important in 
chemotaxis [C3a] and anaphylatoxin split product of C5 activation important for histamine release and 
chemotaxis [C5a]) and their potential relationship to C1 INH concentrations

Analysis of the pharmacokinetics of CINRYZE and the effect of plasmapheresis, plasma exchange, or 
immune adsorption treatments and sucrose-free IVIg for the treatment of AMR on C1 INH levels
Health Economics and Outcomes Endpoints:

Measurement of the EQ-5D-5L

Measurement of healthcare resource utilization (HRU)
Primary hypothesis and statistical model used to analyze the primary efficacy endpoint:
The FAS population will be used to report the primary efficacy data. Subjects who do not have the primary efficacy 
endpoint assessed at 6 months post-dose will be assigned as failures. The primary endpoint will be presented as the 
proportion of subjects with new or worsening TG occurring at 6 months post-treatment, and their difference between 
treatments (
Placebo
Cinryze

) is defined as follows:
Placebo
Cinryze
Placebo
Cinryze






Where 
Cinryze

is the proportion of subjects with new or worsening TG at 6 months post-treatment in the CINRYZE
group and 
Placebo

is the proportion of subjects with new or worsening TG at 6 months post-treatment in the 
placebo group.  
The analysis will employ a type I error rate of 0.025 (1-sided test) to test null hypothesis:
0
:
0




Placebo
Cinryze
H
Against the 1-sided alternative:
0
:




Placebo
Cinryze
a
H
In the initial plan, the statistical difference between treatments will be evaluated by the CHW weighted test statistics 
CHW
Z
(Cui et al. 1999) when the first 60 subjects complete the assessments for the primary endpoint (second 
interim analysis). If the 
0249
.0
Z
Z CHW 
(equivalent to the p-value from the test is 0.0249 [1-sided test]), it will be 
concluded that CINRYZE is efficacious based on the proportion of subjects with new or worsening TG at 6 months 
post-treatment and the result will serve as evidence of efficacy based on these 60 subjects. However, the number of 
subjects might be changed (increased) depending on the results of the first interim analysis in which the sample size 
will be re-estimated based on the first 30 subjects who complete the Month 6 TG assessment.


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Design features are in place to protect the study-wise error level at 0.025 (1-sided test) for testing the hypotheses 
related to primary and key secondary endpoints. As, for declaration of a successful study, statistical significance 
must be declared successively on the surrogate endpoint of proportions of subjects with new or worsening TG at 
6 months post-treatment and on the endpoint of all-cause graft failure. No adjustment for multiple co-primary 
endpoints is needed. The alpha spent at each endpoint will be controlled by sequential testing boundaries assuring 
that no more than 0.025 alpha (1-sided test) is expended in the multiple analyses across time for each of the primary 
and key secondary endpoints.
Safety variables and analysis:
Safety endpoints include TEAEs, vital signs measurements, antibodies to C1 INH, and clinical safety laboratory 
testing. The safety analysis set will be used to report the safety data. Treatment-emergent AEs will be summarized 
according to the coded MedDRA preferred term and system organ class. Treatment-emergent AEs will be further 
summarized by severity and relationship to investigational product. Treatment-emergent AEs leading to withdrawal, 
SAEs, and deaths will be similarly summarized and listed. Clinical laboratory tests, vital signs, and antibodies to 
C1 INH will be summarized. Potentially clinically significant laboratory values will also be summarized and listed.


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STUDY SCHEDULES
Table 1 Schedule of Assessments (Screening through Day 25)
Study Procedure
(Screening)a
Investigational Product Administration Period
Post-Treatment 
Evaluations
1st
Episode
Retreatment
(recurrent AMR) 
within 180 days
Day 1a
Day 3
Day 5
Day 7
Day 9
Day 11
Day 13
Day 25 
(±48 hours)
Informed consent

Medical history, presence/absence of diabetes


Inclusion/exclusion eligibility
a
a
b
Screening Registration/Randomization via 
IV/WRS (IRT)


b
Physical examination


b
Lower extremity examination c


b







Height


Body weight


b







Vital signs (BP, HR) d 


b







12-lead ECG e

Central lab Pregnancy testing (also local lab serum and 
urine pregnancy test at screening, and local urine test on Day 1)  f


b
Central lab Virology screen


Central lab Hematology (also local lab WBC and platelets
at screening) g


b


Central lab clinical chemistry gs


b

BUN & Serum Cr with eGFR (both central lab [included 
in chemistry when applicable] and local lab) g
h
h








Central lab Proteinuria: Spot urine protein, urine 
Cr and urine protein/urine creatinine ratio



Kidney allograft biopsy, submission of  pathology 
slides/images i


Central lab Pharmacokinetic/Pharmacodynamic 
Testing j



Central lab Immunogenicity (anti-C1 INH 
antibodies)
k

Central lab DSA identification (also local lab at 
screening)  l



DSA reduction treatments & sucrose-free IVIg m
---------------------------------------------------------------------------------------------------------------
Investigational product administration n







Concomitant medications 


-----------------------------------------------------------------------------------------------------------------o 
p
Adverse event monitoring q
--------------------------------------------------------------------------------------------------------------------------------------
Renal allograft assessment r

-------------------------------------------------------------------------------------------------------------------------


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Table 1 Schedule of Assessments (Screening through Day 25)
Study Procedure
(Screening)a
Investigational Product Administration Period
Post-Treatment 
Evaluations
1st
Episode
Retreatment
(recurrent AMR) 
within 180 days
Day 1a
Day 3
Day 5
Day 7
Day 9
Day 11
Day 13
Day 25 
(±48 hours)
Subject survival status
--------------------------------------------------------------------------------------------------------------------------
EQ-5D-5L


Healthcare Resource Utilization









AE=adverse event; AMR=antibody-mediated rejection; BP=blood pressure; BUN=blood urea nitrogen; C1 INH=C1 inhibitor; Cr=creatinine; DSA=donor-specific antibody; 
ECG=electrocardiogram; eGFRMDRD=estimated glomerular filtration rate calculated by the Modification of Diet in Renal Disease; EQ-5D-5L= EuroQoL Group 5-Dimension 
5-Level Self–report Questionnaire; HR=heart rate; IVIg=intravenous immunoglobulin; IV/WRS=interactive voice/web randomization system; SAE=serious adverse event
a Local laboratory testing will be used to determine subject eligibility. Limited inclusion/exclusion criteria are checked at screening for retreatment only if the investigator plans to retreat (retreatment is 
only allowed for New AMR episodes diagnosed within the first 180 days after the qualifying biopsy, and if the previous AMR episode resolved).
b Day 1 procedures to be completed prior to the first dose of investigational product.
c A lower extremity exam will be performed and will include a determination of presence or absence of unilateral calf tenderness or leg swelling.  If a deep vein thrombosis is 
suspected, a diagnostic exam will be performed.
d On investigational product dosing days, vital signs should be obtained within 30 minutes prior to investigational product administration and then between 30 minutes and 1 hour 
after completion of investigational product infusion.  Additional vital signs measurements will be performed during the study if clinically indicated.
e During the study, additional ECGs will be performed if clinically indicated.
f  Females of child-bearing potential will have  urine and serum pregnancy tests at Screening and urine pregnancy test on Day 1 of each episode.
g On investigational product dosing days, blood samples for clinical safety laboratory testing should be collected prior to administration of investigational product. Local 
laboratory hematology results (WBC and platelets) will be used to assess eligibility at screening. Central laboratory BUN and creatinine results are included where a sample is 
taken for clinical chemistry. Local laboratory results for BUN and creatinine (including eGFRMDRD calculation) are required at all study visits, as well as pre-AMR and resolution 
of AMR for all AMR episodes.
h At screening, the first creatinine value obtained after the qualifying biopsy (or recurrent AMR biopsy if applicable) should be used as the screening creatinine and eGFR values 
to assess AMR severity for stratification.
i Qualifying renal allograft biopsy for assessment of histologic parameters associated with AMR. In the event that the subject has a new episode of AMR as defined in Section 
7.2.2.4, the subject may be retreated with the same treatment to which they were previously randomized and following the procedures outlined in Table 1, beginning at Day 1 
with the exception of randomization and limited inclusion/exclusion criteria. For each biopsy, the pathology slides and images are to be submitted.
j Blood samples for pharmacokinetic/pharmacodynamic analysis will be collected at the time points specified in Table 3.
k If sucrose-free IVIg is administered on the same day as the screening visit, blood samples for immunogenicity should be obtained both prior to and after sucrose-free IVIg administration. Subjects 
where anti-C1 INH antibodies are detected will be followed until negative.
l DSA antibody will be determined by central and local laboratory analysis at screening (for initial or recurrent episode of AMR), and only by the central laboratory at all other 
time points specified. DSA testing may be performed locally at other time points after screening for all clinical assessments as part of standard of care. Additional serum may be 
collected by the central laboratory for future antibody and titer testing.
m Subjects will have a minimum of 5 plasmapheresis, plasma exchange, or immune adsorption treatments each followed by sucrose-free IVIg from the time of diagnostic biopsy 
for qualifying episode of acute AMR through Study Day 13. Plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free IVIg may be provided as part 
of standard of care prior to study entry. Protocol-mandated plasmapheresis, plasma exchange, or immune adsorption treatments should be completed by Day 13. Additional DSA 
reduction treatments or doses of sucrose-free IVIg may be administered at the discretion of the investigator as part of standard of care.


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Table 1 Schedule of Assessments (Screening through Day 25)
Study Procedure
(Screening)a
Investigational Product Administration Period
Post-Treatment 
Evaluations
1st
Episode
Retreatment
(recurrent AMR) 
within 180 days
Day 1a
Day 3
Day 5
Day 7
Day 9
Day 11
Day 13
Day 25 
(±48 hours)
n A total of 7 doses of investigational product will be administered: an initial IV infusion of 5000 U CINRYZE or placebo on Day 1, followed by 2500 U of CINRYZE or placebo IV 
on Days 3, 5, 7, 9, 11, and 13. If plasmapheresis, plasma exchange, or immune adsorption treatments therapy occurs on the same day as investigational product dosing, 
investigational product will be administered after completion of the DSA reduction therapy session and administration of sucrose-free IVIg.
o All medications (and selected blood products) taken from the day of the first dose of investigational product (Day 1) through the day of the last dose of investigational product (Day 13) will be 
recorded. In addition, medications used to treat AEs, SAEs, and adverse events of special interest (AESI) from time of informed consent through 30 days after the last dose of investigational product 
for each treatment period will also be recorded.
p The following medications will be collected for the duration of the study: Any IV steroids, Rituximab, Muromonab-CD3, Alemtuzumab, Anti-thymocyte globulin (rabbit), 
Lymphocyte immune globulin, anti-thymocyte globulin (equine), any IV immunoglobulin preparation, Daclizumab or basiliximab. See Section 5.5 for additional medications to 
record.
q Adverse events and SAEs will be recorded from the time of Informed Consent through 30 days after the last dose of investigational product regardless of relationship to study 
treatment. Following the 30-day capture period for all AEs and SAEs, only AE/SAEs deemed related to investigational product or other protocol-mandated procedures, as well as 
the following AESIs regardless of relationship to investigational product: any hypersensitivity reaction, any thrombotic or thromboembolic event, any new episode of kidney 
allograft rejection (excluding AMR) even if the event does not qualify for retreatment with investigational product, and any kidney allograft failure, will be collected during the 
long-term follow-up phase of the study.
r Renal allograft function will be assessed by eGFRMDRD. Allograft failure and need for splenectomy will be assessed at all timepoints.
s Clinical chemistry includes BUN and serum creatinine


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Table 2
Schedule of Assessments (Month 3 through Month 48 [End of Study])a
Study Procedure
Post-Treatment Evaluations
Month 3 
(±21 days)b
Month 6 
(±21 days)b
Month 12 
(±21 days)b
Month 18 
(±28 days)b
Month 24 
(±28 days)b
Month 30 
(±28 days)b
Month 36 
(±28 days)b
Month 42 
(±28 days)b
Early 
Discontinuation 
Visit Between 
Day 13 & Month 
6
EOS/Month 48 
or at patient 
discontinuation 
if after Month 6 
(±28 days)b
Presence/absence of diabetes


Body Weight










BUN & Serum Cr with eGFR 
(both central and  local lab)
c










Central lab Proteinuria:Spot 
urine protein, urine Cr and 
urine protein/urine creatinine 
ratio 










Kidney allograft biopsy & 
submission of pathology slides 
& images d


Central lab Immunogenicity 
(anti-C1 INH antibodies)


e
e
e
e
e
e
e
Central lab DSA identification 
f










Concomitant medications g










Adverse event monitoring h










Renal allograft assessment










Subject survival status










EQ-5D-5L









Health Resource Utilization









BUN=blood urea nitrogen; C1 INH=C1 inhibitor; Cr=creatinine; DSA=donor-specific antibody; eGFRMDRD=estimated glomerular filtration rate calculated by the Modification of 
Diet in Renal Disease; EOS=End of Study Visit; EQ-5D-5L= EuroQoL Group 5-Dimension 5-Level Self–report Questionnaire; SAE=serious adverse event; TG=transplant 
glomerulopathy
a The duration of the study will be event driven, and is based upon an assumption that there will be approximately 51 all-cause graft failures including death. The trial will continue 
until 51 such events are accrued and adjudicated by the independent, blinded nephrology EAC. See Section 9.5.1 for additional details. However the maximum amount of time 
each subject will be followed in the study will be 4 years post initial treatment with investigational product. Subjects will complete visits every 6 months until the study is ended. If 
the study is stopped prior to the last enrolled subject completing Month 48, all subjects who have not reached Month 48 will be asked to return to the investigational site for their 
End of Study (EOS) visit.
b Visit dates for each visit from Month 3 through EOS will reference back to Day 1 of study entry and will be based on calendar months. Visit windows for each visit in Table 2
will be ±21 days for Months 3, 6, and 12. Visit windows will be ±28 days for Months 18, 24, 30, 36, 42, 48, Early Discontinuation, and End of Study (EOS). 
c In addition to Central laboratory testing, the local laboratory must obtain BUN, and creatinine values and calculate eGFR values for documentation in CRFs for each of the time 
points indicated as well as pre-AMR and  resolution of AMR for all AMR episodes. Subjects who discontinue before 6 months should complete the Early Discontinuation Visit 
Between Day 13 & Month 6. 


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Table 2
Schedule of Assessments (Month 3 through Month 48 [End of Study])a
Study Procedure
Post-Treatment Evaluations
Month 3 
(±21 days)b
Month 6 
(±21 days)b
Month 12 
(±21 days)b
Month 18 
(±28 days)b
Month 24 
(±28 days)b
Month 30 
(±28 days)b
Month 36 
(±28 days)b
Month 42 
(±28 days)b
Early 
Discontinuation 
Visit Between 
Day 13 & Month 
6
EOS/Month 48 
or at patient 
discontinuation 
if after Month 6 
(±28 days)b
d In the event of discontinuation of a fully-dosed subject prior to the Month 6 Visit, every attempt will be made to obtain a biopsy at discontinuation to send to the independent, 
blinded pathology EAC for determination of TG. The required slides and images for the Screening, Month 6, early discontinuation before Month 6 (if applicable), and any other 
unscheduled standard of care biopsies, must be submitted to the Sponsor's designee within 30 days after the biopsy procedure, for subsequent submission to the EAC for review.
e Subjects where anti-C1 INH antibodies are detected will be followed to measure titers. At Months 12, 18, 24, 36, and 48 the test will be performed ONLY if anti-C1 INH 
antibodies are detected at the previous time point. At Month 3 and Month 6 the test will be performed in each patient.
f DSA antibody analysis will be performed by the central laboratory and will not be reported back to the investigator. Additional DSA testing at these and other time points may be 
performed by the local laboratory for all clinical assessments as part of standard of care. Additional serum may be collected for the central laboratory for future antibody and titer 
testing.
g  For the duration of the study, the following concomitant/post-treatment medications will be collected in the case report form: Any IV steroids, Rituximab, Muromonab-CD3, 
Alemtuzumab, anti-thymocyte globulin (rabbit), lymphocyte immune globulin, anti-thymocyte globulin (equine), any IV immunoglobulin preparation, Daclizumab or basiliximab. 
In addition, medications used to treat any related AEs/SAEs or AESIs will also be recorded for the duration of the study as well as those listed in Section 5.5.
h Adverse events and SAEs will be collected from the time of Informed Consent through 30 days after the last dose of investigational product regardless of relationship to study treatment. Following the 
30-day capture period for all AEs and SAEs, only AE/SAEs deemed related to investigational product or other protocol-mandated procedures as well as the following AESIs regardless of relationship to 
investigational product: any hypersensitivity reaction, any thrombotic or thromboembolic event, any new episode of kidney allograft rejection (excluding AMR) even if the event does not qualify for 
retreatment with investigational product, and any kidney allograft failure will be collected during the long-term follow-up phase of the study.  


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Table 3
Blood Sample Collection Time Points for Pharmacokinetic/
Pharmacodynamic Testing (All Subjects)
Sample Day and Time
C1 INH (antigen and 
function), C3a, and C5a
Day 1:  Prior to start of DSA reduction therapy, if performed, on Day 1
X
Day 1:  Prior to Day 1 investigational product infusion (within 15 min)
X
Day 1:  1 h (+ 5 min) after start of Day 1 investigational product infusion
X
Day 7:  Prior to start of DSA reduction therapy, if performed, on Day 7
X
Day 7:  Prior to Day 7 investigational product infusion (within 15 min)
X
Day 7:  1 h (+ 5 min) after start of Day 7 investigational product infusion
X
Day 13:  Prior to start of DSA reduction therapy, if performed, on Day 13
X
Day 13:  Prior to Day 13 investigational product infusion (within 15 min)
X
Day 13:  1 h (+ 5 min) after start of Day 13 investigational product infusion
X
C1 INH=C1 inhibitor; C3a= anaphylatoxin split product of C3 activation important in chemotaxis; C5a=anaphylatoxin split 
product of C5 activation important for histamine release and chemotaxis; DSA=donor-specific antibody.


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1.
BACKGROUND INFORMATION
1.1
Preclinical Experience
Acute and repeated-dose toxicity studies were performed in rats with intravenous (IV) 
administration of CINRYZE® (lyophilized formulation) at dose levels of 20, 100, and 
400 U/kg/day. No signs of toxicity at up to 28× the normal human dose (based upon a 70 kg 
adult) were observed in the single-dose study. In the repeated-dose study, the signs of toxicity 
were limited to minor increases in inflammatory changes in the lungs and germinal center 
hypertrophy in the spleens of animals dosed at 400 U/kg/day for 14 days, as compared to control 
animals. The amount of germinal center hypertrophy in the spleens of rats treated at 
400 U/kg/day was within the normal background histopathological range in both incidence and 
severity, but did correlate with a small increase in splenic weights, which may have been a 
reflection of the inflammatory increase in the lungs. Since CINRYZE is derived from human 
plasma, an immunological effect in rats is to be expected. An in vivo thrombogenicity study 
performed by ViroPharma Inc. in 1994 in rabbits suggested a potential for clot formation when 
another C1 inhibitor (C1 INH) product was administered at doses 14-fold greater than the 
recommended clinical dose (greater than 200 U/kg). However, results of an ex vivo 
thrombogenicity study utilizing healthy human volunteer whole blood/platelet poor plasma 
showed no evidence of a hypercoagulable effect of CINRYZE at concentrations of 0.14 to 
7.0 U/mL (approximately 7× physiologic concentration) (Levy et al. 2014). No effects of 
C1 INH on embryo-fetal development were observed at dose levels up to 400 U/kg. No animal 
studies have been completed to evaluate the effects of CINRYZE on carcinogenesis, mutagenesis, 
or impairment of fertility.
A 14-day study in male and female Sprague Dawley rats is in progress to evaluate the 
toxicological potential of a liquid formulation of C1 esterase inhibitor [human]. C1 esterase 
inhibitor [human] liquid for injection was administered once daily for 14 days in the following 
doses: 0 (vehicle control), 200, 400, and 1000 U/kg subcutaneous (SC) and 0 and 1000 U/kg IV. 
Audited draft data shows that all animals survived to necropsy. There were no test-article related 
clinical observations, effects on body weight or food consumption, or ophthalmic findings. Nor 
were there any test-article related hematology, coagulation, or urinalysis parameter alterations or 
organ weight differences at the end of dosing or recovery periods. Non-adverse treatment-related 
findings included an increased incidence and severity of localized dermal, muscular, and SC 
inflammation at the SC injection sites and secondary responses to the localized antigenic 
stimulation (higher globulin values, lower albumin to globulin ratio values, higher total protein 
values (200 and 1000 U/kg/day SC females only), enlarged axillary lymph nodes, and an 
increased incidence of enlarged mediastinal lymph nodes (400 and 1000 U/kg/day SC) which 
were reversible. Reversible secondary responses to the localized antigenic stimulation in the 
1000 U/kg/day IV males and females included higher globulin values (females only), lower 
albumin to globulin ratios (females only), and enlarged axillary lymph nodes. Toxicokinetic 
data are not yet available. Therefore, based upon the absence of overt toxicity, the 
no-observed-adverse-effect level (NOAEL) was considered to be 1000 U/kg/day administered 
via SC or IV injection.


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1.2
Indication and Current Treatment Options
Each year, several thousand end-stage renal disease patients are prohibited from receiving a 
potentially life-saving kidney transplant because of pre-existing antibody directed against the 
donor’s cell surface human leukocyte antigens (HLA). The presence of these circulating 
donor-specific antibodies (DSA), identified through pre-transplant cross-match screening, is a 
contraindication to transplantation (Patel and Terasaki 1969; Bryan et al. 1998). Donor-specific 
antibodies can cause immediate, or “hyperacute,” antibody-mediated rejection (AMR) (of renal 
allograft) resulting in complement-mediated destruction and loss of the kidney soon after 
transplant. In the US, there are more than 25,000 people on the wait list that have HLA 
antibodies (Department of HHS 2009) and thus, experience a prolonged wait for an organ to 
which they are not sensitized. More than 6,000 patients currently on the wait list have 
willing living kidney donors, but transplantation is not performed because of DSA. Another 
3,500 patients per year have willing donors, but will be added to the wait list because of DSA 
(Montgomery 2010). The inability to transplant sensitized patients with kidneys from willing live 
donors further increases the demand for deceased donor kidneys, and thus, increases wait times 
for all listed patients. Further, it has recently been described that the majority of standard (no 
identified pre-transplant DSA) kidney transplant grafts lost due to chronic rejection are the result 
of de novo development of DSA from graft sensitization after the transplant. An effective 
treatment regimen for AMR would not only increase access to transplants for patients with 
pre-existing DSA, it could salvage a portion of the grafts lost to acute and early chronic AMR 
from de novo DSA that form following transplantation.
Decreasing DSA titers in cross-match-positive patients through the use of intravenous 
immunoglobulin (IVIg) (Glotz et al. 2002) or a combination of plasmapheresis and IVIg 
(Sonnenday et al. 2002; Montgomery and Zachary 2004) has allowed for “desensitization” and 
conversion to negative cross-match for successful kidney transplantation (Akalin et al. 2003; 
Jordan et al. 2003). However, despite such practices, more than 10% of patients will lose their 
graft immediately or very early after transplantation due to hyperacute rejection or aggressive 
acute AMR (Lefaucheur et al. 2008), and 25-50% will still experience acute AMR, most within 
the first 1 to 3 months post-transplant (Montgomery 2010; Stegall et al. 2010; Loupy et al. 2009). 
In fact, 1-year graft survival was only 60-70% in patients with DSA and AMR compared to 
approximately 95% in patients with no DSA (Lefaucheur et al. 2008). Nevertheless, for some 
patients, the morbidity and mortality rates associated with dialysis warrant the risks of 
cross-match-positive kidney transplantation. It is clear that there remains an unmet medical need 
to improve overall outcomes for DSA-positive transplant recipients at high risk for AMR.
Because of the selection bias that excludes patients from transplant access if they have identified 
DSA, acute AMR episodes are extremely rare, so a small study for treating AMR is a necessity 
given the limited patient population. In addition, graft loss due to acute AMR may be delayed for 
several years due to therapies such as plasmapheresis, plasma exchange, or immune adsorption 
treatments and IVIg. However, it has been shown that graft survival for patients with acute AMR 
(where DSA is identified and the 4th complement protein degradation product [C4d] is 
demonstrated on biopsy) begins to deviate from standard kidney graft survival within 3 years, so 
assessing efficacy with a surrogate marker earlier in the disease process and continuing to follow 
patients for long-term graft survival to confirm clinical benefit is warranted. 


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Finally, transplant glomerulopathy (TG), defined by double contouring of the glomerular 
basement membrane (GBM), is the most plausible and reliable of surrogate markers for poor 
outcomes in kidney transplantation. Early evidence of transplant glomerulopathy can be 
identified by electron microscopy (EM) when contouring of the GBM is associated with 
evidence of endothelial swelling (Haas 2014); however, long-term association with early graft 
loss has not been demonstrated with such early changes. Despite treatment with plasmapheresis 
and IVIg, TG evident by light microscopy (chronic glomerulopathy [cg] ≥1b, ie, ≥1 glomerular 
capillaries with GBM double contours in 1 nonsclerotic glomerulus by light microscopy; EM 
confirmation recommended if available [Haas 2014]) has been associated with later formation of 
irreversible scarring observed on biopsy as interstitial fibrosis, glomerulosclerosis, and/or 
fibrointimal thickening (Montgomery 2010; Racusen et al. 1999) that eventually results in graft 
loss. Patients with TG on biopsy have greatly shortened graft survival compared with patients 
who have no evidence of TG (Sharif et al. 2014; Sun et al. 2012). Furthermore, TG on light 
microscopy has been universally accepted by transplant physicians and pathologists as a reliable 
surrogate marker of impending allograft loss.
Since TG, as described above, is indicative of poor graft survival, an effective treatment for 
AMR must modulate the underlying destructive host immune response that results in TG.  
Plasmapheresis, plasma exchange, or immune adsorption treatments and IVIg can decrease DSA 
titers; however, their use may not address the tissue destruction that occurs as a result of 
complement activation. Human leukocyte antigen-DSA complexes activate the classical pathway 
of the complement cascade, ultimately resulting in the formation of membrane attack complexes 
and continuous release of inflammatory cytokines and leukocyte infiltration (Levy and 
O’Donnell 2006).
As evidence of the role of complement in graft destruction, accumulation of C4d along with 
inflammation of the peritubular capillaries (PTC) is pathognomonic for AMR and is associated 
with poor allograft survival (Mauiyyedi et al. 2002; Sis et al. 2010). After adjusting for risk 
factors commonly associated with graft failure, patients who required renal allograft biopsy for 
diminished kidney function and who had DSA in their serum with C4d staining on biopsy had a 
risk of graft failure 3× higher than patients without DSA or C4d staining on biopsy (Haririan et 
al. 2009). Therefore, a complement inhibitor may be a useful adjunct in the treatment of AMR to 
mitigate tissue damage and prolong allograft survival.
1.3
Product Background and Clinical Information
CINRYZE (C1 esterase inhibitor [human]) consists of a protein fraction prepared from human 
plasma. The manufacturing process includes 3 virus inactivation/removal steps: polyethylene 
glycol precipitation, pasteurization, and nanofiltration. CINRYZE is a normal human plasma 
protein that is not subject to Cytochrome P450 metabolism, excretion, or pharmacokinetic 
drug-drug interactions exhibited by low molecular weight compounds. CINRYZE (lyophilized 
formulation) was approved by the US FDA for routine prophylaxis against angioedema attacks 
in adolescent and adult patients with hereditary angioedema (HAE) in October 2008. CINRYZE
was approved throughout the EU, via the Centralized Procedure, in June 2011 for treatment and 
pre-procedure prevention of angioedema attacks in adults and adolescents with HAE, and routine 
prevention of angioedema attacks in adults and adolescents with severe and recurrent attacks of 


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HAE who are intolerant to or insufficiently protected by oral prevention treatments, or patients 
who are inadequately managed with repeated acute treatment. Additional approvals have 
occurred in Canada (2012), Australia (2012), and Switzerland (2013). 
1.3.1
Clinical Experience with Hereditary Angioedema
Per the approved CINRYZE US Prescribing Information, more than 14,000 IV infusions of 
CINRYZE were administered to over 260 different subjects in 8 completed clinical studies in the 
HAE development program for IV CINRYZE. The vast majority of infusions were CINRYZE doses 
of 1000 U. In the placebo-controlled study with the longest administration period (Study LEVP 
2005-1/B, prevention of angioedema attacks), 1000 U of IV CINRYZE was administered every 
3 or 4 days for 12 weeks. In this study, the only CINRYZE-related treatment-emergent adverse 
events (TEAEs) that occurred in more than 1 subject were viral upper respiratory tract infection 
and rash, each occurring in 3 subjects (12%). Across studies, there were only occasional reports 
of infusion site pain, bruising, rash, or other local reactions. No subjects were discontinued from 
CINRYZE due to an adverse event (AE) in any of the studies. Refer to the CINRYZE investigator’s 
brochure for efficacy results.
Evaluation of the clinical pharmacokinetics and pharmacodynamics following IV administration 
of CINRYZE in subjects with HAE was primarily based on the results of Protocol LEVP 2006-5. 
After IV administration of CINRYZE 1000 U, functional C1 INH concentrations increased from a 
mean baseline value of 0.31 U/mL to a maximum concentration (Cmax) of 0.68 U/mL. Two 
consecutive 1000 U doses administered 60 minutes apart produced a mean Cmax of 0.85 U/mL. 
Median tmax was approximately 1 to 2 hours. The mean t1/2 of functional C1 INH was 
approximately 60 hours using non-compartmental methods. Mean clearance (CL) values for 
functional C1 INH were 0.85 and 1.17 mL/minute for the single and double doses, respectively. 
Mean Cmax values for C1 INH antigen following IV administration of CINRYZE were 1.48 and 
1.70 U/mL for the single and double doses, respectively. Median tmax was approximately 
1.5 hours. The mean t1/2 of antigenic C1 INH was approximately 45 to 47 hours and mean CL 
was 0.70 mL/minute.
CINRYZE, in doses utilized to treat HAE, does not require pre-administration medications such as 
antihistamines or acetaminophen.
1.3.2
Clinical Experience with Antibody-mediated Rejection
One clinical study (0624-201) was conducted to assess the safety and effect of CINRYZE in the 
treatment of acute AMR in HLA-donor-sensitized kidney transplant recipients. Eighteen subjects 
with AMR were enrolled in the study and received an initial IV infusion of 5000 U of CINRYZE
or placebo on Day 1, followed by 2500 U of CINRYZE or placebo IV on Days 3, 5, 7, 9, 11, and 
13. All 18 subjects completed treatment and the study. Seven of 9 (78%) subjects who received 
CINRYZE and 6/9 (67%) who received placebo had a resolution of the qualifying episode of AMR 
based on clinical improvement of renal function and on classic Banff categorization of 
histopathology findings. The median number of days from the first dose of investigational 
product until AMR resolution was 20.0 days (range: 19 to 86 days) for subjects who received 
CINRYZE and 20.5 days (range: 20 to 22 days) for subjects who received placebo. All 7 (100%) 
subjects who received CINRYZE and had resolution of the qualifying episode had AMR resolution 
determined by histopathology. 


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Of the 6 subjects who received placebo and had resolution of the qualifying episode, 3 (50%) 
had AMR resolution based on clinical criteria and 4 (67%) had AMR resolution based on 
histopathology.
All 18 subjects had early protocol-mandated biopsies at Day 20; however, the 14 subjects from 
Johns Hopkins Medical Institute also had center-mandated biopsies 3-6 months after completion 
of investigational product therapy (n=7 CINRYZE; n=7 placebo). Since these 14 subjects had also 
been treated with the same standard of care regimen, the Central Pathologist read the long-term 
follow-up biopsies blinded to treatment assignment and determined the presence or absence of 
new TG by the published Banff criteria (Racusen et al. 1999; Sis et al. 2010). Of these 
14 subjects, 3 of 7 placebo subjects had evidence of new TG as determined by double contouring 
of the GBM (cg≥1b; personal communication) with thickening of the PTC and ongoing PTC 
inflammation on histopathology. Notably, there were no new cases of Banff-qualified TG 
(cg≥1b; personal communication) with PTC inflammatory changes in the 7 subjects receiving 
CINRYZE (Montgomery et al. 2014).
Intravenous administration of an initial infusion of 5000 U of CINRYZE followed by 2500 U 
CINRYZE every other day for 2 weeks (20,000 U over 13 days) was safe and generally well 
tolerated in kidney transplant patients with acute AMR. Fifteen (83.3%) subjects had 1 or more 
TEAEs during the study (6 [67%] subjects in the placebo group and 9 [100%] subjects in the 
CINRYZE group). No subject discontinued from investigational product or had their 
investigational product interrupted due to an AE. Only 1 (11%) subject in the CINRYZE group 
had a TEAE that was considered by the investigator to be related to investigational product (mild 
blurred vision that resolved without treatment). The majority of TEAEs were of mild or 
moderate intensity. Four (22.2%) subjects had 1 or more treatment-emergent serious adverse 
events (SAEs) during the study (3 [33%] subjects in the placebo group and 1 [11%] subject in 
the CINRYZE group). None of the SAEs were considered to be related to investigational product. 
No subject died during the study and no subject experienced a thrombotic or thromboembolic 
event. There were no clinically significant safety signals in clinical laboratory parameters or vital 
signs associated with CINRYZE administration.
CINRYZE-treated subjects achieved higher exposure of C1 INH functional activity on Day 13, 
with baseline-corrected steady-state Cmax and area under the concentration-time curve from the 
time of dosing to the last measurable concentration for functional activity ranging from 3.7 to 
8.8-fold higher than placebo subjects. Mean minimum concentration (Cmin) C1 INH functional 
activity obtained prior to each CINRYZE dose was consistent across the entire study period, 
indicating that accumulation of C1 INH was minimal. For subjects receiving plasmapheresis as 
part of their standard of care, it was observed that this decreased the mean C1 INH functional 
activity by 43.3%, for the combined treatment groups compared to the pre-dose level.
Always refer to the latest version of the CINRYZE investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of CINRYZE.


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2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale
2.1.1
Rationale for the Study
Transplantation of an organ involves exposure of the recipient to non-self HLA. Recipient 
immune recognition of these non-self markers results in production of DSA. The process of DSA 
production may occur before transplantation (ie, blood transfusion, pregnancy, or prior 
transplant) or any time after transplantation. Donor specific antibody complexes with the first 
complement protein (C1) to activate the classical pathway of the complement system resulting in 
AMR. If there is pre-existing DSA prior to the transplant, the process can result in rapid graft 
loss with activation of all 3 major inflammatory pathways (coagulation, contact, and complement 
systems) and immediate clotting of the transplanted organ within hours. This process is known as 
hyperacute rejection and is the reason why the presence of pre-existing DSA is a contraindication 
to transplantation.
Clinical evidence from Haririan et al. (2009) indicates that patients who had DSA with evidence 
of complement activation on biopsy had a risk of graft loss 3× higher than patients without DSA 
or complement activation. Monkeys with a chronic form of AMR (DSA and complement 
activation on biopsy) developed TG (Smith et al. 2008), which is a marker of eventual graft loss. 
Sensitized kidney transplant patients who received peri-transplant eculizumab still had evidence 
of early-stage complement pathway activation on biopsy (evidenced by ongoing C4d staining). 
The incidence of early AMR was significantly less than a historic control, although the incidence 
of chronic glomerulopathy (cg score >0) at 1 year on protocol biopsies was not improved for 
subjects receiving eculizumab for AMR prophylaxis after transplantation (31.9%) compared with 
historical controls that received plasma exchange without eculizumab for desensitization (26.7%) 
(Cornell et al. 2015). Thus, an earlier stage complement pathway inhibitor, like C1 INH, may be 
more advantageous for the treatment of AMR given its activity early in the complement, contact,
and coagulation pathways.
Preclinical studies support this hypothesis as mice deficient in complement protein C3 or C4 had 
impaired immune responses to disparate skin grafts, while C5-deficient mice did not exhibit an 
impaired immunity (Marsh et al. 2001). As proof of concept that C1 INH may be a useful agent 
for AMR, baboons presensitized by transfusion with allogeneic blood of another (kidney donor) 
baboon and in which DSA were formed did not reject the transplanted graft during treatment 
with recombinant human C1 inhibitor (rhC1INH). In contrast, presensitized baboons that did not 
receive rhC1INH rejected the kidney grafts within 48 hours. In baboons receiving IV rhC1INH 
3× daily, cessation of investigational product led to accelerated graft loss from acute AMR 
(Tillou et al. 2010).
2.1.2
Rationale for Dose Selection
An in vitro model analogous to the treatment of acute AMR required concentrations of rhC1INH 
approximately 2-3× serum physiologic concentration to inhibit >90% antibody-dependent 
cytotoxicity (Poirier and Blancho 2008).


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Recombinant human C1 INH was used in a baboon allotransplant model to successfully prevent 
acute AMR. This study demonstrated successful prevention of acute AMR when rhC1INH was 
given at a dose of 200 U/kg (Tillou et al. 2010). Notably, all baboons rejected their grafts upon 
cessation of C1 INH therapy, indicating that additional adjunctive therapy is most likely 
necessary to address the continuing presence of DSA.
It is also important to point out that the complement system could theoretically contribute to 
thrombus formation by enhancing blood-clotting properties and augmenting the inflammatory 
response, which, in turn, potentiates coagulation (Amara et al. 2008). This procoagulatory 
potential for C1 INH has been noted in animals when used at single doses of 200 U/kg (Horstick 
et al. 2001), and clinically, in neonates undergoing cardiac surgery and cardiopulmonary bypass 
who were given intra- and post-operative doses up to 500 U/kg (German Federal Medical 
Council 2000).
Based on available preclinical and clinical data, the levels of C1 INH sufficient for complement 
pathway inhibition elicited by antigen-antibody complexes are at least 100% above normal 
physiologic levels. Preliminary data from the pilot pharmacokinetic study 0624-100 
demonstrated that following IV administration of 2000 U of CINRYZE in healthy subjects, the 
mean change from baseline in functional C1 INH activity was approximately 50-60%. Given that 
1 U of C1 INH activity is found in 1 mL of plasma, to increase the functional activity of C1 INH 
by at least 100% (2-fold) in patients with acute AMR, a dose of ~5000 U will be required in an 
average adult. Given that CINRYZE has a half-life of ~60 hours in HAE patients and possibly 
shorter in patients with active inflammation such as AMR patients, subsequent doses of 2500 U 
given every other day are likely to maintain adequate functional C1 INH levels throughout the 
dosing period. Therefore, subjects randomized to the CINRYZE group in the randomized Phase 2 
AMR pilot study (0624-201) received a loading dose of 5000 U (not to exceed 100 U/kg) 
followed by 2500 U (not to exceed 50 U/kg) every other day for a total of 7 doses. This regimen 
balanced the apparent dose-dependent nature of inhibiting complement activation elicited by 
antigen-antibody complexes, while minimizing the potential risk of coagulation observed in 
preclinical and clinical studies of C1 INH at doses 200 U/kg. In fact, in the pilot study 
0624-201 in kidney transplant recipients with acute AMR, CINRYZE subjects achieved a mean 
C1 INH functional activity of 1.73 U/mL, near but not quite at twice the physiologic level for 
which we aimed. In the 0624-201 study, 14/18 subjects at a single site had a 6-month 
post-transplant allograft biopsy per center standard of care (n=7 CINRYZE; n=7 placebo). A lower 
incidence of new TG (cg≥1b with PTC inflammation) was observed in the CINRYZE cohort 
biopsies as compared to placebo (0 vs 43%, respectively) 3-6 months after initial AMR treatment 
(6 months post-transplant).
Balancing the risk of thrombotic events and the lower incidence of new TG observed in the 
CINRYZE cohort of the 0624-201 study, it is felt that 20,000 U given over 13 days is the optimal 
dosing regimen that maintains an appropriate balance between clinical requirements for 
replacement of endogenous C1 INH and the risk of AEs with a higher dose.


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2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of CINRYZE administered with 
plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free 
immunoglobulin (IVIg) for the treatment of acute AMR of renal allograft in kidney transplant 
recipients as measured by the proportion of subjects with new or worsening transplant 
glomerulopathy (TG) at 6 months after treatment initiation.
2.2.2
Secondary Objectives
The key secondary objective is to evaluate the efficacy of CINRYZE administered with 
plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free IVIg for 
the treatment of acute AMR of renal allograft in kidney transplant recipients as measured by the 
proportion of subjects with all-cause graft failure at 4 years following treatment initiation for the 
initial qualifying AMR episode.
Secondary objectives from study entry to 6 months:

To assess renal function

To assess proteinuria

To assess change in histopathology

To assess graft outcomes
Secondary objectives from study entry to graft failure or 4 years:

To assess renal function

To assess proteinuria

To assess graft outcomes

To assess resolution of AMR

To assess safety and tolerability of CINRYZE in kidney transplant recipients

To assess subject survival status
2.2.3
Exploratory Objectives


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3.
STUDY DESIGN
3.1
Study Design and Flow Chart
This randomized, double-blind, placebo-controlled multicenter, multinational study will assess 
the efficacy and safety of CINRYZE with protocol-mandated DSA reduction treatment and 
sucrose-free IVIg for the treatment of acute AMR in kidney transplant recipients. Eligible study 
subjects will have had a kidney transplant with adequate function defined as having a pre-AMR 
baseline eGFRMDRD ≥20 mL/min/1.73m2 if the qualifying AMR episode occurs ≤21 days after 
transplant or pre-AMR baseline eGFRMDRD ≥30 mL/min/1.73m2 if the qualifying AMR episode 
occurs >21 days after transplant. The pre-AMR baseline is the highest eGFRMDRD value obtained
following the kidney transplant and within 30 days prior to the biopsy for the qualifying AMR 
episode. If more than 1 eGFRMDRD value is available, a mean of the 2 highest values (at least 
1 day apart and both prior to the AMR episode) will be used as the pre-AMR baseline value. If 
no eGFRMDRD was obtained within 30 days prior to the biopsy for the qualifying AMR episode, 
it can be evaluated within a 60-day period.
The qualifying episode of biopsy-proven AMR will be defined by 2013 Banff criteria and will 
have evidence of circulating DSA. Once the qualifying AMR episode is diagnosed through a 
biopsy, subjects will enter a screening period for additional eligibility assessments at the 
investigative site. During this screening, the first eGFRMDRD value obtained after the qualifying 
biopsy should be used for the screening visit period. Biopsy slides and images (including, but not 
limited to EM) will be sent to an independent, blinded pathology Endpoint Adjudication 
Committee (EAC) for confirmation of AMR. Subjects will be stratified across centers for (1) 
living vs deceased donor and (2) severity of acute AMR as defined by screening period 
eGFRMDRD (≤15 mL/min/1.73m2 for severe, or >15 mL/min/1.73m2 for mild to moderate). 
CINRYZE or placebo treatment should be started as soon as possible and within 7 days after the 
biopsy procedure. 
Approximately 112 eligible subjects with biopsy-proven AMR will be randomized (56 per 
treatment arm) to receive either CINRYZE or placebo in a 1:1 ratio after being stratified for 
(1) living vs deceased donor and (2) severity of acute AMR as described above. Additional 
eligible subjects may be enrolled and randomized based on the interim data analysis of the first 
30 subjects who complete the Month 6 TG assessment for the re-estimation of sample size 
(Section 9.5.1). During the study treatment period, subjects will receive a total of 7 doses of 
investigational product over 13 days in addition to protocol-mandated DSA reduction treatment 
and sucrose-free IVIg for each qualifying episode of AMR. To minimize variability, the use of 
DSA reduction treatments and sucrose-free IVIg for the treatment of AMR will be administered 
as mentioned below. 
Donor-specific Antibody Reduction Treatment: Subjects will be required to receive a minimum 
of 5 plasmapheresis, plasma exchange, or immune adsorption treatments from the time of 
diagnostic biopsy for qualifying episode of acute AMR through Study Day 13. Each DSA 
reduction treatment will be followed by sucrose-free IVIg (no less than 100 mg/kg). Additional 
DSA reduction treatments and sucrose-free IVIg may be administered at the discretion of the 
investigator as per local standard of care. 


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NOTE: If plasmapheresis, plasma exchange, or immune adsorption treatment occurs on the same 
day as investigational product dosing, investigational product will be administered after 
completion of the DSA reduction therapy session and dosing of sucrose-free IVIg. Collection of 
blood samples for laboratory testing (other than those specified on Table 3) will be performed 
prior to each DSA reduction treatment, if performed. 
As shown in Table 2, in addition to the qualifying kidney biopsy, an additional kidney biopsy 
will be obtained at the Month 6 study visit. See Section 7.2.2.2 for details. Biopsy slides and 
pertinent micrographs (including, but not limited to EM images) for the qualifying and Month 6 
biopsies will be provided to an independent, blinded pathology EAC for confirmation of AMR 
diagnosis and the assessment of the primary endpoint (new or worsening TG at 6 months of 
initiation of treatment).
 
 
Subjects will remain in the study until the clinical confirmatory endpoint of all-cause graft failure 
is evaluated up to a maximum of 4 years. Graft failure is evaluated by the nephrology EAC.  
Graft failure, for the purpose of this study, will be defined as 1 or more of the following: 
(1) institution of permanent dialysis (defined as dialysis treatment >30 days), (2) current 
transplant nephrectomy, or (3) clinical determination of cessation of kidney graft function and 
eGFR ≤15 mL/min/1.73m2. If a subject is discontinued for any reason prior to the Month 6 
follow-up Visit, every effort will be made to obtain AEs, serum blood urea nitrogen (BUN) and 
creatinine (Cr) results, eGFRMDRD, and a biopsy to send slides and images to the pathology and 
nephrology EACs for determination of TG and graft function status, respectively (see Table 2 for 
Early Discontinuation Visit procedures). If a subject is discontinued for any reason prior to the 
end of the study at 4 years, every effort will be made to obtain AEs, serum BUN and Cr and 
eGFRMDRD results to send to the nephrology EAC for determination of graft function status (see 
Table 2 for End of Study Visit procedures).  
There will be 3 analyses (2 interim, 1 final) of proportions of subjects with all-cause graft failure, 
at approximately 50% (~26 events), 75% (~39 events) and 100% (~51 events) of the study data. 
Following the Month 6 evaluation, subjects will enter a long-term follow-up stage of the 
protocol, which will include allograft function evaluations every 6 months up to a maximum of 
4 years. The duration of the study will be event driven, and is based upon an assumption that 
there will be approximately 51 all-cause graft failures. The study will continue until 51 such 
events are accrued and adjudicated by the nephrology EAC. However the maximum amount of 
time each subject will be followed in the study will be 4 years post initial treatment with 
investigational product. See Section 9.5.2 for additional details.
Resolution will be achieved when, after treatment, the local eGFRMDRD value increases to 
at least within 20% or above the eGFRMDRD value collected as a pre-AMR baseline. If an 
AMR episode is diagnosed, in absence of significant decline (≥20%) of eGFR from 
pre-AMR baseline, a follow-up biopsy within 3 months is recommended in order to assess 
resolution. 


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Resolution is defined initially by the local pathologist according to histological findings and later 
confirmed by the pathology EAC, and should be based on improvement from previous biopsy 
and characterized by Banff criteria as: glomerulitis (g + ptc) <2 if C4d-negative; (g + ptc) = 0 if 
C4d-positive. The investigator will record the applicable eGFRMDRD values and the date of 
resolution of the qualifying and recurrent AMR episodes in the CRF, when applicable, including 
the criteria used for determination of resolution (clinically and/or through histopathology).
Recurrence is defined as biopsy-proven new evidence of AMR upon resolution of the previous 
AMR episode. Investigators will also be asked to record the date of recurrence of AMR, when 
applicable. During the first 180 days after the qualifying biopsy, if the qualifying AMR episode 
resolves and there is new biopsy-proven acute AMR per protocol definition in the inclusion 
criteria, the subject may be retreated at the investigative site with the same investigational 
product to which they were originally randomized as well as DSA reduction treatment and 
sucrose-free IVIg per protocol. Between the qualifying biopsy that is diagnostic for a recurrent 
episode of AMR and the first retreatment dose of investigational product, subjects will complete 
a subset of the screening procedures as indicated in Table 1. Subjects will follow the assessments 
noted in Table 1 and Table 2. For each new episode of AMR occurring during the first 180 days 
after the qualifying biopsy. Retreatment should occur as soon as possible within 7 days of the 
biopsy that defined the new AMR episode. Retreatment may not occur for recurrent AMR 
episodes diagnosed through biopsies done after the first 180 days after the qualifying biopsy 
date. Biopsies at 6 months following retreatment are not required to be performed by the 
protocol. The only mandated follow-up biopsy will be at Month 6 after initial treatment. With the 
exception of the Month 6 biopsy, completion of follow-up biopsies after the qualifying AMR 
episode is at the discretion of the study sites per local standard of care. Biopsy slides and images 
for unscheduled standard of care biopsies will also be submitted to the EAC.
The effect on the quality of life will be measured by using the EQ-5D-5L. The effect on 
healthcare utilization will also be assessed. 
Complement and C1 INH levels will be assessed at specified time points up to Day 13 for 
pharmacokinetic/pharmacodynamic evaluation (Table 2 and Table 3).
Safety will be monitored through the recording of AEs and changes in physical examinations, 
vital signs, antibodies to C1 INH, and clinical safety laboratory testing. Adverse events and 
SAEs will be recorded from the time the informed consent is signed through 30 days after the 
last dose of investigational product regardless of relationship to study treatment. Following the 
30-day capture period for all AEs and SAEs, only those AEs/SAEs deemed related to 
investigational product or other protocol-mandated procedures will be collected during the 
long-term follow-up phase of the study. If the subject undergoes retreatment with investigational 
product for a new AMR episode, AEs and SAEs will also be captured as described above for the 
treatment of the initial occurrence of AMR. In addition, the following adverse events of special 
interest (AESI) will be closely monitored, both serious and non-serious, and reported throughout 
the study to Shire Pharmacovigilance and Risk Management (PVRM) via SAE form, regardless 
of relationship to investigational product:  

Any thrombotic or thromboembolic event (Section 8.2.4)


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
Any hypersensitivity reaction

Any new episode of kidney allograft rejection (excluding AMR), even if the event does not 
qualify for retreatment with investigational product (Section 7.2.2.4)

Any new kidney allograft failure
Stopping rules: If clinically significant drug-related thrombotic or thromboembolic events (as 
defined in Section 4.5.3) are reported as a study-drug-related SAE, enrollment will be halted 
(See Section 4.5.3). The DMC will review the case and will issue a recommendation to the 
Sponsor with regard to re-starting enrollment.
Please see Section 8.2.4 and Appendix 4 for further information on thrombotic and 
thromboembolic events.
The schedules of study procedures are provided immediately following the synopsis:

Table 1: Schedule of Assessment (Screening though Day 25)

Table 2: Schedule of Assessments (Month 3 through Month 48 [End of Study])a

Table 3: Blood Sample Collection Time Points for Pharmacokinetic/Pharmacodynamic 
Testing (All Subjects)


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Figure 1
Study Design Flow Chart
3.2
Duration and Study Completion Definition
The duration of the study will be event driven, and is based upon an assumption that there will be 
approximately 51 all-cause graft failures that will be adjudicated by the nephrology EAC. The 
trial will continue until 51 such events are accrued and adjudicated by the nephrology EAC. See 
Section 9.5.2 for additional details. However the maximum amount of time each subject will be 
followed in the study will be 4 years post initial treatment with investigational product. Subjects 
will complete visits every 6 months until the study is ended. 
a: Biopsy-proven AMR 72 hours to 12 months after current transplant.
b: Subjects will have a minimum of 5 DSA reduction treatments 
(plasmapheresis, plasma exchange, or immune adsorption treatments) 
each followed by sucrose-free IVIg for each qualifying AMR episode. 
DSA reduction treatments/IVIg may be provided as part of standard of 
care prior to study entry.
c: First dose of investigational product (Day 1) must be administered 
within 7 days after qualifying biopsy.
d: Additional new episodes of acute AMR may be retreated if subject is 
eligible after screening for re-treatment and if the biopsy diagnostic for 
the new AMR occurs during the first 180 days after the qualifying 
biopsy date. Treatment must be with the same investigational product 
assignment (CINRYZE or Placebo) to which the subject was originally 
randomized in addition to DSA reduction treatment and sucrose-free 
IVIg per protocol.
e: Day 25: (± 2 days) after first dose of investigational product.  Renal 
function will be assessed at this visit.
f: Month 3: (± 21 days) after first dose of investigational product.
g: 6-Month Post-Treatment Biopsy: (± 21 days) relative to first dose of 
investigational product:  A renal allograft biopsy will be obtained.
h: Subjects will be assessed every 6 months up to 4 years.  At these visits, 
renal function will be determined as well as graft failure (yes/no).


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If a subject is discontinued from the study (not only from treatment) for any reason prior to the 
Month 6 follow-up Visit, every effort will be made to obtain AEs, serum BUN and Creatinine 
results, eGFRMDRD, and a biopsy to send to the pathology and nephrology EACs for 
determination of TG and graft function status, respectively (see Table 2 for Early 
Discontinuation Visit procedures). If a subject is discontinued from treatment for any reason for 
the remainder of a treatment cycle before receiving 7 doses, the subject will continue in the study 
and no Early Discontinuation Visit will be performed. In this instance, the next scheduled 
treatment visit in the treatment cycle should be conducted and all procedures for that visit should 
be performed other than those related to study drug administration, and the scheduled Day 25 
post-treatment visit will follow (any remaining treatment visits for that cycle are not required). If 
a subject is discontinued from the study for any reason after the Month 6 visit and prior to the 
end of the study at 4 years, every effort will be made to obtain AEs, serum BUN and Cr and 
eGFRMDRD results to send to the nephrology EAC for determination of graft function status (see 
Table 2 for End of Study Visit procedures). 
The subject’s maximum duration of participation is expected to be approximately 4 years.  
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
Approximately 40 sites in approximately 6 countries are expected to participate in this study in 
North America and Europe.


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4.
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed. Local laboratory 
testing will be used to determine subject eligibility.
4.1
Inclusion Criteria
To be eligible for this protocol, a subject must:
1. Be 18 and ≤70 years of age.
2. Weigh 45 kg with a body mass index (BMI) <35 kg/m2 at screening.
3. Have HLA DSA identified at the time of diagnosis of AMR. If it is anticipated that the local 
DSA results will not be available within the screening period, previously obtained local DSA 
results can be used to assess eligibility, if obtained after kidney transplant and within 30 days 
prior to the qualifying AMR episode. In any instance, a local DSA test should still be 
performed at the time of AMR diagnosis.
4. Have a first qualifying episode of AMR in the subject’s current renal allograft between 
72 hours and 12 months after transplant defined by a renal allograft biopsy demonstrating 
neutrophil and/or monocyte infiltration in the PTC and/or glomeruli with or without evidence 
of C4d deposition by immunohistopathology according to 2013 Banff criteria.
5. Have achieved adequate renal function defined as: Pre-AMR baseline eGFRMDRD
≥20 mL/min/1.73m2 for a qualifying AMR episode occurring ≤21 days after transplant or 
pre-AMR baseline eGFRMDRD ≥30 mL/min/1.73m2 for a qualifying AMR episode occurring 
>21 days after transplant. The pre-AMR baseline is the highest eGFRMDRD value obtained 
following the kidney transplant and within 30 days prior to the qualifying AMR episode. If 
more than 1 eGFRMDRD value is available, a mean of the 2 highest values (at least 1 day apart 
and both prior to the AMR episode) will be used as the pre-AMR baseline value. If no 
eGFRMDRD was obtained within 30 days prior to biopsy, it can be evaluated within a 60 day 
period.
6. Receive first dose of investigational product after 7 days after the kidney transplant 
procedure and within 7 days after the qualifying renal allograft biopsy procedure that was 
positive for AMR.
7. Be informed of the nature of the study and provide written informed consent before any 
study-specific procedures are performed.
8. If female and of child-bearing potential, must have a negative urine pregnancy test confirmed 
by a negative serum beta human chorionic gonadotropin (beta-HCG) pregnancy test at the 
Screening Visit and must have a negative urine pregnancy test at the Day 1 visit.
9. Agree to comply with any applicable contraceptive requirements of the protocol.


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4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Have received pediatric en bloc kidney transplant.
2. Have primary Focal Segmental Glomerulosclerosis, rapidly progressive glomerulonephritis, 
membrano-proliferative glomerulonephritis type 1 (including C3 glomerulopathy), “dense 
deposit disease”, or thrombotic microangiopathy as the cause of native kidney failure.
3. Have prior or concurrent non-renal solid organ transplant or hematopoietic stem cell 
transplant (HSCT) or have more than 2 completed kidney transplant procedures (note: 1 
double kidney transplant procedure is considered to be 1 procedure).
4. Have a known neoplastic lesion in the transplanted allograft
5. Have, any ongoing infection that causes hemodynamic compromise or as determined by the 
investigator, any surgical or medical condition that could interfere with the administration of 
investigational product, interpretation of study results, or could compromise patient safety, 
including (as determined by the transplanting surgeon and documented in the operative 
report) any major technical complications of the renal artery, renal vein, or ureteral 
anastomosis
6. Have ongoing treatment for HCV infection.
7. Have had a recent myocardial infarction (MI) within the past 6 months and/or at the time of 
screening are treated with anticoagulants and/or antiplatelet agents (excluding aspirin) for a 
previous myocardial infarction.
8. Have a history of:

abnormal bleeding, 

clotting events or disorders (excluding a history of clotted hemodialysis access or 
superficial thrombophlebitis in the absence of medically confirmed coagulopathy), 
any coagulopathy (documented or clinically suspected) 
For example, patients should be excluded if they have a history of renal allograft arterial or 
venous thrombosis, deep vein thrombosis, pulmonary embolism, ischemic cerebrovascular 
accident (stroke) or transient ischemic attack (TIA), any large vessel thrombosis.
9. Have a history of allergic reaction to CINRYZE or other blood products.
10. Have had any change in androgen therapy (eg, danazol, oxandrolone, stanozolol, 
testosterone), tranexamic acid, epsilon-aminocaproic acid, or other fibrinolytics within 
3 months before the first dose of investigational product.
11. Have participated in the active dosing phase of any other investigational drug study within 
30 days prior to dosing with investigational product.
12. Have any of the following local laboratory values reported prior to dosing with 
investigational product:

Within 24 hours prior to subject dosing, white blood cell (WBC) count <0.5×109/L or 
>20×109/L (the value of >20×109/L should be excluded if obtained during steroid 
treatment)

Within 24 hours prior to subject dosing platelet count < 25×109/L or >600×109/L


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13. Be pregnant or breastfeeding.
14. Have received any of the following agents within 1 month prior to the first dose of 
investigational product:

Sucrose-containing IVIg

Any C1 INH (plasma-derived [eg, CINRYZE®, Berinert®, Cetor®] or recombinant
[eg, Rhucin®])

Eculizumab (Soliris®)

Ecallantide (Kalbitor®)
4.3
Restrictions 
There will be no special restrictions for subjects participating in this study. Subjects are to 
maintain their normal or recommended renal diets per standard of care, medications (with the 
exception of those listed in Section 5.4), and activities of daily living as determined by the 
investigator.
4.4
Reproductive Potential
4.4.1
Female Contraception
Sexually active females of child-bearing potential should be using an acceptable form of 
contraception, as described below. Females of child-bearing potential must be advised to use 
acceptable contraceptives from the time of screening and through 3 months following the last 
dose of investigational product. If hormonal contraceptives are used they should be administered 
according to the package insert. Females of child-bearing potential who are not currently 
sexually active must agree to use acceptable contraception, as defined below, if they become 
sexually active during the period of the study from the time of screening and for 3 months 
following the last dose of investigational product.
Female subjects should be either:

Post-menopausal (12 consecutive months of spontaneous amenorrhea)

Surgically sterile (having undergone one of the following surgical acts: hysterectomy, 
bilateral tubal ligation, bilateral oophorectomy, or bilateral salpingectomy) and at least 
6 weeks post-sterilization, or

Females of child-bearing potential with a negative urine pregnancy test (confirmed by a 
negative serum beta-HCG pregnancy test) at the Screening Visit and a negative urine 
pregnancy test at the Day 1 Visit. Females of child-bearing potential must agree to abstain 
from sexual activity that could result in pregnancy or agree to use acceptable methods of 
contraception.
Acceptable methods of contraception are:

Intrauterine devices plus condoms


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
Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the Screening Visit, plus condoms. Note: if subject becomes sexually 
active during the study, they should use one of the other acceptable methods noted above in 
addition to the hormonal contraceptive until it has been stabilized for 30 days.
4.4.2
Male Contraception
Male subjects will be required to use a condom in conjunction with spermicidal gel, foam, 
cream, film, or suppository from time of dosing until 3 months after the last dose of 
investigational product. Child-bearing female partners of male study participants will be required 
to follow the acceptable methods of contraception for this study (described in Section 4.4.1) from 
the time of first dosing until 3 months after the last dose of investigational product. For male 
subjects, sexual intercourse with pregnant partners should also be avoided during the course of 
the study unless condoms are used from the time of the first dose until 3 months after the last 
dose of investigational product. Male subjects must not donate sperm until 3 months after the last 
dose of investigational product.
4.5
Discontinuation or Withdrawal of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from the study with the medical monitor when 
possible.
If a subject is discontinued from the study (not only from treatment) for any reason prior to the 
Month 6 follow-up Visit, every effort will be made to obtain AEs, serum BUN and Cr results, 
eGFRMDRD, and a biopsy to send to the pathology and nephrology EACs for determination of TG 
and graft function status, respectively (see Table 2 for Early Discontinuation Visit procedures). If 
a subject is discontinued from treatment for any reason for the remainder of a treatment cycle for 
before receiving 7 doses, the subject will continue in the study and no Early Discontinuation 
Visit will be performed. In this instance, the next scheduled treatment visit in the treatment cycle 
should be conducted and all procedures for that visit should be performed other than those 
related to study drug administration, and the scheduled Day 25 post-treatment visit will follow 
(any remaining treatment visits for that cycle are not required). If a subject is discontinued from 
the study for any reason after the Month 6 visit and prior to the end of the study at 4 years, every 
effort will be made to obtain AEs, serum BUN and Cr and eGFRMDRD results to send to the 
nephrology EAC for determination of graft function status (see Table 2 for End of Study Visit 
procedures).
Whenever possible and with the consent of the subject, the investigator will attempt to obtain 
information on graft and subject survival status from discontinued subjects at remaining 
scheduled assessment times through Month 48. The reason for termination, date of stopping 
investigational product, and the total amount of investigational product taken must be recorded in 
the case report form (CRF) and source documents.


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Subjects who discontinue will not be replaced. Approximately 112 eligible subjects with 
biopsy-proven AMR will be randomized to provide 56 subjects per treatment arm. Additional 
eligible subjects may be enrolled based on the interim data analysis of the first 30 subjects who 
complete the Month 6 TG assessment (Section 9.5.1).
4.5.1
Reasons for Discontinuation and/or Withdrawal
The reason for investigational product early discontinuation and/or withdrawal from the study 
must be determined by the investigator and recorded in the subject’s medical record and in the 
CRF. In the case of early discontinuation of the medicinal product and/or withdrawal from the 
study for more than 1 reason, each reason should be documented in the source document and the 
most clinically relevant reason should be entered in the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol violation

Consent withdrawal by subject

Other, specify (e.g., pregnancy, etc.)
4.5.2
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any timepoint prior to the last scheduled study visit (office visit or telephone contact). At least 
1 of these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations.
4.5.3
Stopping Rules
If any of the clinically significant thrombotic or thromboembolic events listed below (exclusive 
of superficial thrombophlebitis, dialysis access clotting, or catheter-related thrombotic events) is 
reported as a study-drug-related SAE in any subject, as defined by the Principal Investigator at 
the site and confirmed through a diagnostic examination as indicated in section 8.2.4, enrollment 
of new subjects will be halted. 

Renal allograft arterial or venous thrombosis

Deep vein thrombosis

Myocardial infarction

Pulmonary embolism

Ischemic cerebrovascular accident (stroke), or transient ischemic attack (TIA), exclusive 
of cerebrovascular hemorrhage (subarachnoid or subdural hemorrhage)

Any large vessel thrombosis (exclusive of the presence of an indwelling catheter)
Study procedures for subjects already randomized will continue, including treatment according 
to their assigned dosing regimen.


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The DMC will perform a safety review of this specific event and of the patient population 
included in the study and will forward its recommendation to the Sponsor about the opportunity, 
in terms of patient safety, of restarting enrollment. Enrollment may be restarted by the Sponsor 
in consultation with the DMC. 
Please see Section 8.2.4 and Appendix 4 for further information on thrombotic and 
thromboembolic events.  


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5.
CONCOMITANT AND POST-TREATMENT MEDICATIONS
5.1
Concomitant Medications
All prescription and over-the-counter medications will be recorded in the CRF as concomitant 
medications from 2 weeks prior to the first dose of investigational product (Day 1) through the 
day of the last dose of investigational product (Day 13) for each treatment period (Table 1). 
Medications used to treat AEs or SAEs, regardless of relatedness of the AEs/SAEs to 
investigational product, will be recorded through 30 days after the last dose of investigational 
product for each treatment period. AEs of special interest and the medications listed in 
Section 5.3 and 5.5 will be recorded for the duration of the study. Topical medications will be 
recorded only if used for treatment of an AE. Prophylactic treatment for deep vein thrombosis 
(DVT) (including mechanical treatment, eg, compression) will also be collected through the 
duration of the study. 
Administration of the following will not be recorded unless the investigator considers this 
important to the assessment of an AE:

Intravenous fluids

Enteral or parenteral nutrition

Vitamins or other dietary supplements

Electrolyte supplementation

Oxygen
5.2
Concomitant Blood Products
The dates and amount of the following blood products will be recorded in the CRF if 
administered from the day of the first dose of investigational product (Day 1) through the day of 
the last dose of investigational product (Day 13) for each treatment period (Table 1):

Albumin

Packed red blood cells

Whole blood 

Fresh frozen plasma 

Cryoprecipitate 

Platelets
5.3
Immunosuppressive Agents or Treatments
From the day of the first dose of investigational product (Day 1) through Year 4, the following 
concomitant medications will be collected in the CRF:

Any IV or oral steroids


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
Rituximab

Bortezomib

Muromonab-CD3

Alemtuzumab

Anti-thymocyte globulin (rabbit)

Lymphocyte immune globulin, anti-thymocyte globulin (equine)

Any sucrose-free IVIg preparation

Plasmapheresis, plasma exchange, or immune adsorption treatments

Daclizumab or basiliximab

Tacrolimus and Cyclosporine

Mycophenolate mofetil and mycophenolic acid

Azathioprine

Other immunosuppressive agents (specify)
5.4
Prohibited Medications
Use of the following agents is prohibited from Day 1 through the EOS evaluation:

Sucrose-containing IVIg

Any C1 INH: plasma-derived (eg, Berinert®, Cetor®) or recombinant (eg, Rhucin®)

Eculizumab (Soliris®)

Ecallantide (Kalbitor®)

Any unapproved/investigational biologic agent or drug
5.5
Other Medications
From the day of the first dose of investigational product (Day 1) through Year 4, the following 
concomitant medications will be collected in the CRF:

Ace-inhibitors (eg, Capoten, Vasoten, Lotensin), sartans (eg, Diovan, Micardis), renin 
inhibitors (eg, Tekturna)

Antiplatelet medications (eg, ASA, Plavix, Ticlid)

Anticoagulant agent (eg, Comadin, Xarelto)


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6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is CINRYZE, which will be provided by the sponsor as a lyophilized powder of 
500 U C1 INH/vial. Vials of CINRYZE also contain the following inactive ingredients: trisodium 
citrate, sodium chloride, L-Valine, L Alanine, L-Threonine, and sucrose. Each vial of CINRYZE
will be reconstituted with sterile water for IV injection and administered with 0.9% sodium 
chloride solution for infusion. 
The placebo product is 0.9% sodium chloride solution for infusion.
Additional information is provided in the pharmacy manual.
6.1.1
Blinding the Treatment Assignment
Qualified subjects will be randomized in a 1:1 ratio to receive CINRYZE or placebo using a 
centralized procedure. An Interactive Voice/Web Response System (IV/WRS, IRT) will be used 
to randomize subjects and provide the treatment assignment to the unblinded pharmacist. The 
unblinded pharmacist will prepare the blinded IV solution (CINRYZE or placebo) accordingly.
A Sponsor representative(s) not affiliated with the core team will be unblinded to treatment 
assignment in order to review drug accountability on an ongoing basis throughout the study 
(Section 6.4). This unblinded representative will remain independent of other study activities. 
For the first interim analysis, the EACs, sponsor, investigator, and subjects will be blinded to the 
study treatment. When the criterion to conduct the second interim analysis is met, treatment 
assignment for those subjects will be unblinded to designated sponsor representatives for 
analysis. The treatment assignments for all other subjects will be blinded to the EACs, 
investigator, and subjects during the conduct of the study. 
6.1.2
Commercially Obtained Investigational Product
CINRYZE product approved for commercial distribution in the US and sterile water for injection 
will be labeled for clinical use and supplied by the sponsor. 
Mix 2 transfer devices for reconstitution will also be supplied by the sponsor.
Sites will be responsible for sourcing 0.9% sodium chloride solution for infusion of either the 
active drug or the placebo.
6.2
Administration of Investigational Product(s)
Reconstitution and administration instructions for CINRYZE will be provided as a separate 
document to investigative sites.


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6.2.1
Interactive Voice/Web Response System Technology for Investigational 
Product Management
An IV/WRS (IRT) will be employed in this study to manage the tracking and confirmation of 
shipment, supply, inventory, ordering, expiration, and site-assignments of the investigational 
product. The IV/WRS provider will provide a user manual and training to each site, with detailed 
instruction on the use of the IV/WRS.
6.2.2
Allocation of Subjects to Treatment 
This is a double-blind, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule automatically assigned by the IV/WRS 
(IRT).
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
level of the severity of AMR and donor characteristic (as defined in the paragraph below) across 
sites, the subject number is assigned to subjects according to the sequence of presentation for 
study participation. Subject number is unique within a protocol.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined. A randomization number will be 
assigned by the IV/WRS at the Baseline Visit (Day 1) after subject eligibility has been confirmed 
using the randomization criteria. The randomization schedule will be stratified for (1) living vs 
deceased donor and (2) severity of acute AMR as defined by the screening period eGFRMDRD
≤15 mL/min/1.73m2 (severe) or >15 ml/min/1.73m2 (mild to moderate).  
6.2.3
Dosing
Eligible subjects in this study will receive a total of 7 doses of investigational product over a 
13-day period: an initial 100 mL IV infusion containing 5000 U CINRYZE or placebo (100 mL
0.9% sodium chloride for infusion) on Day 1, followed by 2500 U of CINRYZE in 100 mL of IV 
infusion or placebo (100 mL 0.9% sodium chloride for infusion) IV on Days 3, 5, 7, 9, 11, and 
13 (Table 4). If DSA reduction therapy occurs on the same day as investigational product dosing, 
investigational product will be administered after completion of the plasmapheresis, plasma 
exchange or immune adsorption treatment session and dosing of the sucrose-free IVIg.
Table 4
Investigational Product Dosing Day, Volume and Amount
Volume
CINRYZE
Placebo
Day 1
100 mL 
5000 Units of CINRYZE
(50 mL of CINRYZE/
50 mL of normal saline) 
100 mL 
of normal saline
Day 3, 5, 7, 9, 11, 
and 13
100 mL 
2500 Units of CINRYZE
(25 mL of CINRYZE/
75 mL of normal saline) 
100 mL 
of normal saline
Note: All doses must be brought up to 100 mL


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Additionally, if a study subject has resolution of their qualifying episode of acute AMR and, 
during the first 180 days after the biopsy of the qualifying episode of AMR, has a new episode of 
AMR as defined in Section 3.1, the subject may be retreated with investigational product per the 
same randomization assignment per protocol.
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in the following situations:
1. Emergency situations where the identification of the investigational product is required for 
further treatment of the subject. The investigator should contact the Sponsor’s 
representative(s) not affiliated with the core team as soon as possible after the subject has 
been unblinded. 
2. The first interim analyses for sample size re-estimation after the first 30 subjects complete 
the Month 6 TG assessment. Only the DMC members will be unblinded for this interim 
analysis.  
3. The second interim analysis is conducted when an adequate number of subjects complete the 
Month 6 TG assessment for the primary endpoint. The adequate number of subjects will be 
determined based on the first interim analysis. When the criterion to conduct the second 
interim analysis is met, treatment assignment for those subjects will be unblinded to 
designated sponsor representatives for analysis. The treatment assignments for all other 
subjects will be blinded to the EACs, investigator, and subjects during the conduct of the 
study. 
4. When approximately 50% (~26 events), 75% (~39 events), and 100% (~51 events) of the 
study information (ie, total number of subjects with all-cause graft failure) is collected. Only 
the DMC members will be unblinded for the 50% and 75% time points in these interim 
analyses.
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code are recorded on the source documents. 
Upon breaking the blind, the subject is withdrawn from the study, but should be followed up for 
safety purposes. Any code-breaks that occur must be reported to the contract research 
organization (CRO) and the Sponsor’s representative(s). Code-break information is held by the 
pharmacist/designated person at the site and by the CRO Medical Monitor for the study or 
designee.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information are applied to the investigational product(s) container. All 
investigational product is labeled with a minimum of the protocol number, dosage form, 
directions for use, storage conditions, expiry date and batch number/packaging reference, the 
statements ‘For clinical trial use only’, and/or ‘CAUTION: New Drug - Limited by Federal (or 
US) Law to Investigational Use’, Keep out of reach of children’, and the sponsor's name and 
address. Any additional labeling requirements for participating countries and/or controlled 
substances will also be included on the label.


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Space is allocated on the label so that the site representative can record a unique subject 
identifier.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label

Obscure the clinical study label

Identify the study subject by name.

Additional labels may not be added without the sponsor’s prior full agreement
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
CINRYZE will be supplied as open-label material in labeled cartons containing 1 labeled vial.
Sterile water will also be supplied as open-label material in labeled cartons containing 1 labeled 
vial.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject number on the investigational product labels as they 
are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified min/max thermometer) 
would require manual resetting upon each recording. The sponsor must be notified immediately 
upon discovery of any excursion from the established range. Temperature excursions will require 
site investigation as to cause and remediation. The sponsor will determine the ultimate impact of 
excursions on the investigational product and will provide supportive documentation as 
necessary. Under no circumstances should the product be dispensed to subjects until the impact 
has been determined and the product is deemed appropriate for use by the sponsor.


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The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol. The investigator or designee will acknowledge receipt of the investigational 
product, documenting shipment content and condition. Accurate records of all investigational 
product dispensed, used, returned, and/or destroyed must be maintained as detailed further in this 
section.
The investigator has overall responsibility for administering investigational product. Where 
permissible, tasks may be delegated to a qualified designee (eg, a study nurse) who is adequately 
trained in the protocol and who works under the direct supervision of the investigator. This 
delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying his/her treatment assignment. All administered 
medication will be documented in the CRFs and/or other investigational product record.
No investigational product stock or returned inventory from a Shire ViroPharma, Inc.-sponsored 
study may be removed from the site where originally shipped without prior knowledge and 
consent by the sponsor. If such transfer is authorized by the sponsor, all applicable local, state, 
and national laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records provided that the blind of the study is not compromised.
If the investigational product is to be destroyed by the study sites, sites must follow their own 
process/policy that describes such activities. All drug destruction processes will be documented 
and the sites must retain copies of these documents within the site regulatory binder. The sites 
must ensure that the clinical trial material accountability and destruction log is complete, 
accurate, and ready for review and/or audit at each monitoring visit.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
All doses of investigational product will be administered to subjects at the investigational site. 
The pharmacist/nominated person will record details of dispensed product on the drug 
accountability form and the clinical staff will record details of administration of product in the 
subject’s medical record.


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7.
STUDY PROCEDURES
7.1
Study Schedule
See Table 1, Table 2, and Table 3 for study procedures. Screening procedures and timing are 
listed below. For detailed descriptions of each procedure, see Section 7.2 Study Evaluations and 
Procedures. See Section 7.2.3.5 for details on which laboratory tests are required locally in 
addition to those sent to the central laboratory.
7.1.1
Screening Period
Screening will occur after the biopsy diagnosis of the qualifying AMR episode and before the 
first dose of investigational product. Investigational product may not be administered within 
7 days of kidney transplant. Submission of pathology slides/images will occur to confirm the 
qualifying AMR episode. Local laboratory testing at screening will be used to determine subject 
eligibility.

Informed consent

Screening registration in the IV/WR (IRT) system

Medical history including the presence/absence of diabetes, pre-AMR creatinine and 
eGFRMDRD

Inclusion/exclusion eligibility 

Physical examination, including height and body weight

Lower extremity examination, including a determination of presence or absence of unilateral 
calf tenderness or leg swelling; a diagnostic exam will be performed if a DVT is suspected

Vital signs

12-lead electrocardiogram (ECG)

Central Pregnancy testing (also local lab serum and urine) for female subjects of 
child-bearing potential

Central Virology screen

Central Hematology (also local hematology lab results will be used to assess subject 
eligibility at screening)

Central Clinical chemistry (includes central lab testing for creatinine and BUN)

Local Serum BUN, creatinine and eGFRMDRD (at screening the first local laboratory creatinine 
value obtained after the biopsy that is diagnostic of AMR should be used to determine AMR 
severity for stratification)

Central Proteinuria: spot urine protein, urine creatinine, and urine protein to urine creatinine 
ratio

Renal allograft assessment, including: function, and failure 


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
Central Anti-C1 INH antibodies

Donor-specific antibody identification. In addition to the central laboratory, per protocol this 
test is required to be performed locally only at screening. Eligibility will be based on the 
local results. If it is anticipated that the local screening DSA results will not be available 
within the screening period, previously obtained local DSA results, if available, can be used 
to assess eligibility if obtained after kidney transplant and within 30 days prior to the 
qualifying biopsy that is diagnostic of an AMR episode. In any instance, a local DSA test 
should still be performed at the time of AMR diagnosis.

Donor-specific antibody reduction treatment and sucrose-free IVIg (plasmapheresis, plasma 
exchange, or immune adsorption treatments/sucrose-free IVIg may be provided as part of 
standard of care prior to study entry). All blood sample collections for laboratory analysis 
should be performed prior to receiving DSA reduction therapy, except as otherwise specified 
for PK/PD samples.

Concomitant medications

Adverse event monitoring

EuroQoL Group 5-Dimension 5-Level Self–report Questionnaire

Healthcare resource utilization
Once eligibility for participation in the study is determined, the subject should be randomized or 
registered as screen failure, as applicable, via IV/WRS (IRT). A screen failure is a subject who 
has given informed consent and failed to meet the inclusion and/or met at least 1 of the exclusion 
criteria and has not been randomized or administered investigational product(s). Subjects cannot 
be rescreened once they have been designated as a screen failure.
Note:  In the event of new biopsy-proven acute AMR allowing retreatment, screening procedures 
will be completed as detailed in the screening retreatment column of Table 1. 
7.1.2
Investigational Product Administration Period
Subjects will be required to receive a minimum of 5 plasmapheresis, plasma exchange, or 
immune adsorption treatments from the time of diagnostic biopsy for qualifying episode of acute 
AMR through Study Day 13. Each DSA reduction treatment will be followed by sucrose-free 
IVIg (no less than 100 mg/kg). Additional DSA reduction treatments or sucrose-free IVIg may 
be administered at the discretion of the investigator per standard of care. NOTE: If 
plasmapheresis, plasma exchange, or immune adsorption treatment occurs on the same day as 
investigational product dosing, investigational product will be administered after completion of 
the DSA reduction therapy session and dosing of sucrose-free IVIg. See Section 7.2.3.5 for 
details on which laboratory tests are required locally in addition to those sent to the central 
laboratory.
7.1.2.1
Day 1
The first dose of investigational product on Day 1 should be administered as soon as possible and 
within 7 days after the qualifying biopsy procedure. 


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All blood sample collection for laboratory testing should be collected prior to receiving DSA 
reduction therapy (if given) except as specified for PK/PD samples.

Inclusion/exclusion eligibility prior to first dose of investigational product

Randomization via IV/WRS (IRT) prior to first dose of investigational product 

Physical examination, including body weight prior to first dose of investigational product

Lower extremity examination prior to first dose of investigational product, including a 
determination of presence or absence of unilateral calf tenderness or leg swelling; a 
diagnostic exam will be performed if a DVT is suspected

Vital signs (obtained within 30 minutes prior to investigational product administration and 
then between 30 minutes and 1 hour after completion of investigational product infusion)

Pregnancy testing (with local urine test) prior to first dose of investigational product for 
female subjects of child-bearing potential

Central Hematology prior to first dose of investigational product

Central Clinical chemistry,  local BUN and serum creatinine with eGFRMDRD prior to first 
dose of investigational product

Central lab blood collection for pharmacokinetic/pharmacodynamic analysis prior to the start 
of DSA reduction therapy (if done), within 15 minutes prior to the start of investigational 
product infusion, and 1 hour (+5 minutes) after the start of investigational product infusion

Donor-specific antibody reduction treatment and sucrose-free IVIg (plasmapheresis, plasma 
exchange, or immune adsorption treatments/sucrose-free IVIg may be provided as part of 
standard of care prior to study entry)  

Investigational product administration (after DSA reduction therapy and sucrose-free IVIg, if 
done)

Concomitant medications

AE monitoring

Renal allograft assessment including: function, and failure

Subject survival status

Healthcare resource utilization
7.1.2.2
Days 3, 5, 7, 9, and 11

Lower extremity examination, including a determination of presence or absence of unilateral 
calf tenderness or leg swelling; a diagnostic exam will be performed if a DVT is suspected

Body weight 

Vital signs (obtained within 30 minutes prior to investigational product administration and 
then between 30 minutes and 1 hour after completion of investigational product infusion)


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
Serum BUN and creatinine with eGFRMDRD (central and local laboratories) prior to 
investigational product administration

For Day 7 only: Central lab blood collection for pharmacokinetic/pharmacodynamic analysis 
prior to the start of DSA reduction therapy (if done), within 15 minutes prior to the start of 
investigational product infusion, and 1 hour (+5 minutes) after start of investigational product 
infusion

Donor-specific antibody reduction treatment and sucrose-free IVIg (plasmapheresis, plasma 
exchange, or immune adsorption treatments/sucrose-free IVIg may be provided as part of 
standard of care prior to study entry) 

Investigational product administration (after DSA reduction therapy and sucrose-free IVIg, if 
done)

Concomitant medications

AE monitoring

Renal allograft assessment including: function and failure 

Subject survival status

Healthcare resource utilization
7.1.2.3
Day 13

Lower extremity examination including a determination of presence or absence of unilateral 
calf tenderness or leg swelling; a diagnostic exam will be performed if a DVT is suspected

Body weight

Vital signs (obtained within 30 minutes prior to investigational product administration and 
then between 30 minutes and 1 hour after completion of investigational product infusion)

Central Hematology prior to administration of investigational product

Central Clinical chemistry (includes BUN and creatinine) and local BUN and serum 
creatinine with eGFRMDRD prior to administration of investigational product

Central lab blood collection for pharmacokinetic/pharmacodynamic analysis prior to the start 
of DSA reduction therapy (if done), within 15 minutes prior to the start of investigational 
product infusion, and 1 hour (+5 minutes) after start of investigational product infusion

Donor-specific antibody reduction treatment and sucrose-free IVIg (plasmapheresis, plasma 
exchange, or immune adsorption treatments/sucrose-free IVIg may be provided as part of 
standard of care prior to study entry)

Investigational product administration (after DSA reduction therapy and sucrose-free IVIg, if 
done)

Concomitant medications 

Adverse event monitoring

Renal allograft assessment including: function and failure

Subject survival status

Healthcare resource utilization


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7.1.3
Post-Treatment Follow-Up Period
See Section 7.2.3.5 for details on which laboratory tests are required locally in addition to those 
sent to the central laboratory.
7.1.3.1
Day 25 (±48 hours)

Lower extremity examination including a determination of presence or absence of unilateral 
calf tenderness or leg swelling; a diagnostic exam will be performed if a DVT is suspected

Body weight

Vital signs

Central lab Hematology

Serum BUN and creatinine with eGFRMDRD (local and central laboratories)

Central lab Proteinuria: spot urine protein, urine creatinine, and urine protein to urine 
creatinine ratio

Central lab Anti-C1 INH antibodies

Central lab Donor-specific antibody identification 

Concomitant medications 

Adverse event monitoring 

Renal allograft assessment including: function and failure 

Subject survival status

EuroQoL Group 5-Dimension 5-Level Self–report Questionnaire

Healthcare resource utilization

Submission of pathology slides/images from screening qualifying AMR biopsy (if not 
submitted earlier, after randomization)
7.1.3.2
Month 3 (±21 days)

Body weight

Serum BUN and creatinine with eGFRMDRD (local and central laboratories)

Central lab Proteinuria: spot urine protein, urine creatinine, and urine protein to urine 
creatinine ratio

Central lab Anti-C1 INH antibodies

Central lab Donor-specific antibody identification 

Concomitant  medications

Adverse event monitoring 

Renal allograft assessment including: function and failure


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
Subject survival status

EuroQoL Group 5-Dimension 5-Level Self–report Questionnaire

Healthcare resource utilization
7.1.3.3
Month 6 (±21 days)

Presence/absence of diabetes

Body weight

Serum BUN and creatinine with eGFRMDRD (local and central laboratories)

Central lab Proteinuria: urine protein, urine creatinine, and urine protein to urine creatinine 
ratio

Kidney allograft biopsy and submission of pathology slides/images

Central lab Anti-C1 INH antibodies

Central lab Donor-specific antibody identification 

Concomitant medications

Adverse event monitoring

Renal allograft assessment including: function and failure

Subject survival status

EuroQoL Group 5-Dimension 5-Level Self–report Questionnaire

Healthcare resource utilization
7.1.3.4
Months 12 (±21 days), Months 18, 24, 30, 36, 42 (all ±28 days)

Body weight

Serum BUN and creatinine with eGFRMDRD (local and central laboratories)

Central lab Proteinuria: spot urine protein, urine creatinine, and urine protein to urine 
creatinine ratio

Central lab Anti-C1 INH antibodies (only if antibodies are detected at the previous time 
point)

Central lab Donor-specific antibody identification 

Concomitant medications

Adverse event monitoring

Renal allograft assessment including: function and failure

Subject survival status

EuroQoL Group 5-Dimension 5-Level Self–report Questionnaire

Healthcare resource utilization


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7.1.3.5
EOS Visit/Month 48 [±28 days] or at patient discontinuation if after 
Month 6 Visit 

Presence/absence of diabetes

Body weight

Serum BUN and creatinine with eGFRMDRD (local and central laboratories)

Central lab Proteinuria: spot urine protein, urine creatinine, and urine protein to urine
creatinine ratio

Central lab Anti-C1 INH antibodies

Central lab Donor-specific antibody identification

Concomitant medications

Adverse event monitoring

Renal allograft assessment including: function and failure

Subject survival status

EuroQoL Group 5-Dimension 5-Level Self–report Questionnaire

Healthcare resource utilization
All AEs and SAEs that are not resolved at the time of this contact will be followed to closure 
(see Section 8.1).
7.1.3.6
Early Discontinuation Visit: Discontinuation between End of 
Investigational Product Dosing (Day 13) and Month 6 (not applicable if discontinuation 
is from treatment only)

Body weight

Serum BUN and creatinine with eGFRMDRD (local and central laboratories)

Proteinuria: spot urine protein, urine creatinine, and urine protein to urine creatinine ratio

Renal allograft biopsy and submission of pathology slides/images

Donor-specific antibody identification

Concomitant medications

Adverse event monitoring

Renal allograft assessment including: function and failure

Subject survival status
7.1.4
Additional Care of Subjects After the Study
No after care is planned for this study.


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7.2
Study Evaluations and Procedures
Subjects meeting the eligibility criteria listed in Section 4 may be enrolled in the study after the 
nature and purpose of the protocol have been explained and written informed consent to 
participate has been voluntarily granted by the subject. All subjects will have a screening 
evaluation performed after the qualifying biopsy such that the first dose of investigational 
product can be administered within 7 days from the biopsy that is diagnostic of the qualifying 
AMR episode. The schedules of study procedures and blood sample collection for 
pharmacokinetic/pharmacodynamic assessments are provided in Table 1, Table 2, and Table 3, 
respectively.
7.2.1
Demographic and Other Baseline Characteristics
Age and/or birth date, sex, race, and ethnicity will be recorded for all subjects.
7.2.2
Efficacy
7.2.2.1
Donor-specific Antibody Identification 
A histocompatibility screen for DSA identification and specificity by solid phase immunoassays 
will be performed by the local and central laboratories at Screening, and per-protocol only by the 
central laboratory at Day 25, and subsequent study visits as specified in Table 2. DSA 
identification is mandatory for the local lab at Screening and may be performed at other time 
points by the local laboratory at the discretion of the investigator as part of standard of care. 
Clinical decisions will be based on local laboratory analysis.  
Samples will be sent to a central laboratory at Screening, Day 25, Month 3, 6, 12, 18, 24, 30, 36, 
42, and 48. Panel reactive antibody will also be assessed. Additional antibody and titer testing 
may be performed in the future.  
All results will be recorded.
7.2.2.2
Renal Allograft Biopsies
Qualifying Biopsy
The qualifying renal allograft biopsy will have been performed as standard of care between 
72 hours and 12 months after transplant and prior to screening for this study. The qualifying 
biopsy will be used to establish the diagnosis of AMR. Biopsy slides and a representative 
micrograph images (including, but not limited to EM) will be sent, within 30 days after the 
biopsy, to the Sponsor's designee, and then to the independent, blinded pathology EAC for 
confirmation of acute AMR and as a baseline for comparison with the Month 6 biopsy. It is 
recommended that at least 2 separate cores containing cortex be obtained for the qualifying 
biopsy. 
Month 6 (Post-treatment) Biopsy
The Month 6 (post-treatment) biopsy is required by this protocol. At least 2 separate cores 
containing cortex must be obtained (this requirement must be applied for subjects who 
discontinue prior to 6 months as well). 


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The biopsy slides and representative micrographs (including, but not limited to EM images) will 
be sent within 30 days after the Month 6 biopsy, to the Sponsor's designee, and then to the 
independent, blinded pathology EAC for comparison with the qualifying biopsy to assess 
changes in histopathology.
Additional Biopsies
Subjects may have additional “for-cause” or scheduled biopsies as part of their standard-of-care 
treatment. For biopsies obtained at any time from enrollment through the study follow-up period, 
pathology slides and representative micrographs (including, but not limited to EM images) will 
be sent, within 30 days after the biopsy, to the Sponsor's designee, and then to the pathology 
EAC. Biopsies that demonstrate evidence of infiltrating neutrophils and/or monocytes with or 
without the presence of C4d, following resolution of the prior AMR episode, will qualify as new
biopsy-proven acute AMR, and retreatment may be given with the same investigational product 
to which the subject was originally randomized as well as plasmapheresis, plasma exchange, or 
immune adsorption treatments and sucrose-free IVIg per protocol. The retreatment qualifying 
biopsy slides and representative micrographs (including, but not limited to EM images) will be 
sent, within 30 days after the biopsy, to the Sponsor's designee, and then to the pathology EAC 
for confirmation of acute AMR. Available biopsy slides and micrographs used to determine 
AMR episode resolution must also be sent to the pathology EAC for confirmation of acute AMR 
resolution. Additionally, any subject that discontinues from the study after receiving dosing for 
the qualifying episode of AMR and prior to the Month 6 follow-up Visit, will have a biopsy 
(±2 weeks from discontinuation) and its slides and EM images sent to the pathology EAC for 
determination of TG. 
Histopathology
Additional instruction outside of this protocol will be provided to all sites regarding details on 
slides and image requirements.
Representative histopathology sections of each renal allograft biopsy (qualifying and all 
post-treatment biopsies) will be sent for processing to the investigative site’s pathologist. Glass 
slides are required for Periodic acid Schiff, hematoxylin and eosin, trichrome and silver stains. If 
possible, glass slides for CD34 and CD68 must also be provided. The pathologist will process 
sections: (1) for hematoxylin and eosin stain and Periodic acid Schiff, trichrome, and silver stains 
and (2) for C4d presence by immunofluorescence (C4d images are required even if negative). If 
immunofluorescence images are not available, immunohistochemical glass slides must be 
provided instead. Whenever possible, sections will also be processed for immunoperoxidase 
stain for CD34 and CD68. Additionally, biopsy tissue remaining after the qualifying biopsy 
assessment should be preserved in paraffin or another method appropriate for EM processing. 
Electron microscopy images will be obtained locally for patients enrolled in the study. Biopsy 
tissue from the Month 6 biopsy will be also obtained for EM processing. Representative EM 
images obtained locally will be sent to the pathology EAC for determination of the presence of 
early GBM and/or endothelial damage not seen on light microscopy. This will be used for an 
exploratory analysis of long-term outcomes associated with such early changes seen only on EM.  


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Further details on glass slides and images required for submission to the pathology EAC will be 
provided in a separate document.
Biopsy slides and representative micrographs (including, but not limited to EM images) will be 
sent by the sites to the Sponsor's designee within 30 days after the biopsy, and will be provided 
to an independent, blinded pathology EAC for determination of the presence of new or 
worsening TG at 6 months of initiation of treatment. Furthermore, any additional biopsy that 
qualifies the subject for retreatment per protocol or that will be used to define AMR episode 
resolution will also be sent to the pathology EAC. Acute AMR confirmation will be according to 
published Banff criteria. These data will be recorded. 
Electron Microscopy
Tissue specimens will be processed locally for EM. EM images for the qualifying biopsy are 
required if EM was performed as standard of care, or if biopsy tissue remaining after the 
qualifying biopsy assessment is available for EM processing. EM images are required for the 
Month 6 visit, or if a patient discontinues the study after initial treatment and prior to the Month 
6 visit (if possible to obtain). Representative images will be sent to the independent, blinded 
pathology EAC to assess new or worsening TG at 6 months of initiation of treatment. In 
addition, the pathology EAC will use the EM images to determine the extent of GBM disease 
and endothelialitis consistent with early TG, and to determine the association of such early 
changes not yet evident on light microscopy with long-term outcomes to support an exploratory 
analysis.  
Determination of Antibody-Mediated Rejection on Biopsy
The independent, blinded pathology EAC will record categorical information using the Banff 
criteria from the qualifying biopsies, Month 6 biopsies, and any other biopsies processed for light 
microscopy (and EM) and sent for their evaluation according to the EAC Charter.
7.2.2.3
Resolution of Qualifying and Recurrent AMR Episodes
Serum creatinine may be tested locally outside of the protocol-mandated time points at the 
discretion of the investigator as part of standard of care, in order to assess resolution of AMR. 
The pre-AMR baseline is the highest eGFRMDRD value obtained following the kidney transplant 
and within 30 days prior to the qualifying AMR episode. If more than 1 eGFRMDRD value is 
available, a mean of the 2 highest values (at least 1 day apart and both prior to the AMR episode) 
will be used as the pre-AMR baseline value. If no eGFRMDRD was obtained within 30 days prior 
to the qualifying AMR episode, it can be evaluated within a 60 day period. Resolution will be 
achieved when, after treatment, the local eGFRMDRD value increases to at least within 20% or 
above the eGFRMDRD value collected as a pre-AMR baseline. If an AMR episode is diagnosed, in 
the absence of significant decline (≥20%) eGFR from pre-AMR baseline, a follow-up biopsy 
within 3 months is recommended in order to assess resolution. Resolution is defined initially by 
the local pathologist according to histological findings and later confirmed by the pathology 
EAC, and should be based on improvement from previous biopsy and characterized by Banff 
criteria as: (g + ptc) <2 if C4d-negative; (g + ptc) = 0 if C4d-positive. 


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The investigator will record the applicable eGFRMDRD values and the date of resolution of the 
qualifying and recurrent AMR episodes in the CRF, when applicable, including the criteria used 
for determination of resolution (clinically and/or through histopathology).
7.2.2.4
Recurrence of AMR During the First 180 days of the Study
Recurrence is defined as biopsy evidence of AMR after resolution of a previous AMR episode. 
The investigator will record the date of recurrence of AMR episode in the CRF, when applicable. 
During the first 180 days after the qualifying biopsy, if the qualifying AMR episode resolves and 
there is new biopsy-proven acute AMR per protocol inclusion criteria, the subject may be 
retreated at the investigative site with the same investigational product to which they were 
originally randomized as well as DSA reduction treatment and sucrose-free IVIg per protocol. 
Prior to the first retreatment dose of investigational product, subjects will complete a subset of 
the screening procedures as indicated in the Screening Retreatment column in Table 1 and then 
will follow subsequent study treatment visits and procedures as noted in Table 1 and Table 2. 
Inclusion criteria 1 and 5 are not applicable for retreatment eligibility and signing of a new 
consent form is not required for retreatment. Retreatment should occur as soon as possible within 
7 days of the biopsy that defined the new AMR episode. Retreatment may not occur for recurrent 
AMR episodes diagnosed through biopsies done after the first 180 days after the qualifying 
biopsy date. Biopsies at 6 months following retreatment are not required. The only biopsy 
follow-up mandated by the study will be at Month 6 after initial treatment. With the exception of 
the Month 6 biopsy, completion of follow-up biopsies after the qualifying AMR episode is at the 
discretion of the study sites per local standard of care. Biopsy slides and images for unscheduled 
standard of care biopsies will also be submitted to the EAC.
7.2.2.5
Allograft Failure
Allograft failure due to AMR is determined by the presence of the following criteria: institution 
of permanent dialysis (defined as dialysis treatment >30 days), current renal allograft 
nephrectomy, and/or a clinical determination that the allograft irreversibly and irrevocably ceases 
functioning and eGFRMDRD ≤15 mL/min/1.73m2. Renal allograft function will be assessed and an 
eGFRMDRD and recorded at all timepoints. If the subject returns to or permanent dialysis is 
initially instituted in the case of pre-emptive kidney transplant recipients, the date of return or 
institution of permanent dialysis will be recorded. All cause graft failure may occur due to causes 
other than chronic ongoing AMR and include the following: (1) chronic cellular rejection, 
(2) heart disease, (3) hypertension, (4) diabetes, (5) drug toxicity, and (6) recurrent native kidney 
disease. The independent blinded nephrology EAC will assess graft failure events to determine 
and document the cause.  
7.2.2.6
Splenectomy
The date of splenectomy (if necessary) performed any time from Screening through the EOS 
Visit will be recorded in the CRF.
7.2.2.7
Subject Survival Status
Subject survival status (yes/no) will be determined at all timepoints. The date and cause of death 
will be recorded in the CRF.


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7.2.2.8
Donor-specific Antibody Reduction Treatments and Intravenous 
Immunoglobulin
To reduce DSA, subjects will be required to receive a minimum of 5 plasmapheresis, plasma 
exchange, or immune adsorption treatments (the choice of any of these procedure(s) will be 
based on standard-of-care at each study site) from the time of diagnostic biopsy for qualifying 
episode of acute AMR through Study Day 13. Each DSA reduction treatment will be followed by 
no less than 100 mg/kg sucrose-free IVIg. Protocol-mandated plasmapheresis, plasma exchange, 
or immune adsorption treatments should be completed by Day 13. Additional DSA reduction 
treatments and sucrose-free IVIg may be administered at the discretion of the investigator as part 
of standard of care. NOTE: If plasmapheresis, plasma exchange, or immune adsorption treatment 
occurs on the same day as investigational product dosing, investigational product will be 
administered after completion of the DSA treatment session and dosing of sucrose-free IVIg. 
Blood collection for laboratory assessments, other than those specified on Table 3, should be 
performed prior to the DSA reduction treatments. Investigators will record details of each DSA 
reduction treatment and each sucrose-free IVIg dose in the CRF.
7.2.3
Safety
The name and address of each third party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.
7.2.3.1
Medical History
All medical history findings that have been present/active within 5 years prior to enrollment will 
be recorded regardless of clinical relevance or presence at study start. Medical history findings 
that have not been active within the 5 years prior to enrollment will be recorded only if deemed 
clinically relevant by the investigator to the conduct of the study. The medical history should 
include any history of allergic reactions to drugs.
In addition, the following information will be recorded:

Primary cause of native renal failure: diabetes (type 1 or type 2); hypertension; diabetes and 
hypertension; any glomerulonephritis (eg, focal sclerosing segmental glomerulosclerosis, 
rapidly progressing glomerulonephritis, membrano-proliferative glomerulonephritis); any 
autoimmune nephropathy (eg, systemic lupus erythematosus, Goodpasture’s syndrome, 
Immunoglobulin A nephropathy); drug toxicity (eg, lithium, non-steroidal anti-inflammatory 
abuse); congenital defect (eg, posterior urethral valves); Polycystic Kidney Disease or other  

Diabetes (yes/no)

Onset date of AMR and pre-AMR eGFRMDRD that qualifies the subject to the study

Total number of lifetime kidney transplants (one bilateral kidney transplant procedure counts 
as one procedure)

Other transplants (eg, heart, lung, liver, small bowel, pancreas, other) 

Total number of plasmapheresis, plasma exchange, or immune adsorption treatments in the 
14 days prior to transplant through 14 days post-transplant


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
Prior splenectomy (yes/no; if yes, then date of splenectomy)

Date of current transplant

Type of current transplant (deceased donor, living related donor, or unrelated living donor, 
extended criteria donor (per site standard), donor after cardiac death)

Confirmation that there is no existing lesion in the transplanted allograft 

Active treatment of HCV

MI or TIA within 6 months prior to study entry

ABO incompatible kidney transplant (yes/no)

Lowest serum Cr within 30 days after the current transplant (and before the qualifying 
episode of AMR)

Highest serum Cr on day of qualifying renal allograft biopsy (±2 days)

Need for any dialysis within the first 14 days after the current transplant (yes/no)

Need for any dialysis within 14 days prior to first dose of investigational product (yes/no)

Specificity of DSA prior to current kidney transplant, if applicable (HLA class I [yes/no; if 
yes, specify antigen] and/or HLA class II [yes/no; if yes, specify antigen])

Specificity of DSA closest to and within ±7 days of the qualifying biopsy (HLA class I 
[yes/no; if yes, specify antigen] and/or HLA class II [yes/no; if yes, specify antigen])

Use of any of the following medications administered for immunosuppression within the 
period of 2 weeks before through 2 weeks after the current transplant, including the date of 
transplant (yes/no for each):

Any IV steroids

Rituximab 

Muromonab-CD3

Alemtuzumab

Anti-thymocyte globulin (rabbit)

Lymphocyte immune globulin, anti-thymocyte globulin (equine)

Any sucrose-free IVIg preparation

Daclizumab or basiliximab

Other: specify
Refer to Section 5.3 and 5.5 for additional requirements on medication history.
7.2.3.2
Physical Examination (Including Height and Weight)
Abnormalities identified during the Physical Examination done at the Screening Visit will be 
documented in the subject’s source documents and on the medical history CRF. 


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If the abnormality is clearly caused by an event that occurred after the subject signed informed 
consent and before the Physical Examination of the Screening Visit, the event will be captured as 
an AE (Section 7.2.3.3). Changes after the Physical Examination of the Screening Visit will be 
captured as AEs on the AE CRF page, as deemed by the investigator. 
The investigator or designee will perform physical examinations at time points specified in
Table 1. Physical examinations will be performed in accordance with standard practices at the 
investigational site. Body weight and height will also be measured at time points specified in 
Table 1 and Table 2.
Additionally, a lower extremity exam will be performed at specified time points (Table 1) and 
will include a determination of presence or absence of unilateral calf tenderness or leg swelling 
that may be new since the previous examination. If a DVT is suspected, a diagnostic study will 
be performed (Section 8.2.4).
7.2.3.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events and SAEs will be recorded from the time the informed consent is signed through 
30 days after the last dose of investigational product regardless of relationship to investigational 
product. This includes events occurring during the screening period (does not include 
abnormalities identified during the Physical Examination at the Screening Visit, that are not 
directly caused by an event that occurred after signing informed consent and before the 
Screening Physical Examination), regardless of whether or not investigational product has been 
administered. Following the 30-day capture period for all AEs and SAEs, only those AEs/SAEs 
deemed related to investigational product or other protocol-mandated procedures will be 
collected during the long-term follow-up phase of the study. If the subject undergoes retreatment 
with investigational product for a new AMR episode, AEs and SAEs will be captured as 
described above for the treatment of the initial occurrence of AMR. In addition, the following 
events of special interest, both serious and non-serious, will be closely monitored and reported to 
PVRM via SAE form throughout the study, regardless of relationship to investigational product: 
any thrombotic or thromboembolic event (Section 8.2.4), any hypersensitivity reaction, any new 
episode of kidney allograft rejection (excluding AMR), and any kidney allograft failure as 
defined by Section 7.2.2.5. Refer to Section 8, Adverse and Serious Adverse Events Assessment.
7.2.3.4
Vital Signs
Vital signs include blood pressure and pulse. Any deviations from Screening in vital signs that
are deemed clinically significant in the opinion of the investigator are to be recorded as an AE. 
On investigational product dosing days, vital signs should be obtained within 30 minutes prior to 
investigational product administration and then between 30 minutes and 1 hour after completion 
of investigational product infusion. Additional vital signs measurements will be performed 
during the study if clinically indicated.


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7.2.3.5
Clinical Laboratory Evaluations
7.2.3.5.1 Central Laboratory Testing
Clinical laboratory safety tests will be performed by a central laboratory at the time points on 
Table 1 and Table 2. Eligibility will be determined based on local laboratory DSA values. On 
investigational product dosing days, blood samples for clinical safety laboratory testing should 
be collected prior to the administration of investigational product. All clinical laboratory assays 
will be performed according to the central laboratory’s normal procedures. Reference ranges will 
be supplied by the central laboratory and will be used to assess the clinical laboratory data for 
clinical significance and out-of-range pathological changes. The investigator should assess 
out-of-range clinical laboratory values for clinical significance, indicating if the value(s) is/are 
not clinically significant or clinically significant. Abnormal clinical laboratory values that are 
unexpected or not explained by the subject’s clinical condition may, at the discretion of the 
investigator or sponsor, be repeated as soon as possible until confirmed, explained, or resolved.
The following clinical laboratory assessments will be performed by the central laboratory: 
DSA Identification 
Please see Section 7.2.2.1. Collection for the Central laboratory will be performed at all 
timepoints according to Table 1 and Table 2.
Chemistry

albumin

glucose

alanine aminotransferase

lactate dehydrogenase

alkaline phosphatase

phosphorus

aspartate aminotransferase

potassium

blood urea nitrogen

sodium

calcium

spot urine protein

bicarbonate

total bilirubin

chloride

total cholesterol

creatinine (including eGFRMDRD 
calculation)

total protein

direct bilirubin

uric acid

gamma-glutamyl transferase
BUN and serum creatinine with eGFRMDRD calculation (for time points that do not include the 
above chemistry panel)
Hematology

complete blood count with differential

platelet count

hematocrit

red blood cell count

hemoglobin

white blood cell count with differential


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Virology Screen

Hepatitis (Hepatitis B Surface Antigen, Hepatitis C Antibody)
Anti-C1 INH Antibodies
Blood samples will be collected at screening (pre-dose sample should always be collected at 
screening), on Day 25, and at Months 3 and 6 for determination of anti-C1 INH antibodies. If 
sucrose-free IVIg is administered at the screening visit, a sample for anti-C1 INH will be 
collected before (pre-dose sample) and after sucrose-free IVIg administration (post-dose 
sample). Subjects with anti-C1 INH antibodies will be followed at the time points specified in 
Table 2, to measure titers. For Months  12, 18, 24, 36, and 48 the test will be performed ONLY if 
anti-C1 INH antibodies are detected at the previous time point. For Months 3 and 6 the test will 
be performed for each subject. See Table 2.
Pharmacokinetic/Pharmacodynamic Assessments
See section 7.2.4.1
Urinalysis
A urine sample will be collected at the visits specified on Tables 1 and 2 for the assessment of 
proteinuria, to include spot urine protein, urine creatinine, and urine protein to creatinine ratio.
7.2.3.5.2 Local Laboratory Testing
Local laboratory testing will be used to determine subject eligibility and for all clinical decisions.  
The following tests will be performed by the local laboratory:
DSA Identification 
Please see Section 7.2.2.1. DSA testing at the local laboratory is only required at screening. If it 
is anticipated that the local DSA results will not be available within the screening period, 
previously obtained local DSA results can be used to assess eligibility, if obtained after kidney 
transplant and between 30 days prior to the biopsy that is diagnostic of the qualifying AMR 
episode and the time of obtaining informed consent. In any instance, a screening local DSA test 
should be performed after obtaining informed consent. Additional DSA tests may also be done 
locally at other time points at the discretion of the investigator according to local standard of 
care.
Safety Laboratories
Safety local laboratory values including white blood cell (WBC) count and platelets from the 
local laboratory will be used to determine eligibility. 
BUN, Creatinine and eGFR Calculation
BUN and Serum Creatinine will be tested locally at all protocol-required study visits, and 
creatinine can be tested outside of the protocol-required study visits at the discretion of the 
investigator as part of standard of care in order to calculate eGFR and assess pre-AMR and 
resolution of AMR for all AMR episodes (qualifying and recurrent).


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Pre-AMR eGFR values are required for all episodes of AMR in order to assess eligibility for 
enrollment into the study and for re-treatment of recurrent AMR episodes occurring within the 
first 180 days after the qualifying biopsy. The eGFRMDRD need to also be obtained at screening 
(or screening for retreatment), using the first creatinine value available after the qualifying (or 
recurrent) biopsy that is diagnostic for AMR. At screening, this will be used for the purpose of 
assessing AMR severity for stratification. Pre-AMR and Resolution of AMR eGFR values are 
also required for all AMR episodes when AMR resolution is assessed clinically. Otherwise, 
resolution can only be assessed through histopathology (see Section 7.2.2.3).  
Clinical sites will calculate the eGFR, including the pre-AMR eGFR baseline for each episode of 
AMR as well as their clinical resolution, using the local serum creatinine results and the 
appropriate MDRD equation as follows:
For standardized (IDMS-calibrated) serum creatinine assays:
eGFRMDRD = 175 x (standardized serum Cr)-1.154 x (Age)-0.203 x[1.210 if Black] x [0.742 if 
female] x [0.808 if Japanese]
For non-standardized (non-IDMS-calibrated) serum creatinine assays:
eGFRMDRD = 186 x (serum Cr)-1.154 x (age) -0.203 x[1.210 if Black] x [0.742 if female] x [0.808 if 
Japanese]
eGFR is expressed in mL/min1.73m2, serum creatinine is expressed in mg/dL, and age is 
expressed in years.
Coagulopathy Panel
In the event that a subject experiences an unexplained clinically significant thrombotic or 
thromboembolic event (Section 8.2.4), a coagulopathy panel will be performed at the site’s local 
laboratory when clinically feasible to obtain, which may include at the discretion of the 
investigator some of the following test parameters:

Activated protein C resistance ratio

Homocysteine level

Alpha 2 Antiplasmin functional

Plasminogen Activator Inhibitor-1

Anti-phospholipid antibody

Protein C activity

Antithrombin III antigenic level

Protein C antigen

Antithrombin III functional

Protein S activity

Factor V, VIII, IX, XI levels

Protein S antigen
7.2.3.6
Pregnancy Test
A urine pregnancy test and a confirming serum beta-HCG pregnancy test (central and local 
laboratories) will be performed on females of child-bearing potential at the Screening Visit, and 
a urine pregnancy test will be performed on females of child-bearing potential on Day 1 of each 
AMR episode prior to investigational product administration.


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7.2.3.7
Electrocardiogram
A 12-lead ECG will be performed at the Screening visit and at any additional time during the 
study if clinically indicated per standard of care. Each ECG will include heart rate, RR Duration, 
PR duration, QT duration, QRS duration. QTcF will be programmatically derived. The 
investigator will be responsible for providing the interpretation for all ECGs in terms of clinical 
significance to the subject.
7.2.4
Others
7.2.4.1
Pharmacokinetic/Pharmacodynamic Assessments
Blood samples for the determination of plasma concentrations of functional and antigenic 
C1 INH and complement components C3a and C5a will be collected at time points shown in 
Table 3. “Time of dose” is defined as the start of the investigational product infusion.
Of note, if plasmapheresis, plasma exchange, or immune adsorption treatments are performed on 
a dosing day, blood samples for pharmacokinetic/ pharmacodynamic testing will be obtained 
before the DSA reduction and sucrose-free IVIg treatments, as well as prior to investigational 
product administration (ie, post-DSA reduction treatment), and at time points relative to the start 
of the investigational product infusion, as outlined in Table 3. The actual date and time of each 
sample collection will be recorded. Plasma samples for the determination of antigenic and 
functional C1 INH concentrations and complement C3a and C5a levels will be analyzed 
according to validated methodology.  
In addition, plasma samples will be stored and may be used to investigate additional complement 
or cytokine levels that might correlate with response to treatment.
7.2.4.2
Health Outcomes and Outcomes Research Assessments
The validated quality of life EQ-5D-5L questionnaire will be administered to subjects at the time 
points on Table 1 and Table 2.
7.2.4.3
Healthcare Resource Utilization 
Healthcare resource utilization will be assessed at the time points on Table 1 and Table 2.


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8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995).
All AEs and SAEs will be recorded from the time the informed consent is signed through 
30 days after the last dose of investigational product regardless of relationship to investigational 
product. This includes events occurring during the screening period, regardless of whether or not 
investigational product has been administered. Following the 30-day capture period for all AEs 
and SAEs, only those AEs/SAEs deemed related to investigational product or other 
protocol-mandated procedures as well as the events of special interest regardless of relationship 
to investigational product (any thrombotic or thromboembolic event, any hypersensitivity 
reaction, any new episode of kidney allograft rejection [excluding AMR] - Section 8.1.4) will be 
collected during the long-term follow-up phase of the study. If the subject undergoes retreatment 
with investigational product for a new AMR episode, AEs and SAEs will be captured as 
described above for the treatment of the initial occurrence of AMR. Where possible, a diagnosis 
rather than a list of symptoms should be recorded. If a diagnosis has not been made, then each 
symptom should be listed individually. All AEs should be captured on the appropriate AE pages 
in the CRF and in source documents. In addition to untoward AEs, unexpected benefits outside 
the investigational product indication should also be captured on the AE CRF.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).


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The medical assessment of severity is determined by using the following definitions:
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of daily 
living.
Moderate:  A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses no significant 
or permanent risk of harm to the research subject.
Severe:  A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.
8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source document.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product is compelling and/or follows a known or suspected response 
pattern to that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident.
Not Related
The event can be readily explained by other factors such as the subject’s underlying 
medical condition, concomitant therapy, or accident and no plausible temporal or 
biologic relationship exists between the investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the CRF. Outcomes are 
as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae 


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
Recovering/Resolving

Unknown
8.1.4
Adverse Events of Special Interest
In addition, the following events of special interest, both serious and non-serious, will be closely 
monitored and reported to Shire PVRM via SAE form throughout the study, regardless of 
relationship to investigational product:

Any thrombotic or thromboembolic event: thrombotic or thromboembolic events will be 
assessed for relatedness to investigational product. Stopping rules related to thrombotic or 
thromboembolic events are described in Section 4.5.3.

Any hypersensitivity reaction

Any new episode of kidney allograft rejection (excluding AMR)

Kidney allograft failure as defined in Section 7.2.2.5
AESIs reported via SAE form that do not meet the serious criteria definition (Section 8.2.3) 
should be reported on the SAE form as being non-serious.  
8.1.5
Symptoms of the Disease Under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. Please note that AMR should not be classed as an AE.
8.1.6
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pre-treatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.


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8.1.7
Pregnancy
All pregnancies are to be reported from the time informed consent is signed and throughout the 
defined post-treatment follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Pharmacovigilance Department using 
the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire Medical Monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days post-partum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Trial Serious Adverse Event 
Form. NOTE: An elective abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Trial Serious Adverse Event Form as well 
as the Shire Investigational and Marketed Products Pregnancy Report Form. The test date of the 
first positive serum/urine beta-HCG test or ultrasound result will determine the pregnancy onset 
date.
8.1.8
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as described 
in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to reports of 
abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society

Misuse – Intentional use of investigational product other than as directed or indicated at any 
dose (Note: this includes a situation where the investigational product is not used as directed 
at the dose prescribed by the protocol)

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a pre-specified total daily dose of 125 U/kg of the product.


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
Medication Error – An error made in prescribing, dispensing, administration, and/or use of 
an investigational product. For studies, medication errors are reportable to the sponsor only 
as defined below.
Cases of subjects missing doses of the investigational product are not considered reportable as 
medication errors. Medication errors should be reported for all products under investigation. The 
administration and/or use of the unassigned treatment is/are always reportable as a medication 
error. The administration and/or use of an expired investigational product should be considered 
as a reportable medication error.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information (RSI) for this study is located in the Investigator’s 
Brochure, which the sponsor has provided under separate cover to all investigators. 
There is limited clinical experience with CINRYZE in kidney transplant patients with acute AMR 
at the dose intended for clinical use (ie, 9 subjects in the Phase 2 pilot study 0624-201). Safety 
data from these 9 patients were reviewed, and it has not been possible to define any expected 
adverse reactions (ADRs) to date.
Therefore, there is currently not enough information to establish a list of expected AEs in this
population.
8.2.2
Reporting Procedures
All initial and follow-up SAE and AESI reports must be reported by the investigator to the Shire 
Pharmacovigilance Department and the PPD Clinical Study mailbox within 24 hours of the first 
awareness of the event. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors (Section 8.1.8) unless they result in an 
SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event
Form and verify the accuracy of the information recorded on the form with the corresponding 
source documents (NOTE: Source documents are not to be sent unless requested) and fax or 
e-mail the form to the Shire Pharmacovigilance Department and the PPD Clinical Study mailbox. 
A copy of the Shire Clinical Trial Serious Adverse Event Form (and any applicable follow-up 
reports) must also be sent to the Shire Medical Monitor / PPD Medical Monitor using the details 
specified in the emergency contact information section of the protocol.


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8.2.3
Serious Adverse Event Definition
A Serious Adverse Event (SAE) is any untoward medical occurrence (whether considered to be 
related to investigational product or not) that at any dose:

Results in death

Is life-threatening. Note: The term ‘life-threatening’ in the definition of “serious” refers to an 
event in which the subject was at risk of death at the time of the event; it does not refer to an 
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not be 
classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity

Is a congenital abnormality/birth defect

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 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.

For the purposes of this study: clinically significant thrombotic or thromboembolic event  
(Section 8.2.4)
8.2.4
Thrombotic or Thromboembolic Events
Evaluation of any suspected thrombotic or thromboembolic events will follow the algorithm 
outlined in Appendix 4. Clinically significant thrombotic or thromboembolic events (except 
superficial thrombophlebitis, dialysis access clotting, or catheter-related thrombotic events, 
unless these meet serious criteria as defined in Section 8.2.3) will be reported via SAE form as 
SAE and will include established diagnoses of any of the following:

Renal allograft arterial or venous thrombosis

Deep vein thrombosis

Myocardial infarction

Pulmonary embolism

Ischemic cerebrovascular accident (stroke), or transient ischemic attack (TIA), exclusive of 
cerebrovascular hemorrhage (subarachnoid or subdural hemorrhage)

Any large vessel thrombosis (exclusive of the presence of an indwelling catheter)


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Diagnosis must be established with a confirmatory diagnostic examination that, at the discretion 
of the investigator, may include but is not limited to: ultrasound or angiography of the allograft 
consistent with absence of flow in the renal vein or renal artery; ultrasound of the deep veins 
suggesting non-compressibility and/or a venography confirming occlusion of the vessel (DVT); 
coronary arteriography confirming occlusion of the vessel within the distribution of the ECG 
deficit (myocardial infarction); pulmonary angiography confirming pulmonary artery occlusion 
or definitive defect on nuclear medicine lung V/Q scan (pulmonary embolism); cerebral 
angiogram confirming occlusion of a major cerebral artery (ischemic cerebrovascular accident); 
or any other angiogram confirming thrombotic or thromboembolic occlusion of any large artery 
or vein.
Evaluation of subjects with unexplained clinically significant thrombotic or thromboembolic 
events should include a coagulopathy panel when clinically feasible to obtain (Section 7.2.3.5).
8.2.5
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to investigational product) are collected from the time the 
subject signs the informed consent until the defined follow-up period stated in Section 8.1, and 
must be reported to the Shire Pharmacovigilance Department and the CRO/Shire Medical 
Monitor within 24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
8.2.6
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.7
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded. For all other events 
ongoing at the time of death that did not contribute to the subject’s death, the outcome should be 
considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or “not 
applicable” (if the subject never received investigational product).


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8.2.8
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical CRO are responsible for notifying the relevant regulatory authorities 
US institutional review boards (IRBs) and EU central ethics committees (ECs) of related, 
unexpected SAEs.
In addition the clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP616 program.  
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.


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9.
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the CRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the CRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the CRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the CRF entry within approximately 3 business days of the subject’s 
visit.
9.2
Clinical Data Management
Data will be entered into a clinical database as specified in PPD’s data management plan.  
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data will be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification will 
be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Data Handling Considerations
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, treatment allocation, and investigational product preparation/ accountability data) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available. If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
All statistical analyses will be performed using SASVersion 9.3 or higher (SAS Institute, Cary, 
NC 27513).
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused and spurious data will be addressed. 
The SAP will be finalized prior to the first interim analysis to preserve the integrity of the 
statistical analysis and study conclusions.


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9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
9.5.1
Interim Analysis and Adaptive Design
The study is designed to have 2 analyses (1st and 2nd interim analyses) assessing the primary 
endpoint of new or worsening TG at 6 months after initiation of treatment. In addition, there will 
be 3 analyses (3rd and 4th interim analyses plus 1 final analysis) assessing proportions of 
subjects with all-cause graft failure, at approximately 50% (~26 events), 75% (~39 events), and 
100% (~51 events) of the study information. 
For the first interim analysis, the EACs, sponsor, investigator, as well as the subject will be 
blinded to the study treatment. When the criterion to conduct the second interim analysis is met, 
treatment assignment for those subjects will be unblinded to designated sponsor representatives 
for analysis. The treatment assignments for all subjects will be blinded to the EACs, investigator, 
and subjects during the conduct of the study. 
The purpose of the first interim analysis is to allow early stopping of the study for futility, to 
assess safety of the treatment, and potentially to adjust the sample size. This analysis will be 
performed when 30 subjects complete the Month 6 visit. A fraction of alpha (0.0001) will be 
spent at the first interim analysis and accounted for in the overall type I error rate. Even if the 
value of test-statistics exceeds the efficacy boundary, the trial will not be stopped for efficacy. 
Alternatively, as appropriate, the trial may be stopped for futility at the interim analysis or the 
sample size of the study may be adjusted up using the CHW method (Cui et al. 1999). The 
futility of the study at the first interim analysis will be determined by calculating the conditional 
power (CP) based on observed trend at interim. The pre-defined conditional power lower limit 
(CPLL) and upper limit (CPUL) will be used for decision making and are documented in the 
Statistical Analysis Plan for the interim analysis (IA).   
The purpose of the second interim analysis is to allow early stopping if the primary endpoint is 
not met or for claiming of efficacy based on new or worsening TG within at 6 months of 
initiation of treatment. This analysis will be done when a required number of subjects (based on 
the first interim analysis) complete the Month 6 TG assessments. If the result of the second 
interim analysis is statistically significant at 0.0249, the primary null hypothesis will be rejected. 
The test statistic at the second interim stage will be derived using CHW method and specified in 
the interim SAP.
The efficacy boundary of TG at 6 months of initiation of treatment will be pre-specified by 
Haybittle-Peto boundary (Haybittle 1971; Peto et al. 1976). The alpha level of 0.0001 is to be 
spent at the first interim analysis in developing the efficacy boundary of the second interim 
analysis of TG at 6 months of initiation of treatment. The overall significance level for the 
efficacy analysis of TG at 6 months of initiation of treatment will be preserved at 0.025 (1-sided 
test) by using a significance level of 0.0249 for the second interim analysis.
If the result of the second interim analysis of the primary endpoint indicates significant treatment 
effect on TG at 6 months of initiation of treatment, the study will continue to assess the 
long-term study outcomes including the key secondary endpoint (ie, proportion of subjects with 
all-cause graft failure).


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For the key secondary endpoint, the study information is event based. The study will continue 
until approximately 51 confirmed clinical events are reached unless stopped prematurely based 
on findings at an interim analysis or the last enrolled subject has been followed for 4 years. There 
will be 3 analyses (2 interim and 1 final) of proportions of subjects with all-cause graft failure, at 
approximately 50% (~26 events), 75% (~39 events), and 100% (~51 events) of the study 
information. The purpose of the 2 interim analyses is to allow early stopping of the study for 
overwhelming efficacy and assessing safety of the treatment. An alpha spending function 
approximating the O’Brien-Fleming boundary shape (O’Brien and Fleming 1979) will 
be employed to maintain an overall significance level at 0.025. The test statistics and 
boundary values for decision making at the 3 analyses (2 interim and 1 final) will be specified in 
the SAP.  
The actual stopping boundaries for this sequential design will be predetermined so that the 
overall significance level for the comparison of proportions of subjects with all-cause graft 
failure is maintained at =0.025. Further details regarding the sequential monitoring plan and 
decision rules will be prepared before the start of data monitoring and documented in the interim 
SAP.
The alpha-spending boundaries represent guidelines for further evaluation of the endpoints and 
other data. Excursions across the boundaries do not constitute stopping rules, per se. Decisions to 
alter the study conduct will be based on other information, as well.
If serious safety concerns are noted at the time of either interim analysis, the sponsor will 
communicate with the regulatory authorities and clinical sites as appropriate regarding stopping 
the clinical trial. If the 3rd or 4th interim analysis indicates the study can be stopped early for 
efficacy, the Sponsor will communicate with appropriate regulatory authorities to obtain 
agreement on the decision.
Full details of the analysis will be provided in the SAP.
9.5.2
Data Monitoring Committee
An independent DMC will be established to assess safety, efficacy, and futility during the 
study, as well as to ensure the validity and scientific merit of the trial. The DMC will monitor 
ongoing data generated by the study at defined intervals, as specified in the DMC charter, for the 
duration of the study including, but not limited to, after 30 subjects complete the Month 6 
TG assessment; after the re-estimated number of subjects, based on the first interim analysis 
recommendation, complete the Month 6 TG assessment; and after approximately 50% 
(~26 subjects) and 75% (~39 subjects) targeted subjects have experienced all-cause graft 
failure. Their role is to protect the interests of the subjects in the study and of those still to be 
entered, by review of accumulating data generated in the study.
The DMC charter will define the primary responsibilities of the DMC; guide its activities, 
its relationship with other study components, its membership, and the purpose and timings 
of its meetings. It will provide the procedures for ensuring the independence, 
confidentiality, formal communication, and outline of the content of reports that will be 
provided by the DMC. 


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For each interim analysis, the p-values, CP, summary statistics, and data listings will be provided 
to the DMC by an independent statistician supported by an independent statistical reporting 
group not otherwise assigned to the study.
In addition, the DMC will review reported SAE cases of specific drug-related thrombotic and 
thromboembolic events in the context of study stopping rules (Section 4.5.3), and will also 
evaluate interim efficacy data and make recommendations regarding study continuation, 
stopping or sample size adjustment based on observed results of the study. The recommendations 
made by the DMC to alter the conduct of the study will be forwarded to Shire. Shire will review 
the results with regulatory authorities, as appropriate, prior to any decisions regarding stopping 
the study or publically discussing interim results. 
9.5.3
Endpoint Adjudication Committee
9.5.3.1
Pathology Endpoint Adjudication Committee
An independent (no members employed by the sponsor or participating as an investigator in the 
study), blinded pathology EAC will be established to assess biopsy slides and images for 
confirmation of AMR for qualifying diagnoses and for determination of the presence of new or 
worsening TG at 6 months of initiation of treatment (Section 7.2.2) and for any additional 
biopsies evaluated. In addition, they will also assess graft failure events to determine the cause. 
The roles, responsibilities and rules governing operation of the pathology EAC are discussed in 
full in the pathology EAC charter.
9.5.3.2
Nephrology Endpoint Adjudication Committee
An independent (no members employed by the sponsor or participating as an investigator in the 
study), blinded nephrology EAC will be established to assess the outcomes of kidney allografts. 
This committee will confirm that the most current kidney allograft has failed to function and 
determine the primary cause of allograft (ie, AMR-related, recurrent kidney disease, drug 
toxicity, cardiac disease, diabetes, other-cause failure). The roles, responsibilities and rules 
governing operation of the nephrology EAC are discussed in full in the nephrology EAC charter.
9.6
Sample Size Calculation and Power Considerations
A total of 112 subjects (56 CINRYZE, 56 Placebo) will be randomized in a 1:1 ratio into 
2 treatment groups: CINRYZE or placebo. Sample size was calculated for the primary endpoint 
and the key secondary endpoint using nQuery Advisor 7.0.
The primary endpoint in the study is the proportion of subjects with new or worsening TG at 
6 months after treatment initiation. A 43% absolute difference in TG at 6 months between 
treatment groups (3/7 in placebo and 0/7 in CINRYZE) was observed in a subset of subjects 
(14/18) in the completed randomized Phase 2 pilot study (0624-201). For this study, the assumed 
proportion of subjects with new or worsening TG at 6 months will be 50% in the placebo group 
and 10% in the CINRYZE group. A sample size of 60 subjects (30 in placebo and 30 in CINRYZE) 
would be needed to obtain at least 90% power to detect a significant treatment difference at an 
alpha level of 0.025 (1-sided test).


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The key secondary endpoint in the study is the proportion of subjects with all-cause graft failure. 
Assuming the proportions of subjects with graft failure due to AMR are 64% and 25% for 
placebo and CINRYZE, respectively, and all-other-cause graft failure rate is 12% for both placebo 
and CINRYZE, then the proportions of subjects with all-cause graft failure are 68% and 34% for 
placebo and CINRYZE, respectively. A total of 100 subjects will provide 90% power to detect an 
absolute treatment difference of 34% at an alpha level of 0.025 (1-sided test) for all-cause graft 
failure. These assumptions are based on literature (Haririan et al. 2009; Sharif et al. 2014; 
OPTN/STRT Annual Data Report 2012). Considering a 10% drop-out rate during the study, 
112 subjects will be randomized to the study. Under these assumptions, the expectation is that 
there will be approximately 34 all-cause graft failures on placebo and approximately 17 all-cause 
graft failures on CINRYZE, giving 51 events total. The trial will continue until 51 such events are 
accrued and adjudicated by the nephrology EAC unless stopped prematurely based on findings at 
an interim analysis or until the final subject enrolled has been followed for 4 years post initial 
treatment with investigational product.  
9.7
Study Population
The All-enrolled Set will consist of subjects who have signed informed consent.
The Intent-to-Treat Population will consist of all subjects in the All-enrolled Set for whom a 
randomization number has been assigned. This set will be used for sensitivity analyses of 
efficacy endpoints.
The Full Analysis Set (FAS) will consist of all subjects who have taken at least 1 dose of 
investigational product. The FAS will be used for efficacy analysis according to assigned 
treatment.
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of 
investigational product. The Safety Analysis Set will be used for safety analysis according to 
actual treatment received.
The Per Protocol Analysis Set-1 will consist of all subjects in the FAS who have taken at least 
5 of the 7 planned doses, are assessed for TG at 6 months after initiation of treatment or have 
post-baseline biopsy-proven new or worsening TG within 6 months of initiation of treatment, 
and do not have predefined major protocol deviations that may affect the primary efficacy 
endpoint.
The Per Protocol Analysis Set-2 will consist of all subjects in the FAS who have taken at least 
5 of the 7 planned doses, are assessed for graft failure at 4 years, or have shown graft failure 
within 4 years, or died, and do not have predefined major protocol deviations that may affect the 
key secondary endpoint.
The Pharmacokinetic (PK) and Pharmacodynamic (PD) Analysis Set is defined as all 
subjects who received at least 1 dose of CYNRIZE and have at least 1 evaluable post-dose 
PK/PD concentration value.


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9.8
Efficacy Analyses
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as the proportion of subjects with new or worsening TG 
at 6 months post-treatment as determined by Banff criteria. The FAS set is the primary set for 
efficacy analysis. Subjects who do not have the primary efficacy endpoint assessed at 6 months 
post-dose will be assigned as failures.
The primary endpoint will be presented as the proportion of subjects with new or worsening TG 
occurring at 6 months post-treatment, and their difference between treatments (
Placebo
Cinryze

) is 
defined as follows:
Placebo
Cinryze
Placebo
Cinryze






Where 
Cinryze

is the proportion of new or worsening TG at 6 months post-treatment in the 
CINRYZE group and 
Placebo

is the proportion of new or worsening TG at 6 months post-treatment 
in the placebo group.
The analysis will employ a type I error rate of 0.025 (1-sided test) to test null hypothesis:
0
:
0




Placebo
Cinryze
H
Against the 1-sided alternative:
0
:




Placebo
Cinryze
a
H
In the initial plan, the statistical difference between treatments will be evaluated by the CHW 
weighted test statistic 
CHW
Z
when the first 60 subjects complete the assessments for the primary 
endpoint (second interim analysis). If the 
0249
.0
Z
Z CHW 
(equivalent to p-value from the test is 
0.0249 [1-sided test]), it will be concluded that CINRYZE is efficacious based on the proportion 
of subjects with new or worsening TG at 6 months after initiation of treatment and the result will 
serve as evidence of efficacy based on these 60 subjects. However, the number of subjects might 
be changed (increased) depending on the results of the first interim analysis in which the sample 
size will be re-estimated (Section 9.5.1).
Design features are in place to protect the study-wise error level at 0.025 (1-sided test) for testing 
the hypotheses related to primary and key secondary endpoints. In order to declare a successful 
study, statistical significance must be met successively on the surrogate endpoint of proportions 
of subjects with new or worsening TG at 6 months of initiation of treatment and on the endpoint
of all-cause graft failure. No adjustment for multiple co-primary endpoints is needed. The alpha 
spent at each endpoint will be controlled by sequential testing boundaries assuring that no more 
than 0.025 alpha (1-sided test) is expended in the multiple analyses across time for each of the 
primary and key secondary endpoints.


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A number of sensitivity analyses will be performed to assess any impact on the primary endpoint 
results, inference, and conclusions due to missing data. In addition, descriptive analyses on the 
primary endpoint will be provided in selected subgroups.
9.8.2
Secondary Efficacy Endpoints
9.8.2.1
Key Secondary Efficacy Endpoint
The key secondary endpoint is defined as the proportion of subjects with all-cause graft failure 
(ie, return to permanent dialysis and/or removal of the transplanted kidney and/or clinical 
determination of cessation of graft function) at 4 years following treatment of the initial 
qualifying AMR episode. The FAS population will be used to report the efficacy data for 
all-cause graft failure. Subjects who do not have the key secondary efficacy endpoint assessed 
post-dose will be assigned as failures.
The proportion of subjects with all-cause graft failure will be summarized by treatment group.  
Subjects with an assessment of all-cause graft failure or who drop out due to graft failure will be 
included in the hypothesis testing. 
The test statistics and boundary values for decision making at the 3 analyses (2 interim and 
1 final) will be specified in the SAP.
The null hypothesis for the proportion of subjects with all-cause graft failure post-treatment will 
be tested at the overall accumulative alpha level of 0.025 (1-sided test). This hypothesis will only 
be tested if testing for the primary endpoint of new or worsening TG at 6 months of initiation of 
treatment is statistically significant.
A number of sensitivity analyses will be performed to assess any impact on the key secondary 
endpoint results, inference, and conclusions due to missing data. In addition, descriptive analyses 
on the key secondary endpoint will be provided in selected subgroups.
9.8.2.2
Secondary Efficacy Endpoints
Secondary efficacy endpoints from study entry to 6 months are defined as:

Measurement of renal function (eGFRMDRD) at 6 months

Change in renal function (eGFRMDRD) from pre-AMR to 6 months 

Change in renal function (eGFRMDRD) from screening to 6 months

Measurement of proteinuria (spot urine protein, urine creatinine, and urine protein/urine 
creatinine ratio) at 6 months

Change in proteinuria (spot urine protein, urine creatinine, and urine protein/urine creatinine 
ratio) from screening to 6 months 

Change in histopathology per Banff criteria from pre-AMR to 6 months 

Proportion of subjects with all-cause graft failure at 6 months


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9.8.2.3
Secondary efficacy endpoints from study entry to 4 years are defined as:

Measurement of renal function (eGFRMDRD) and change from pre-AMR baseline and 
screening at 1, 2, 3, and 4 years following the qualifying AMR episode

Measurement of proteinuria (spot urine protein, urine creatinine, and urine protein/urine 
creatinine ratio) and change from screening at 1, 2, 3, and 4 years following the qualifying 
AMR episode

Proportion of subjects with graft failure due to AMR at 4 years

Time to all-cause graft failure

Time to graft failure due to AMR

Proportion of subjects with resolution of the qualifying AMR episodes

Time to resolution of AMR episodes

Proportion of subjects alive at 4 years 

Time to all-cause mortality
Time to all-cause graft failure, time to graft failure due to AMR, time to resolution of AMR after 
initial treatment, and time to overall survival for both treatment groups will be summarized by 
Kaplan-Meier estimates, and the difference between treatments will be assessed by proportional 
hazard regression. The FAS population will be used in these analyses.
The proportion of subjects with graft failure due to AMR, with resolution of the qualifying AMR 
episodes, and overall survival will be assessed by treatment group. The FAS population will be 
used in these analyses.
Graft function, defined as eGFR 40 mL/min/1.73m2 at 3 months post-transplant, will be 
estimated by the MDRD formula shown below:  
eGFRMDRD = 175 × serum Cr -1.154 × age - 0.203 × [1.210 if Black] × [0.742 if female] 
× [0.808 if Japanese]
Histopathology, graft function, and other secondary endpoints will be evaluated at the specified 
time-points or as change from the corresponding baseline value. Summary statistics will be 
provided by treatment group. 
9.8.3
Exploratory Efficacy Endpoints
Exploratory efficacy endpoints are defined as:


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9.9
Safety Analyses
Safety endpoints include TEAEs, vital signs measurements, antibodies to C1 INH, and clinical 
safety laboratory testing. The safety analysis set will be used to report the safety data.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. The 
number of events, incidence, and percentage of TEAEs will be calculated overall, by system 
organ class, by preferred term, by treatment group, and and/or by AMR episode.  
Treatment-emergent AEs will be further summarized by severity and relationship to 
investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized/listed.
Clinical laboratory tests, vital signs, and anti-C1 INH antibodies will be summarized. Potentially 
clinically significant values will also be summarized and listed.
9.10 Pharmacokinetic/Pharmacodynamic Endpoints 
Pharmacokinetic and pharmacodynamic endpoints include:

Analysis of serum complement factors (anaphylatoxin split product of C3 activation 
important in chemotaxis [C3a] and anaphylatoxin split product of C5 activation important for 
histamine release and chemotaxis [C5a]) and their potential relationship to C1 INH 
concentrations

Analysis of the pharmacokinetics of CINRYZE and the effect of plasmapheresis, plasma 
exchange, or immune adsorption treatments and sucrose-free IVIg for the treatment of AMR 
on C1 INH levels


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The pharmacokinetic and pharmacodynamic Analysis Set will be used to report C1 INH and 
complement data. 
The PK parameters will be summarized by descriptive statistics at each collection timepoint by 
treatment.
Plasma samples at pre-DSA reduction and 1 hour post investigational product administration will 
be assessed for C1 INH (antigen and functional binding). Concentrations of C1 INH (antigen and 
functional binding) will be summarized by treatment using descriptive statistics for each nominal 
collection time, including concentrations corrected by baseline.
Complement C3a and C5a levels in those plasma samples will be measured. Results will be 
summarized using descriptive statistics for values at the designated time points and change from 
pre- to post-infusion of investigational product will be evaluated.
9.11
Health Economics and Outcomes Endpoints
The health economic and outcomes endpoints include:

Measurement of the EuroQoL Group 5 Dimension 5-Level Self-report Questionnaire 
(EQ-5D-5L)

Measurement of healthcare resource utilization (HRU)
The effect on quality of life will be measured by the change from baseline in the EQ-5D-5L by 
treatment per results in the EQ-5D-5L User Guide. EQ-5D-5L will be summarized by the 
number of subjects and the percentage of subjects in each category at each timepoint for FAS.
The effect on HRU will be measured by treatment. Results of the HRU will be summarized at 
each timepoint by treatment.


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10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996) and any updates, EU Directive 
2001/20/EC and its updates, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Indemnity/Liability and Insurance
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines.
The sponsor ensures that suitable clinical study insurance coverage is in place prior to the start of 
the study. An insurance certificate is supplied to the CRO as necessary.
10.1.3
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.4
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of 
the member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. 


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This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for non-pediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary.
10.1.5
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by Article 10 (c) of Directive 2001/20/EC.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and any updates, EU Directive 2001/20/EC and its updates, and applicable regulatory 
requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the coordinating principal investigator, in compliance with Directive 
2001/83/EC as amended by Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.


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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the sponsor (or designee) and should be handled in accordance 
with instructions from the sponsor. The investigator is responsible for maintaining adequate and 
accurate medical records from which accurate information is recorded onto CRFs, which have 
been designed to record all observations and other data pertinent to the clinical investigation. 
Case report forms must be completed by the investigator or designee as stated in the site 
delegation log. All data will have separate source documentation; no data will be recorded 
directly onto the CRF. All data sent to the sponsor must be endorsed by the investigator. The 
clinical research associate (CRA)/study monitor will verify the contents against the source data 
per the monitoring plan. If the data are unclear or contradictory, queries are sent for corrections 
or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, original clinical laboratory reports, and histology and pathology reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). Non-study site personnel will not 
disclose any personal information or personal medical information.
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA, 
EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.


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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent from all study 
subjects prior to any study-related procedures including screening assessments. All consent 
documentation must be in accordance with applicable regulations and GCP. Each subject or the 
subject’s legally-authorized representative, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject has received and 
read (or been read) the written subject information and received an explanation of what the study 
involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities. A copy of the informed consent documentation (ie, a 
complete set of subject information sheets and fully executed signature pages) must be given to 
the subject or the subject’s legally-authorized representative, as applicable. This document may 
require translation into the local language. Signed consent forms must remain in each subject’s 
study file and must be available for verification at any time.
The principal investigator provides the sponsor with a copy of the consent form which was 
reviewed by the IRB/EC and which received their favorable opinion/approval. A copy of the 
IRB/EC’s written favorable opinion/approval of these documents must be provided to the 
sponsor, prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (ie, sponsor 
or coordinating principal investigator) is responsible for this action. Additionally, if the IRB/EC 
requires modification of the sample subject information and consent document provided by the 
sponsor, the documentation supporting this requirement must be provided to the sponsor.


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10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, or 
for multicenter studies the coordinating principal investigator or sponsor, according to national 
provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the sponsor (or designee) has received 
written IRB/EC approval of and copies of revised documents.
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; for sites within the EU, this can be done by the sponsor, the investigator or for multicenter 
studies the coordinating principal investigator, according to national provisions.  The investigator 
must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the CRO.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor and/or its representatives will 
review their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market CINRYZE; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).


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The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results / Publication Policy
Shire ViroPharma, Inc. will endeavor to publish the results of all qualifying, applicable, and 
covered studies according to external guidelines in a timely manner regardless of whether the 
outcomes are perceived as positive, neutral, or negative. Additionally, Shire ViroPharma, Inc. 
adheres to external guidelines (eg, Good Publication Practices 2) when forming a publication 
steering committee, which is done for large, multicenter Phase 2-4 and certain other studies as 
determined by Shire ViroPharma, Inc. The purpose of the publication steering committee is to 
act as a non-commercial body that advises or decides on dissemination of scientific study data in 
accordance with the scope of this policy.
All publications relating to Shire ViroPharma, Inc. products or projects must undergo appropriate 
technical and intellectual property review, with Shire ViroPharma, Inc. agreement to publish 
prior to release of information. The review is aimed at protecting the sponsor’s proprietary 
information existing either at the commencement of the study or generated during the study. To 
the extent permitted by the publisher and copyright law, the principal investigator will own (or 
share with other authors) the copyright on his/her publications. To the extent that the principal 
investigator has such sole, joint or shared rights, the principal investigator grants the sponsor a 
perpetual, irrevocable, royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by Shire ViroPharma, Inc., the institution and 
principal investigator shall withhold submission of such publication for up to an additional 
60 days to allow for filing of a patent application.
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. 


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If such a multicenter publication is not submitted to a journal for publication by the sponsor 
within an 18-month period after conclusion, abandonment, or termination of the study at all sites, 
or after the sponsor confirms there shall be no multicenter study publication of the study results, 
an investigator may individually publish the study results from the specific site in accordance 
with this section. The investigator must, however, acknowledge in the publication the limitations 
of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.


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11.
REFERENCES
Akalin E, Ames S, Sehgal V, Fotino M, Daly L, Murphy B, et al. 2003. Intravenous 
immunoglobulin and thymoglobulin facilitate kidney transplantation in complement-dependent 
cytotoxicity B-cell and flow cytometry T- or B-cell crossmatch-positive patients. 
Transplantation; 76(10): 1444-7.
Amara U, Rittirsch D, Flierl M, Bruckner U, Klos A, Gebhard F et al. 2008. Interaction between 
the coagulation and complement system. Adv Exp Med Biol; 632: 71-9.
Bryan CF, Baier KA, Nelson PW, Luger AN, Martinez J, Pierce GE, et al. 1998. Long-term graft 
survival is improved in cadaveric renal retransplantation by flow cytometric crossmatching. 
Transplantation; 66(12): 1827-32.
Cornell LD, Schinstock CA, Gandhi MJ, Kremers WK, Stegall MD, 2015. Positive crossmatch 
kidney transplant recipients treated with eculizumab: outcomes beyond 1 year. Am J Transplant; 
Mar 2. doi: 10.1111/ajt.13168. [Epub ahead of print].
Cui L, Hung HM, Wang SJ 1999. Modification of sample size in group sequential clinical trials. 
Biometrics; 55: 853-7.
Department of HHS: United Network for Organ Sharing 2009. Explanation of CPRA for 
professionals. Available at: 
http://www.unos.org/SharedContentDocuments/CPRA_Professionals.pdf.
German Federal Medical Council, 2000: German Federal Medical Council. Drug commission of 
the German medical profession: serious thrombogenesis following Berinert® HS. 2000. Ger Med 
J; 97(15): A-1016/B-864/C-812.
Glotz D, Antione C, Julia P, Suberbielle-Boissel C, Boudjeltia S, Fraoui R, et al. 2002. 
Desensitization and subsequent kidney transplantation of patients using intravenous 
immunoglobulins (IVIg). Am J Transplant; 2(8): 758-60.
Haas M. 2014. An updated Banff schema for diagnosis of antibody-mediated rejection in renal 
allografts. Curr Opin Organ Transplant; 19: 315-22.
Haririan A, Kiangkitiwan B, Kukuruga D, Cooper M, Hurley H, Drachenberg C, et al. 2009. The 
impact of C4d pattern and donor-specific antibody on graft survival in recipients requiring 
indication renal allograft biopsy. Am J Transplant; 9(12): 2758-67.
Haybittle JL 1971. Repeated assessment of results in clinical trials of cancer treatment. Brit J
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Horstick G, Berg O, Heimann A, Götze O, Loos M, Hafner G, et al. 2001. Application of 
C1-esterase inhibitor during reperfusion of ischemic myocardium: dose-related beneficial versus
detrimental effects. Circulation; 104(25): 3125-31.
Jordan S, Cunningham-Rundles C, McEwan R 2003. Utility of intravenous immune globulin in 
kidney transplantation: efficacy, safety, and cost implications. Am J Transplant; 3(6): 653-4.
Lefaucheur C, Suberbielle-Boissel C, Hill GS, Nochy D, Andrade J, Antoine C, et al. 2008. 
Clinical relevance of preformed HLA donor-specific antibodies in kidney transplantation. Am J 
Transplant; 8(2): 324-31.
Levy J, Szlam F, Gelone S. 2014. Effects of a plasma-derived C1 esterase inhibitor on 
hemostatic activation, clot formation, and thrombin generation. Blood Coagul Fibrinolysis. (in 
press).
Levy JH and O’Donnell PS. 2006. The therapeutic potential of a kallikrein inhibitor for treating 
hereditary angioedema. Expert Opin Investig Drugs; 15(9): 1077-90.
Loupy A, Suberbielle-Boissel C, Hill GS, Lefaucheur C, Anglicheau D, Zuber J, et al. 2009. 
Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with 
preformed donor-specific antibodies. Am J Transplant; 9(11): 2561-70.
Marsh JE, Farmer CK, Jurcevic S, Wang Y, Carroll MC, Sacks SH 2001. The allogeneic T and B 
cell response is strongly dependent on complement components C3 and C4. Transplantation; 
72(7): 1310-8.
Mauiyyedi S, Crespo M, Collins AB, Schneeberger EE, Pascual MA, Saidman SL, et al. 2002. 
Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and 
pathologic classification. J Am Soc Nephrol; 13(3): 779-87.
Montgomery RA, Zachary AA. 2004. Transplanting patients with a positive donor-specific 
crossmatch: a single center's perspective. Pediatr Transplant; 8(6): 535-42.
Montgomery RA. 2010. Renal transplantation across HLA and ABO antibody barriers: 
integrating paired donation into desensitization protocols. Am J Transplant; 10(3): 449-57.
Montgomery RA, Orandi BJ, Racusen LC, Garonzik-Wang JM, Shah T, Woodle ES, et al. 2014. 
Human plasma-derived C1 esterase inhibitor for the treatment of acute antibody-mediated 
rejection in kidney transplantation. Am J Transplant; 14(S3):129-130. In: Supplement: 2014 
World Transplant Congress Abstracts, 26-31 July, 2014; San Francisco, CA. Abstract 2252.


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O’Brien PC and Fleming TR 1979. A multiple testing procedure for clinical trials. Biometrics; 
35: 549-56.
Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant 
Recipients (SRTR).  OPTN/SRTR 2012 Annual Data Report. Rockville, MD: Department of 
Health and Human Services, Health Resources and Services Administration; 2014.
Patel R and Terasaki PI. 1969. Significance of the positive crossmatch test in kidney 
transplantation. N Engl J Med; 280(14): 735-9.
Peto R., Pike MC, Armitage P, Breslow NE, Cox DR, Howard SV, et al. 1976. Design and 
analysis of randomized clinical trials requiring prolonged observation of each patient: I. 
Introduction and design. Brit. J. Cancer; 34: 585–612.
Poirier N, Blancho G. 2008. Recombinant human C1-inhibitor inhibits cytotoxicity induced by
allo- and xenoantibodies. Transplant Proc; 40: 581-3.
Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T, et al. 1999. The Banff 97 
working classification of renal allograft pathology. Kidney Int; 55(2): 713-23.
Sharif A, Kraus ES, Zachary AA, Lonze BE, Nazarian SM, Segev DL, et al. 2014. Histologic 
phenotype on 1-year posttransplantation biopsy and allograft survival in HLA-incompatible 
kidney transplants. Transplantation; 97: 541-7.
Sis B, Mengel M, Haas M, Colvin RB, Halloran PF, Racusen LC, et al. 2010. Banff '09 meeting 
report: antibody mediated graft deterioration and implementation of Banff working groups. Am J 
Transpl; 10(3): 464-71.
Smith RN, Kawai T, Boskovic S, Nadazdin O, Sachs DH, Cosimi AB, et al. 2008. Four stages 
and lack of stable accommodation in chronic alloantibody-mediated renal allograft rejection in 
Cynomolgus monkeys. Am J Transplant; 8(8): 1662-72.
Sonnenday CJ, Ratner LE, Zachaty AA, Burdick JF, Samaniego MD, Kraus E, et al. 2002. 
Preemptive therapy with plasmapheresis/intravenous immunoglobulin allows successful live 
donor renal transplantation in patients with a positive cross-match. Transplant Proc; 34(5): 
1614-6.
Stegall MD, Diwan T, Cornell LD, et al. 2010. Terminal complement inhibition decreases early 
acute humoral rejection in sensitized renal transplant recipients. Am J Transplant; 10: 39, 
Abstract #1.
Sun Q, Huang X, Jiang S, Zeng C, Liu Z. 2012. Picking transplant glomerulopathy out of the 
CAN: evidence from a clinico-pathologcal evaluation. BMC Nephrol. 13: 128-36.
Tillou X, Poirier N, Le Bas-Bernardet S, Hervouet J, Minault D, Renaudin K, et al. 2010. 
Recombinant human C1-inhibitor prevents acute antibody-mediated rejection in alloimmunized 
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12.
APPENDICES


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Appendix 1 Protocol History 
Document
Date
Global/Country/Site Specific
Original Protocol
Amendment 1
Amendment 2
Amendment 3
01 Apr 2015
28 May 2015
25 Jun 2015
01 Sep 2016
Global
Global
Global
Global
Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
01 Sep 2016
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
Updated the title page to indicate the study is multicenter 
Title page
Updated the Shire signatory to Andrea Vergani, MD, PhD
Protocol Signature page
Added a high-level amendment summary and rationale to provide a general 
overview and justification of amendment revisions
Amendment Summary and 
Rationale
Updated the emergency contact information and removed contract research 
organization contact information as this information will be provided in a separate 
document
Emergency Contact 
Information
Section 8.2.2. 
Updated the contact information for quality complaints
Product 
Quality Complaints
Clarified that intravenous immunoglobulin (IVIg) is to be sucrose-free to avoid 
potential renal toxicity and dosed at no less than 100 mg/kg to allow more 
flexibility and adhere to site standard of care 
Throughout protocol
Removed the limit for a maximum enrollment to add greater flexibility
Synopsis
Section 3.1. 
Section 4.5. 
Section 9.5.1
Combined the US and EU sites to include approximately 40 sites in 6 countries
Synopsis
Section 3.3
Clarified the primary objective as follows:

Removed dosing details from the primary and secondary objectives as they 
are included in protocol dosing Section 6.2.3

Added text to the primary objective to clarify that measurement of transplant 
glomerulopathy (TG) is at 6 months after “initiation of” treatment
Clarified secondary objectives as follows:

Revised the key secondary objective text to clarify that subjects will be 
assessed for all-cause graft failure at 4 years following treatment initiation

Reorganized the secondary objectives into study entry to 6 months and study 
entry to 4 years to provide increased structure and clarity to the protocol

Revised the secondary and exploratory objectives to eliminate details for 
measurements that are included in the endpoints and to broaden scope
Synopsis
Section 2.2
Throughout protocol


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
01 Sep 2016
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change

Added change in proteinuria as a secondary objective to better assess graft 
function

Added time to AMR resolution as a secondary objective to better assess 
CINRYZE effect

Moved assessment of recurrence from secondary to exploratory objectives in 
order to reprioritize study goals

Combined pharmacokinetic (PK) and pharmacodynamic (PD) analyses and 
moved from secondary to exploratory objectives to reprioritize study goals

Revised the stratification for severity to specify estimated glomerular filtration 
rate calculated by Modification of Diet in Renal Disease (eGFRMDRD)
(ie. ≤15 mL/min/1.73m2 or >15 mL/min/1.73m2)
Synopsis
Section 3.1
Section 6.2.2
Removed the details about how the Endpoint Adjudication Committees (EACs) 
will conduct assessments as this information will be in their Charters
Synopsis
Section 3.1 
Section 7.2.2.2
Revised the definition of graft failure to specify that permanent dialysis is defined 
as dialysis treatment >30 days, current transplant nephrectomy, or clinical 
determination of cessation of kidney graft (eGFRMDRD ≤15 mL/min/1.73m2)
Synopsis
Section 3.1 
Added a definition of adequate kidney function using eGFRMDRD values and 
timing in relation to transplant for clarity
Clarified definitions of pre-AMR baseline and resolution of qualifying and 
recurrent AMR episodes
Clarified that treatment should be started as soon as possible after screening and 
within 7 days of the qualifying biopsy procedure to assure treatment of the acute 
phase of the AMR episode 
Synopsis
Section 3.1 
Section 7.1.1
Section 7.1.2.1
Section 7.2.2.3
Clarified that recurrence is defined as biopsy evidence of AMR after resolution of 
the previous episode
Synopsis
Section 3.1 
Section 7.2.2.4
Revised study methods including:

Clarified that AMR will be defined using the most recent Banff 2013 criteria

Clarified that biopsy slides will be required for most staining and to send to a 
central image core for scanning in order to improve homogeneity 

Clarified that during the screening period, the first eGFRMDRD value obtained 
after the qualifying biopsy should be used 

Clarified that the EACs will be blinded and independent

Clarified that collection of blood samples will be done prior to DSA reduction 
treatment and after investigational product (CINRYZE or placebo) 
administration in order to avoid confounding factors

Clarified that timing for the 5 required DSA treatments or sucrose-free IVIg is 
at investigator discretion within the study dosing period to allow more 
flexibility and adhere to site standard of care 

Clarified general assessments to be completed by both EACs
Synopsis
Section 3.1 
Section 3.2
Section 4.1
Section 4.5
Section 6.2.4 
Section 7.1.2
Section 7.2.2.2
Section 9.5.3


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
01 Sep 2016
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change

Clarified that in the event of early discontinuation by a subject, every effort 
will be made to obtain adverse events (AEs), biopsy if applicable, serum 
blood urea nitrogen (BUN) and creatinine (Cr) and eGFRMDRD results for 
EAC evaluation as collection of this information will strengthen study 
conclusions 
Clarified that pregnancy tests are required only for women of child-bearing 
potential
Synopsis
Section 4
Section 7.1
Section 7.2.3.6
Revised the inclusion/exclusion criteria as follows:

Added an age limit for enrollment to ensure subject safety (≤70 years of age)

Revised weight requirements:  Change from ≥40 kg to ≥45 kg to assure 
patient safety

Added that if DSA cannot be promptly identified during screening, that 
previously obtained data can be used if obtained after kidney transplant and 
within 30 days of the qualifying AMR episode to allow for greater enrollment 
flexibility 

Specified that the qualifying episode of AMR must occur between 72 hours 
and 12 months after transplant to improve patient homogeneity

Added criteria for adequate kidney function defined as having a pre-AMR 
baseline eGFRMDRD ≥20 mL/min/1.72m2 if the qualifying AMR episode 
occurs ≤21 days after transplant or pre-AMR baseline eGFRMDRD ≥30 
mL/min/1.72m2 if the qualifying AMR episode occurs >21 days after 
transplant

Separated the criteria for contraception from the pregnancy test criteria per 
protocol standards

Added the exclusion of subjects having C3 Glomerulopathy or Thrombotic 
microangiopathy as the cause of native kidney failure and updated “focal 
sclerosing glomerulosclerosis” to “primary Focal Segmental 
Glomerulosclerosis” to limit the risk of recurrence of glomerular diseases that 
could make TG assessment difficult

Added the exclusion of subjects having received organ transplants other than 
kidneys, hematopoietic stem cell transplant (HSCT), or more than 1 
completed kidney re-transplant procedure to prevent confounding influences 
on study data

Added the exclusion of subjects with any ongoing infection or surgical or 
medical condition that could compromise patient safety or confound efficacy 
assessment

Added the exclusion criteria of subjects being actively treated for hepatitis C 
virus (HCV) infection to ensure subject safety and avoid confounding 
influences on study data

Added the exclusion of subjects with an existing neoplastic lesion in the 
allograft to ensure subject safety and avoid confounding influences on study 
data
Synopsis
Section 4. 
Section 7.2.3.1
Section 7.2.3.5


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
01 Sep 2016
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change

Added the exclusion of subject with a change in androgen therapy to ensure 
subject safety and avoid confounding influences on study data

Added the exclusion of a subject with a history of transient ischemic attack 
(TIA) or myocardial infarction (MI) within 6 months of study entry to ensure 
subject safety and avoid confounding influences on study data 

Added the exclusion for subject receiving sucrose-containing IVIg within a 
month of the first dose in order to avoid the risk of sucrose-containing IVIg 
kidney toxicity in this patient population

Removed the criterion for exclusion of Bortezomib as a prohibited medication 
1 month prior to the first dose in order to provide greater enrollment 
flexibility 

Clarified that local laboratory results should be used for enrollment eligibility 
in order to avoid delays in investigational product administration

Clarified the exclusion criterion for white blood cell count during steroid 
treatment, in order to avoid this confounding factor
Updated the endpoints to reflect the changes in the objectives including details on 
specific measurements to be done
Synopsis
Section 9.8.2
Section 9.8.3
Clarified that the adverse events of special interest (AESI) of new kidney allograft 
rejection exclude AMR
Synopsis
Section 7.2.3.3
Section 8.1
Section 8.1.4
Section 8.1.5
Added language requiring the reporting of non-serious AESI to Shire 
Pharmacovigilance and Risk Management (PVRM) Department using serious 
adverse event (SAE) forms to ensure subject safety
Synopsis
Section 3.1
Section 7.2.3.3
Section 8.1.4
Updated the study schedules and study procedures to reflect the changes to the 
protocol
Table 1 and Table 2
Section 7.1
Added a column to Table 1 to clarify which procedures are to be completed prior 
to retreatment
Table 1
Moved the column for early discontinuation assessments from Table 1 to Table 2 
in order to separate it from the dosing period in Table 1
Table 1 and Table 2
Revised the window for subject assessments from ±14 days to ±21 days for 
months 3 through 12 and to  ±28 days for months after Month 12 to allow greater 
flexibility to subjects and sites
Table 2
Removed analysis of PK/PD samples for a subset of patients at Day 2-12 as this 
information is not required
Table 3
Section 9.10
Clarified that CINRYZE, in doses utilized to treat hereditary angioedema (HAE), 
does not require pre-administration medications such as antihistamines or 
acetaminophen
Section 1.3.1
Added information about the collection of healthcare resource utilization to ensure 
subject safety and to obtain additional information on quality of life
Section 3.1 
Section7.2.4.3
Updated Figure 1 to reflect changes in protocol, including a decrease in the 
retreatment period to the first 6 months
Figure 1


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
01 Sep 2016
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
Removed use of prohibited or experimental drugs from reasons for discontinuation 
in order to allow data capture for these patients as well
Section 4.5.1
Specified that concomitant medications and AEs will be collected through 30 days 
after the last dose of investigational product for each treatment period to ensure 
adequate information is collected for analysis of safety 
Section 5.1
Section 7.2.3.3
Section 8.1
Specified prophylactic treatment for deep vein thrombosis (DVT) will be collected 
throughout the study to ensure comprehensive safety data collection
Section 5.1
Added a table to clarify dosing
Table 4
Clarified that sites will be responsible for sourcing 0.9% sodium chloride solution 
for infusion of either the active drug or the placebo
Section 6.1
Clarified that dosing with investigational product cannot be administered within 
the 7 days after transplant based on data monitoring committee (DMC) 
recommendation and must be administered within 7 days after the qualifying 
biopsy to provide adequate screening time to sites and to ensure subjects receive 
prompt treatment 
Synopsis
Section 3.1
Section 4.1. 
Section 7.1
Section 7.2
Revised text to clarify destruction of investigational product
Section 6.4
Indicated that when the criterion to conduct the second interim analysis is met, 
treatment assignment for those subjects may be unblinded for analysis to 
designated sponsor representatives and to clarify that the treatment assignments 
for all other subjects will be blinded to the EACs, investigator, and subjects to 
ensure the study blind
Section 6.1.1
Section 6.2.4
Section 9.5.1
Clarified the requirements for sites to provide slides and images to ensure that 
sites understand this is required and not optional and indicated that instructions 
will be provided separately to further describe details for the requirements
Section 7.2. 
Clarified DSA identification as follows:

Clinical decision will be based on local laboratory analysis of DSA, including 
additional time points done at the discretion of the investigator as part of 
standard of care 

DSA testing will be done by the central laboratory at Screening, Day 25, 
Months 3, 6, 12, 18, 24, 30, 36, 42, and 48 

Added serum collection for DSA titer testing
Section 7.2.2.1
Specified that immunohistochemical staining is acceptable if immunofluorescence 
is not available in order to collect needed data and allow more flexibility to sites
Section 7.2.2.2
Indicated that whenever possible, biopsy tissue remaining after the qualifying 
biopsy assessment will be preserved in paraffin or another method appropriate for 
electron microscopy (EM) processing to allow for additional information to be 
obtained as needed
Section 7.2.2.2
Added the following for biopsies during the study to allow better tissue sampling 
and analysis:

The recommendation to provide at least 2 separate cores containing 
cortex for the qualifying biopsy

The requirement for at least 2 separate cores containing cortex at the 6 
month biopsy and for subjects who discontinue prior to 6 months
Section 7.2.2.2

Added the definition of resolution: Resolution will be achieved when, 
after treatment, the local eGFRMDRD value increases to at least within 
Section 7.2.2.3


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
3
Amendment Date
01 Sep 2016
Global/Country/Site 
Specific
Global
Description and Rationale for Change
Section(s) Affected by 
Change
20% or above the eGFRMDRD value collected as a pre-AMR baseline.

Added that if an AMR episode is diagnosed per a standard of care biopsy, 
in absence of significant (≥20%) eGFR decline from pre-AMR baseline, 
a follow-up biopsy is recommended within 3 months in order to assess 
resolution and to ensure subject safety
Clarified which assessments are required by local and central laboratories
Section 7.2.3.5
Added in details on how to calculate eGFR from creatinine values
Section 7.2.3.5
Clarified that the choice of plasmapheresis, plasma exchange, or immune 
adsorption treatments will be based on the standard of care at the study site to 
allow more flexibility and adhere to site standard of care
Section 7.2.2.8
Added additional chemistry laboratories and specified that subjects where anti-C1-
inhibitor (C1 INH) antibodies are detected will be followed until negative to 
ensure subject safety
Section 7.2.3.5
Removed the appendix describing the collection of plasma samples and cross 
references to this appendix as this information will be provided in a separate 
document
Section 7.2.4.1
Appendix 4
Removed Section 7.2.5 and information about the volume of blood to be drawn 
from each subject as this information will be provided in a separate document
formerly Section 7.2.5
Revised the reference safety information location to the Investigator’s Brochure to 
prevent duplication of source information location
Section 8.2.1
Added that AESI must be reported within 24 hours by the investigator to the Shire 
Pharmacovigilance Department and the Shire Medical Monitor within 24 hours of 
the first awareness of the event to ensure subject safety
Section 8.2.2
Removed details about the interim analysis as this information will be included in 
the interim analysis statistical plan
Section 9.5.1
Section 9.8.2.1
Specified that the study will not be stopped for efficacy until the Sponsor has 
received confirmation of the decision from the appropriate regulatory agency per 
the request from regulatory agencies
Section 9.5.2
Study population analysis sets have been redefined to ensure data collected is fully 
analyzed
Section 9.7
Specified that a number of sensitivity analyses will be performed to assess any 
impact on the key endpoint results, inference, and conclusions due to missing data 
and that selected analyses on the key endpoint will be provided in selected 
subgroups 
Section 9.8.1
Section 9.8.2.1
Clarified the correct eGFRMDRD formula
Section 9.8.2.2
Added the analysis for the results of the EM to clarify rationale on the images 
requirement
Section 9.8.3
Clarified the analysis for C1 INH, C3a, and C5a
Section 9.10
Added new health economics endpoints and a section to describe and clarify the 
analysis of the health economic and outcome endpoints
Section 9.11
Added in the 2013 updated criteria for Banff classification 
Appendix 2


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Protocol Amendment
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
2
Amendment Date
25 Jun 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Shire signatory was updated to Marc E. Uknis, MD, FACS
Protocol Signature page
Since ultrastructural analysis (electron microscopy; EM) may not be 
available for all Month 6 biopsies and since early pathology evident only 
on EM has not been validated with diminished long-term graft survival, 
the definition of TG was revised from chronic glomerulopathy (cg) score 
>0 to cg score ≥1b (ie, evident changes on light microscopy)
Synopsis
Section 1.1, Section 1.2.3, Section 
2.1.2, Section 3.1, Section 7.2.2.2
Synopsis
Section 2.2.3, Section 7.2.2.2, 
Section 9.8.3
Updated a background statement regarding TG with more recent 
references
Section 1.1, Section 11


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Protocol Amendments
Summary of Change(s) Since Last Version of Approved Protocol
Amendment Number
1
Amendment Date
28 May 2015
Global/Country/Site Specific
Global
Description of Change
Section(s) Affected by Change
Name of sponsor was changed to Shire ViroPharma, Inc for consistency 
among study documents.
Global
Shire signatory was updated to Arian Pano, MD.
Protocol Signature page
Contact information was updated for CINRYZE quality complaints.
Product Quality Complaints page
Added the following secondary objective that was inadvertently omitted 
in Version 1: “To assess the overall subject survival status (proportion 
and time-to-event)” for consistency with endpoints and analyses.
Synopsis
Section 2.2.2, Section 9.8.2.2
Clarified that time to overall survival for both treatment groups will also 
be summarized by Kaplan-Meier estimates.
Section 9.8.2.2
Removed the secondary objective/endpoint of frequency of AMR: “To 
assess the number of acute AMR episodes treated per protocol during the 
follow-up period.”
Synopsis
Section 2.2.2, Section 9.8.2.2
Changed EQ-5D-5L from a secondary objective/endpoint to an 
exploratory objective/endpoint.
Synopsis
Sections 2.2.3, Section 9.8.3
Footnote added to clarify that the screening blood samples for 
immunogenicity should be obtained prior to and following administration 
of IVIg if administered on the same day as screening.
Table 1
Added recording presence/absence of diabetes at screening, Month 6, 
and end of study.
Table 1, Table 2
Section 7.1.1, Section 7.1.3.3 
Section 7.1.3.5
Added the following to be recorded for medical history: 

Diabetes (yes/no)

Onset date of AMR that qualifies the subject to the study

“Other: specify” for medications administrated for 
immunosuppression within 2 weeks of current transplant.
Section 7.2.3.1
Total blood volume was adjusted to 244 mL to include samples required 
for serum BUN/Cr (75 mL) and DSA identification and titer (55 mL).
Section 7.2.5, Table 4
Corrected equation for definition of pooled proportion for the first 
interim analysis.
Section 9.5.1
DMC meeting frequency was updated to align with interim analyses: 
after 30 subjects complete the Month 6 TG assessment; after the re-
estimated number of subjects (based on the first interim analysis 
recommendation) complete the Month 6 TG assessment; and after 
approximately 50% (~26 subjects) and 75% (~39 subjects) targeted 
subjects have experienced all-cause graft failure.
Section 9.5.2


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Appendix 2 Banff Classification of Renal Allograf Biopsy (2013 Update)
In 2007 Banff classification of renal allograft; C4d deposition was as essential feature of 
antibody mediated rejection (ABMR). But with the growing evidence of ABMR (with evidence 
of microvascular injury and donor specific antibody [DSA]) in the absence of C4d deposition, 
classification is revised in 2013 focusing mainly on redefining ABMR. Additionally, electron 
microscopic (EM) findings are incorporated in to cg (chronic glomerulopathy) scoring. Now 
suggestion is made for EM to be considered in all biopsies done ≥6 months post-transplant and 
≥3 months in for-cause post-transplant allografts to assess early changes of transplant 
glomerulopathy. There is also recognition of overlap between ABMR and TCMR as mild to 
moderate arteritis (v1) and severe arteritis (v2) which was solely part of TCMR in 2007 
classification also features in acute/active ABMR in the latest Banff 2013 classification.
In the revised classification, ABMR has been classified as acute/active ABMR and chronic, 
active ABMR. For the diagnosis of acute/active ABMR all three features are required which 
include histologic evidence of acute tissue injury (microvascular inflammation, intimal or 
transmural arteritis, acute thrombotic microangiopathy or acute tubular injury (in the absence of 
any other cause)], evidence of current/recent antibody interaction with vascular 
endothelium (linear C4d staining in peritubular capillaries, at least moderate microvascular 
inflammation or increased expression of gene transcripts in the biopsy tissue indicative of 
endothelial injury) and serologic evidence of DSA.
Similarly for the diagnosis of chronic, active ABMR all three features are required for diagnosis 
including morphologic evidence of chronic tissue injury (transplant glomerulopathy [if no
evidence of chronic thrombotic microangiopathy] or severe peritubular capillary basement 
membrane multilayering [requires electron microscopy] or arterial intimal fibrosis of new onset 
[excluding other causes]), evidence of current/recent antibody interaction with vascular 
endothelium (similar to acute/active ABMR criterion) and serologic evidence of DSA
SCORING AND CLASSIFICATION OF HISTOLOGIC FINDINGS ON ALLOGRAFT 
BIOPSY 
Glomerulitis score
g0
No glomerulitis
g1
Glomerulitis in less than 25% of glomeruli
g2
Segmental or global glomerulitis in 25 to 75% of glomeruli
g3
Glomerulitis (mostly global) in more than 75% of glomerul
Criterion for allograft glomerulopathy
cg0
No GBM double contours by LM or EM
cg1
1a: no GBM double contours by LM but GBM double contours (incomplete or 
circumferential) in at least 3 glomerular capillaries by EM with associated endothelial 
swelling and/or subendothelial electronlucent widening
1b: ≥1 glomerular capillaries with GBM double contours in 1 nonsclerotic glomerulus 
by LM. EM confirmation is recommended if available.


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cg2
Double contours affecting 26 to 50% of peripheral capillary loops in the most affected 
of nonsclerotic glomeruli
cg3
Double contours affecting more than 50% of peripheral capillary loops in the most 
affected of nonsclerotic glomeruli
Tubulitis score
T0
No mononuclear cells in tubules
T1
Foci with 1 to 4 cells/tubular cross section (or 10 tubular cells)
T2
Foci with 5 to 10 cells/tubular cross section
T3
Foci with > 10 cells/tubular cross section, or the presence of at least two areas of 
tubular basement membrane destruction accompanied by i2/i3 inflammation and t2 
tubulitis elsewhere in the biopsy
Intimal arteritis score
V0
No arteritis
V1
Mild-to-moderate intimal arteritis in at least one arterial cross section
V2
Severe intimal arteritis with at least 25% luminal area lost in at least arterial cross 
section
V3
Transmural arteritis and/or arterial fibrinoid change and medial smooth muscle 
necrosis with lymphocytic infiltrate in vessel
Classification of peritubular capillaritis (PTC)
ptc0
No significant cortical ptc, or <10% of PTCs with inflammation
ptc1
≥ 10% of cortical peritubular capillaries with capillaritis, with max 3 to 4 luminal 
inflammatory cells
ptc2
≥ 10% of cortical peritubular capillaries with capillaritis, with max 5 to 10 luminal 
inflammatory cells
ptc3
≥ 10% of cortical peritubular capillaries with capillaritis, with > 10 luminal 
inflammatory cells
one comment on the composition (mononuclear cells vs. neutrophils) and extent (focal, ≤50% vs. 
diffuse, >50%) of peritubular capillaritis is recommended
Interstitial Inflammation score
i0
No or trivial interstitial inflammation
i1
10 to 25% of parenchyma inflamed
i2
26 to 50% of parenchyma inflamed
i3
More than 50% of parenchyma inflamed


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Appendix 3 Scales and Assessments
The following scale/assessment will be utilized in this study: 
Full Title of Scale/Assessment
Version Number
Date Issued
EuroQoL Group 5-Dimension 5-Level Self-Report Questionnaire (EQ-
5D-5L)
2009
25 March 2015
A separate master file containing each scale/assessment listed above will be provided to the site.  
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above and a new master file containing the revised scale/assessment will be provided to the site. 


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Appendix 4 Recommended Procedures for Suspected Thrombotic or Thromboembolic Events 
Suspected thrombotic or thromboembolic event
If not inpatient, then subject to seek immediate medical 
attention and notify study personnel.
Clinical evaluation and diagnostic testing, as appropriate
If diagnosis is superficial thrombophlebitis, 
dialysis access clotting, or catheter-related 
thrombosis:
Record as AE or SAE, as appropriate
Clinical management per investigator / 
site standard practice
Record follow-up information / outcome 
as per standard AE or SAE process
If diagnosis is deep vein thrombosis, pulmonary embolism, 
myocardial infarction, cerebrovascular accident or other large 
vessel thrombotic/thromboembolic event:
Record as SAE (Protocol Section 8.2)
1. Relevant medical history / potential risk factors
2. Any imaging or other diagnostic results
3. Laboratory evaluation to include coagulopathy 
panel if event unexplained by #1 above
Clinical management per investigator / 
site standard practice
Record follow-up information / 
outcome as per standard SAE process
Contact sponsor to discuss 
case 
Sponsor to assess case in 
context of study stopping rules 
(Protocol Section 4.5.3)
Related to study drug
Not related to study drug

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CONFIDENTIAL 
 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
SHP616-302 
Protocol Title: 
A randomized double-blind placebo-controlled study to 
evaluate the efficacy and safety of Cinryze® (C1 esterase 
inhibitor [human]) for the treatment of acute antibody-
mediated rejection in kidney transplant patients 
Drug: 
SHP616, C1 esterase inhibitor [human] 
Sponsor:  
Shire ViroPharma, Inc. (Shire is now part of Takeda) 
300 Shire Way, Lexington, MA  02421 USA 
Version No. and Date 
Version 3.0, Date 27June2019 
 
Version No: 
Document History 
Description of Update 
Author(s) 
Effective Date 
0.1 
Initial draft 
06Mar2015 
0.2 
Updated with all-cause graft failure as 
key secondary endpoint and sensitivity 
analysis 
31Mar2015 
0.3 
Updated to final protocol changes, 
sensitivity analysis, TFL, and PCI 
value 
22Apr2015 
0.4 
Incorporate 
Study 
Team 
review 
suggestions. 
Amended 
efficacy 
analysis details in Section 10 
01May2015 
0.5 
Update after DMC member review 
10May2015 
0.6 
Update after first draft CRF and 
protocol Amendment 1 
29May2015 
1.0 
Final Draft for Protocol Amendment 
1.0 
04Jun2015 


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Version No: 
Document History 
Description of Update 
Author(s) 
Effective Date 
2.0 
Update for Protocol Amendment 2 
dated 22Jun2015 
25Jun2015 
2.1 
Update with regard to the FDA’s IND 
review question: 
1. Protocol SHP616-302 permits 
subjects who have subsequent 
AMR episodes to be retreated 
according to their original 
treatment schedule; 
retreatments usually 
complicate the plan for 
analysis of a study. Please 
indicate where in your 
statistical analysis plan you 
address the analysis of subjects 
who receive retreatments? 
04AUG2015 
2.2 
Update with regard to the FDA’s IND 
review response and DMC 
Organizational Meeting 
06NOV2015 
2.3 
• Correct the alpha level for z 
statistic. 
• Revise lower cut-off point of 
the decision rule of stopping 
for futility. 
24APR2016 
• Add additional time to event 
efficacy endpoints and 
analyses. 
• Add sensitivity analysis for 
change in cg percent. 
28APR2016 
2.4 
Implement the Protocol amendment 3 
14MAR2016 
2.5 
Updated per Shire comments 
 
03AUG2017 


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CONFIDENTIAL 
 
 
Version No: 
Document History 
Description of Update 
Author(s) 
Effective Date 
2.6 
Updated to address the rest comments 
from Shire 
 
 
08SEP2017 
2.7 
 
Updated the conditional power and 
removed the WHODrug version 
 
 
22Sep2017 
Updated the TOC to be consistent with 
the 
shells 
and 
fixed 
a 
few 
typos/formats. 
 
 
02Oct2017 
Deleted Appendix 2 related to CP and 
made a few format changes per 
comments from Shire   
 
 
15Oct2017 
2.8 
Updated tables 1 and 2 for the 
schedule of assessments according to 
the protocol amendment 4, revised 
TOC to be consistent with the shells, 
and fixed a few typos 
 
19JAN2018 
3.0 
Updated protocol version. 
Cosmetic issues and typos updated. 
Updated to be consistent with protocol 
amendment 4. 
Updated definition to be consistent 
with DMC SAP. 
Updated wording to give clear 
explanation. 
Removed average dosing week from 
AE. 
Updated section 17. Changes to 
analyses specified in protocol. 
Updated section 20 TOC. 
 
05JUN2019 
Updated to be consistent with protocol 
amendment v4.0.  
Added link to reference section if 
needed. 
Added standard score definition for 
primary efficacy endpoint.  
 
14JUN2019 


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CONFIDENTIAL 
 
 
Version No: 
Document History 
Description of Update 
Author(s) 
Effective Date 
Updated granular score definition for 
sensitivity efficacy endpoint. 
Updated section 17. Changes to 
analyses specified in protocol. 
Added back section 13.2. 
Added link. 
Updated section 17 and 20. 
 
19JUN2019 
Updated section 20 (TOC). 
Updated section 12 to be consistent for 
PD set definition. 
 
20JUN2019 
Updated Section 12.2.2 and 12.4.2 to 
change handling values who had 
<LLOQ: Updated from ‘treat as 0’ to 
‘treat as 1/2 of the LLOQ value’.  
 
25JUN2019 
Typo fixed. 
 
27JUN2019 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ........................................................................................................... 5 
LIST OF FIGURES .................................................................................................................... 8 
ABBREVIATIONS .................................................................................................................... 9 
1. 
INTRODUCTION ........................................................................................................ 11 
2. 
STUDY DESIGN ......................................................................................................... 12 
2.1 
General Study Design ................................................................................................... 12 
2.2 
Randomization .............................................................................................................. 15 
2.3 
Blinding ........................................................................................................................ 16 
2.4 
Schedule of Assessments .............................................................................................. 16 
2.5 
Determination of Sample Size ...................................................................................... 23 
2.6 
Multiplicity Adjustments for Type I Error Control ...................................................... 23 
3. 
OBJECTIVES .............................................................................................................. 25 
3.1 
Primary Objective ......................................................................................................... 25 
3.2 
Secondary Objectives ................................................................................................... 25 
3.3 
Exploratory Objectives ................................................................................................. 26 
4. 
SUBJECT POPULATION SETS ................................................................................. 27 
4.1 
All-enrolled Set ............................................................................................................ 27 
4.2 
Intent-to-Treat Set (ITT) .............................................................................................. 27 
4.3 
Full Analysis Set (FAS) ............................................................................................... 27 
4.4 
Safety Analysis Set (SAF) ............................................................................................ 27 
4.5 
Per-protocol Analysis Set-1 (PPS1) ............................................................................. 27 
4.6 
Per-protocol Analysis Set-2 (PPS2) ............................................................................. 27 
4.7 
Pharmacokinetic and Pharmacodynamic Analysis Set ................................................ 28 
5. 
SUBJECT DISPOSITION ........................................................................................... 29 
6. 
PROTOCOL DEVIATION AND VIOLATION ......................................................... 30 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ....................... 31 
7.1 
Medical History ............................................................................................................ 31 
7.2 
Transplant History ........................................................................................................ 32 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ............................. 34 


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8.1 
Exposure to Investigational product ............................................................................. 34 
8.2 
Measurement of Treatment Compliance ...................................................................... 34 
9. 
CONCOMITANT AND POST-TREATMENT MEDICATION ................................ 35 
10. 
EFFICACY ANALYSES ............................................................................................. 36 
10.1 
Primary Efficacy Endpoint(s) and Analysis ................................................................. 36 
10.2 
Key Secondary Efficacy Endpoint(s) and Analysis ..................................................... 42 
10.3 
Secondary Efficacy Endpoint(s) and Analysis ............................................................. 45 
10.4 
Exploratory Efficacy Endpoint(s) and Analyses .......................................................... 47 
11. 
SAFETY ANALYSES ................................................................................................. 49 
11.1 
Adverse Events ............................................................................................................. 49 
11.2 
Clinical Laboratory Variables ...................................................................................... 51 
11.3 
Vital Signs .................................................................................................................... 52 
11.4 
Electrocardiogram (ECG) ............................................................................................. 53 
11.5 
Physical Examinations and lower extremity exam ....................................................... 53 
11.6 
Immunogenicity (Anti-C1 INH) ................................................................................... 53 
11.7 
Coagulation Panel ......................................................................................................... 54 
11.8 
Virology ........................................................................................................................ 54 
12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC 
ANALYSES ................................................................................................................. 55 
12.1 
Pharmacokinetics Population ....................................................................................... 55 
12.2 
Pharmacokinetic Methods ............................................................................................ 55 
12.2.1 Concentration Data ................................................................................................ 55 
12.2.2 Handling BLQ Values ........................................................................................... 55 
12.2.3 Population Pharmacokinetic Analysis ................................................................... 56 
12.3 
Statistical Analysis of Pharmacokinetic Data .............................................................. 56 
12.4 
Pharmacodynamic Methods (if applicable) .................................................................. 56 
12.4.1 C3a and C5a Data .................................................................................................. 56 
12.4.2 Handling BLQ Values ........................................................................................... 56 
12.4.3 Population Pharmacodynamic Analysis ................................................................ 57 
12.5 
Statistical Analysis of Pharmacodynamic Data (if applicable) .................................... 57 
12.5.1 Primary Pharmacodynamic Endpoint and Analysis (if applicable) ....................... 57 
12.5.2 Secondary Pharmacodynamic Endpoints and Analysis (if applicable) ................. 57 
12.5.3 Other Pharmacodynamic Variables and Analysis (if applicable) .......................... 57 
12.6 
Analyses of Pharmacokinetic/Pharmacodynamic Relationships (If applicable) .......... 57 


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13. 
OTHER ANALYSES ................................................................................................... 58 
13.1 
Quality of Life Analyses .............................................................................................. 58 
13.2 
Health Outcomes and Outcomes Research Analyses ................................................... 58 
14. 
INTERIM ANALYSIS ................................................................................................. 59 
15. 
DATA MONITORING/REVIEW COMMITTEE ....................................................... 61 
16. 
COMPUTER METHODS ............................................................................................ 62 
17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ....................................... 63 
18. 
DATA HANDLING CONVENTIONS ....................................................................... 64 
18.1 
General Data Reporting Conventions ........................................................................... 64 
18.2 
Derived Efficacy Endpoints ......................................................................................... 64 
18.3 
Repeated or Unscheduled Assessments of Safety Parameters ..................................... 65 
18.4 
Missing Date of Investigational Product ...................................................................... 65 
18.5 
Missing Date Information for Concomitant or Post-Treatment Medications .............. 65 
18.5.1 Incomplete Start Date ............................................................................................ 65 
18.5.2 Incomplete Stop Date............................................................................................. 66 
18.6 
Missing Date Information for Adverse Events ............................................................. 67 
18.6.1 Incomplete Start Date ............................................................................................ 67 
18.6.2 Incomplete Stop Date............................................................................................. 67 
18.7 
Missing Severity Assessment for Adverse Events ....................................................... 67 
18.8 
Missing Relationship to Investigation Product for Adverse Events ............................. 67 
19. 
REFERENCES ............................................................................................................. 68 
20. 
TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS .................... 69 
APPENDIX 1 TRANSFORMATION OF CMH TEST STATISTICS AND FISHER’S 
EXACT P-VALUE FOR MULTIPLE IMPUTATION ............................................... 76 
APPENDIX 2 THE ALGORITHM OF DERIVING THE TG ASSESSMENT BY 
GRANULAR SCORE AND STANDARD SCORE .................................................... 78 
 
 
 


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LIST OF TABLES 
Table 1 
Schedule of Assessments (Screening through Day 25) ......................................... 17 
Table 2 
Schedule of Assessments (Month 3 through Month 48 [End of Study])a .............. 20 
Table 3: 
Blood Sample Collection Time Points for Pharmacokinetic/   
Pharmacodynamic Testing (All Subjects) ............................................................. 22 
Table 4: 
Criteria for Potentially Clinically Important Laboratory Tests ............................. 52 
Table 5: 
Criteria for Potentially Clinically Important Vital Signs ....................................... 53 
 
LIST OF FIGURES 
Figure 1: 
Study Design Flow Chart ....................................................................................... 15 


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ABBREVIATIONS 
AE 
adverse event 
AMR 
antibody-mediated rejection (of renal allograft) 
ANOVA 
analysis of variance 
BLQ 
below the limit of quantification 
BMI 
body mass index 
BUN 
blood urea nitrogen 
C1 INH 
C1 inhibitor [human] 
C3a 
anaphylatoxin split product of C3 activation important in chemotaxis 
C4d 
4th complement protein degradation product 
C5a 
anaphylatoxin split product of C5 activation important for histamine 
release and chemotaxis 
CBC 
complete blood count 
cg 
chronic glomerulopathy (cg score is based on published Banff criteria) 
CI 
confidence interval 
Ctrough  
concentration at end of dosing interval 
CMH 
Cochran-Mantel-Haenszel 
CP 
conditional power 
Cr 
creatinine 
CRF 
case report form 
CRO 
contract research organization 
df 
degree of freedom 
DMC 
data monitoring committee 
DSA 
donor-specific antibody 
EAC 
endpoint adjudication committee  
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
eGFR 
estimated glomerular filtration rate 
EM 
electron microscopy 
EOS 
end of study (visit) 
EQ-5D-5L 
EuroQoL Group 5-Dimension 5-Level Self-Report Questionnaire 
FAS 
Full Analysis Set 
FoTA 
Final on Treatment Assessment 


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GBM 
glomerular basement membrane 
HLA 
human leukocyte antigen 
IV 
intravenous 
IVIg 
intravenous immunoglobulin 
IV/WRS 
Interactive Voice/Web Response System 
LLOQ 
lower limit of quantification 
max 
Maximum 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities Terminology 
MMRM 
Mixed-effects model for repeated measures 
min 
minimum 
n 
number of subjects/observations 
NA 
not applicable 
PRA 
panel reactive antibody 
PCI 
potentially clinically important 
PD 
pharmacodynamics 
PVRM 
pharmacovigilance and risk management 
PK 
pharmacokinetics 
PTC 
peritubular capillary 
QoL 
quality of life 
QTcB 
QT Interval Corrected for Heart Rate using Bazett’s Formula 
QTcF 
QT Interval Corrected for Heart Rate using Fridericia’s Formula 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
TEAE 
treatment-emergent adverse event 
TG 
transplant glomerulopathy 
US 
United States 
VAS 
visual analogue scale 
WBC 
white blood cell (count) 
 
 


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1. 
INTRODUCTION 
This Statistical Analysis Plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of efficacy and safety data as described in the study protocol amendment 4 
dated 22NOV17. The shell of tables, figures, and listings are contained in a separate document 
and will serve as guidance. Modifications of shells might be made if needed. 
 


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2. 
STUDY DESIGN  
2.1 
General Study Design 
This randomized, double-blind, placebo-controlled multicenter, multinational study will assess 
the efficacy and safety of CINRYZE with protocol-mandated DSA reduction treatment and 
sucrose-free IVIg for the treatment of acute AMR in kidney transplant recipients. Eligible study 
subjects will have had a kidney transplant with adequate function defined as having a pre-AMR 
baseline eGFRMDRD≥20 mL/min/1.73m2 if the qualifying AMR episode occurs ≤21 days after 
transplant or pre-AMR baseline eGFRMDRD≥30 mL/min/1.73m2 if the qualifying AMR episode 
occurs >21 days after transplant. The pre-AMR baseline is the highest eGFRMDRD value 
obtained following the kidney transplant and within 30 days prior to the qualifying AMR 
episode. If more than 1 eGFRMDRD value is available, a mean of the 2 highest values (at least 1 
day apart and both prior to the AMR episode) will be used as the pre-AMR baseline value. If 
no eGFRMDRD was obtained within 30 days prior to the qualifying AMR episode, it can be 
evaluated within a 60-day period.  
The qualifying episode of biopsy-proven AMR will be defined by 2013 Banff criteria and will 
have evidence of circulating DSA. Once the qualifying AMR episode is diagnosed through a 
biopsy, subjects will enter a screening period for additional eligibility assessments at the 
investigative site. During this screening, the first eGFRMDRD value obtained after the qualifying 
biopsy should be used for the screening visit period. Biopsy slides and images (including, but 
not limited to EM) will be sent to an independent, blinded pathology Endpoint Adjudication 
Committee (EAC) for confirmation of AMR. Subjects will be stratified across centers for (1) 
living vs deceased donor and (2) severity of acute AMR as defined by screening period 
eGFRMDRD (≤15 mL/min/1.73m2 for severe, or >15 mL/min/1.73m2 for mild to moderate). 
CINRYZE or placebo treatment should be started as soon as possible and within 7 days after 
the biopsy procedure. 
Approximately 112 eligible subjects with biopsy-proven AMR will be randomized (56 per 
treatment arm) to receive either CINRYZE or placebo in a 1:1 ratio after being stratified as 
described above. Additional eligible subjects may be enrolled and randomized based on the 
interim data analysis of the first 30 subjects who complete the Month 6 TG assessment for the 
re-estimation of sample size. 
Cinryze: 5000 U CINRYZE (not to exceed 125 U/kg) for IV on Day 1 followed by 2500 U of 
CINRYZE (not to exceed 62.5 U/kg) for IV on Days 3, 5, 7, 9, 11, and 13 with a total of 20,000  
U. 
Placebo: 50 mL 0.9% sodium chloride for IV on Day 1 followed by 25 mL 0.9% sodium 
chloride for IV on Days 3, 5, 7, 9, 11, and 13. 
 


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During the study treatment period, subjects will receive a total of 7 doses of investigational 
product over 13 days in addition to protocol-mandated DSA reduction treatment and sucrose-
free IVIg for each qualifying episode of AMR. To minimize variability, the use of DSA 
reduction treatments and sucrose-free IVIg for the treatment of AMR will be administered as 
mentioned below. 
Donor-specific Antibody Reduction Treatment: Subjects will be required to receive a minimum 
of 5 plasmapheresis, plasma exchange, or immune adsorption treatments from the time of 
diagnostic biopsy for qualifying episode of acute AMR through Study Day 13. Each DSA 
reduction treatment will be followed by sucrose-free IVIg (no less than 100 mg/kg). Additional 
DSA reduction treatments and sucrose-free IVIg may be administered at the discretion of the 
investigator as per local standard of care. NOTE: If plasmapheresis, plasma exchange, or 
immune adsorption treatment occurs on the same day as investigational product dosing, 
investigational product will be administered after completion of the DSA reduction therapy 
session and dosing of sucrose-free IVIg. Collection of blood samples for laboratory testing 
(other than those specified on Table 3) will be performed prior to each DSA reduction treatment, 
if performed. 
In addition to the qualifying kidney biopsy, an additional kidney biopsy will be obtained at the 
Month 6 study visit. Biopsy slides and pertinent micrographs  for the qualifying and Month 6 
biopsies will be provided to an independent, blinded pathology EAC for the assessment of the 
primary endpoint (new or worsening TG at 6 months of initiation of treatment) and other 
histological changes from baseline. Electron microscopy images will also be used for 
exploratory analyses of GBM double contouring and endothelial swelling and the effect on 
long-term graft survival where these changes are observed only on EM. Biopsy slides and 
pertinent micrographs indicating a new AMR episode or the resolution of an AMR episode will 
also be provided to the pathology EAC. 
Subjects will remain in the study until the clinical confirmatory endpoint of all-cause graft 
failure is evaluated up to a maximum of 4 years. Graft failure is evaluated by the nephrology 
EAC. Graft failure, for the purpose of this study, will be defined as 1 or more of the following: 
(1) institution of permanent dialysis (defined as dialysis treatment >30 days), (2) current 
transplant nephrectomy, or (3) clinical determination of cessation of kidney graft function and 
eGFR ≤15 mL/min/1.73m2. If a subject is discontinued for any reason prior to the Month 6 
follow-up visit, every effort will be made to obtain AEs, serum blood urea nitrogen (BUN) and 
creatinine (Cr) results, eGFRMDRD, and a biopsy to send slides and images to the pathology and 
nephrology EACs for determination of TG and graft function status, respectively (see Table 2 
for Early Discontinuation Visit procedures). If a subject is discontinued for any reason prior to 
the end of the study at 4 years, every effort will be made to obtain AEs, serum BUN and Cr and 
eGFRMDRD results to send to the nephrology EAC for determination of graft function status. 
There will be 2 analyses (1st and 2nd interim analyses) assessing the primary endpoint of new or 
worsening TG at 6 months after initiation of treatment. In addition, there will be 3 analyses (3rd 
and 4th interim analyses plus  1 final analysis) of proportions of subjects with all-cause graft 
failure, at approximately 50% (~26 events), 75% (~39 events) and 100% (~51 events) of the 


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study data. Following the Month 6 evaluation, subjects will enter a long-term follow-up stage 
of the protocol, which will include allograft function evaluations every 6 months up to a 
maximum of 4 years. The duration of the study will be event driven, and is based upon an 
assumption that there will be approximately 51 all-cause graft failures. The study will continue 
until 51 such events are accrued and adjudicated by the nephrology EAC. However the 
maximum amount of time each subject will be followed in the study will be 4 years post initial 
treatment with investigational product. 
Resolution will be achieved when, after treatment, the local eGFRMDRD value increases to at 
least within 20% or above the eGFRMDRD value collected as a pre-AMR baseline. If an AMR 
episode is diagnosed, in absence of significant decline (≥20%) of eGFR from pre-AMR 
baseline, a follow-up biopsy within 3 months is recommended in order to assess resolution.  
Recurrence is defined as biopsy-proven new evidence of AMR upon resolution of the previous 
AMR episode. Investigators will also be asked to record the date of recurrence of AMR, when 
applicable. During the first 6 months of the study only, if the qualifying AMR episode resolves 
and there is new biopsy-proven acute AMR per protocol definition in the inclusion criteria, the 
subject may be retreated at the investigative site with the same investigational product to which 
they were originally randomized as well as DSA reduction treatment and sucrose-free IVIg per 
protocol. Between the qualifying biopsy that is diagnostic for a recurrent episode of AMR and 
the first retreatment dose of investigational product, subjects will complete a subset of the 
screening procedures and follow the assessments noted in the schedule of assessments 
(Screening through Day 25) for each new episode of AMR occurring during the first 6 months 
of the study. Retreatment should occur as soon as possible within 7 days of the biopsy that 
defined the new AMR episode. Retreatment may not occur after the first 6 months of the study. 
Biopsies at Month 6 following retreatment will not be necessary. The only mandated follow-up 
biopsy will be at Month 6 after initial treatment. 
The effect on the quality of life will be measured by using the EuroQoL Group 5-Dimension 5-
Level Self–report Questionnaire (EQ-5D-5L). 
Complement and C1 INH levels will be assessed at specified time points up to Day 13 for 
pharmacokinetic/pharmacodynamic evaluation. 
Safety will be monitored through the recording of adverse events (AEs) and changes in physical 
examinations, vital signs, antibodies to C1 INH, and clinical safety laboratory testing.  The 
following events of special interest will be closely monitored and reported throughout the study, 
regardless of relationship to study medication: any thrombotic or thromboembolic event; any 
hypersensitivity reaction; any new episode of kidney allograft rejection, even if the event does 
not qualify for retreatment with study medication; and any new kidney allograft failure. 
Stopping rules: If a drug-related thrombotic or thromboembolic SAE (as defined in section 4.5.3 
of the protocol) occurs in any subject, as defined by the Principal Investigator at the site, 
enrollment of new subjects will be halted. Study procedures for subjects already enrolled will 
continue and subjects already enrolled will continue on their assigned dosing regimen. 


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See the study design flow chart below. 
 
Figure 1: Study Design Flow Chart 
 
 
 
2.2 
Randomization 
Approximately 112 eligible subjects with biopsy-proven AMR will be randomized (56 per 
treatment arm) to receive either CINRYZE or placebo in a 1:1 ratio.   
The actual treatment given to individual subjects is determined by a randomization schedule 
automatically assigned by the Interactive Web Response System (IWRS) at the Baseline Visit 
(Day 1) after subject eligibility has been confirmed using the eligibility criteria. Subjects will 
be stratified across centers as described in section 2.1. CINRYZE or placebo treatment should 


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be started as soon as possible and within 7 days after the biopsy procedure. Additional eligible 
subjects may be enrolled and randomized based on the interim data analysis of the first 30 
subjects who complete the Month 6 TG assessment for the re-estimation of sample size 
(Protocol Section 9.5.1). 
2.3 
Blinding 
Qualified subjects will be randomized in a 1:1 ratio to receive CINRYZE or placebo using a 
centralized procedure. An Interactive Voice/Web Response System (IV/WRS) will be used to 
randomize subjects and provide the treatment assignment to the unblinded pharmacist. The 
unblinded pharmacist will prepare the blinded IV solution (CINRYZE or placebo) accordingly. 
A Sponsor representative(s) not affiliated with the core team will be unblinded to treatment 
assignment in order to review drug accountability on an ongoing basis throughout the study 
(Protocol Section 6.4). This unblinded representative will remain independent of other study 
activities. 
For the first interim analysis, the EACs, sponsor, investigator, and subjects will be blinded to 
the study treatment. When the criterion to conduct the second interim analysis is met, 
treatment assignment for those subjects will be unblinded to designated sponsor 
representatives for analysis. The treatment assignments for all other subjects will be blinded 
to the EACs, investigator, and subjects during the conduct of the study. 
 
DMC members will remain unblinded for the duration of the study to review efficacy and safety 
data. 
2.4 
Schedule of Assessments  


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Table 1 Schedule of Assessments (Screening through Day 25) 
Study Procedure 
(Screening)a 
Investigational Product Administration Period 
Post-Treatment 
Evaluations 
1st 
Episode 
Retreatment 
(recurrent AMR) 
within 180 days 
Day 1a 
Day 3 
Day 5 
Day 7 
Day 9 
Day 11 
Day 13 
Day 25  
(±48 hours) 
Informed consent 
 
 
 
 
 
 
 
 
 
 
Medical history, presence/absence of diabetes 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion eligibility 
 a 
 a 
b 
 
 
 
 
 
 
 
Screening Registration/Randomization via 
IV/WRS (IRT) 
 
 
 b 
 
 
 
 
 
 
 
Physical examination 
 
 
 b 
 
 
 
 
 
 
 
Lower extremity examination c 
 
 
 b 
 
 
 
 
 
 
 
Height  
 
 
 
 
 
 
 
 
 
 
Body weight 
 
 
 b 
 
 
 
 
 
 
 
Vital signs (BP, HR) d  
 
 
 b 
 
 
 
 
 
 
 
12-lead ECG e 
 
 
 
 
 
 
 
 
 
 
Central lab Pregnancy testing (also local lab serum and 
urine pregnancy test at screening, and local urine test on Day 1) f 
 
 
 b 
 
 
 
 
 
 
 
Central lab Virology screen 
 
 
 
 
 
 
 
 
 
 
Central lab Hematology (also local lab WBC and platelets 
at screening) g 
 
 
 b 
 
 
 
 
 
 
 
Central lab clinical chemistry gs 
 
 
 b 
 
 
 
 
 
 
 
BUN & Serum Cr with eGFR (both central lab 
[included in chemistry when applicable] and local lab) g 
h 
h 
 
 
 
 
 
 
  
 
Central lab Proteinuria: Spot urine protein, urine 
Cr and urine protein/urine creatinine ratio 
 
 
 
 
 
 
 
 
 
 
Kidney allograft biopsy, submission of pathology 
slides/images i 
 
 
 
 
 
 
 
 
 
 
Central lab Pharmacokinetic/Pharmacodynamic 
Testing j 
 
 
 
 
 
 
 
 
 
 
Central lab Immunogenicity (anti-C1 INH 
antibodies) 
 k 
 
 
 
 
 
 
 
 
Central lab DSA identification (also local lab at 
screening)  l 
 
 
 
 
 
 
 
 
 
 
DSA reduction treatments & sucrose-free IVIg m 
--------------------------------------------------------------------------------------------------------------- 
 


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Table 1 Schedule of Assessments (Screening through Day 25) 
Study Procedure 
(Screening)a 
Investigational Product Administration Period 
Post-Treatment 
Evaluations 
1st 
Episode 
Retreatment 
(recurrent AMR) 
within 180 days 
Day 1a 
Day 3 
Day 5 
Day 7 
Day 9 
Day 11 
Day 13 
Day 25  
(±48 hours) 
Investigational product administration n 
 
 
 
 
 
 
 
 
 
Concomitant medications  
 
 
 ----------------------------------------------------------------------------------------------------------------- o  
p 
Adverse event monitoring q 
--------------------------------------------------------------------------------------------------------------------------------------  
Renal allograft assessment r 
 
------------------------------------------------------------------------------------------------------------------------- 
Subject survival status 
 
-------------------------------------------------------------------------------------------------------------------------- 
EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
Healthcare Resource Utilization 
 
 
 
 
 
 
 
 
 
 
AE=adverse event; AMR=antibody-mediated rejection; BP=blood pressure; BUN=blood urea nitrogen; C1 INH=C1 inhibitor; Cr=creatinine; DSA=donor-specific antibody; 
ECG=electrocardiogram; eGFRMDRD=estimated glomerular filtration rate calculated by the Modification of Diet in Renal Disease; EQ-5D-5L= EuroQoL Group 5-Dimension 
5-Level Self–report Questionnaire; HR=heart rate; IVIg=intravenous immunoglobulin; IV/WRS=interactive voice/web randomization system; SAE=serious adverse event 
a Local laboratory testing will be used to determine subject eligibility. Limited inclusion/exclusion criteria are checked at screening for retreatment only if the investigator plans to retreat 
(retreatment is only allowed for New AMR episodes diagnosed within the first 180 days after the qualifying biopsy, and if the previous AMR episode resolved). 
b Day 1 procedures to be completed prior to the first dose of investigational product. 
c A lower extremity exam will be performed and will include a determination of presence or absence of unilateral calf tenderness or leg swelling.  If a deep vein thrombosis is 
suspected, a diagnostic exam will be performed. 
d On investigational product dosing days, vital signs should be obtained within 30 minutes prior to investigational product administration and then between 30 minutes and 
1 hour after completion of investigational product infusion.  Additional vital signs measurements will be performed during the study if clinically indicated. 
e During the study, additional ECGs will be performed if clinically indicated. 
f  Females of child-bearing potential will have  urine and serum pregnancy tests at Screening and urine pregnancy test on Day 1 of each episode. 
g On investigational product dosing days, blood samples for clinical safety laboratory testing should be collected prior to administration of investigational product. Local 
laboratory hematology results (WBC and platelets) will be used to assess eligibility at screening. Central laboratory BUN and creatinine results are included where a sample is 
taken for clinical chemistry. Local laboratory results for BUN and creatinine (including eGFRMDRD calculation) are required at all study visits, as well as pre-AMR and 
resolution of AMR for all AMR episodes. 
h At screening, the first creatinine value obtained after the qualifying biopsy (or recurrent AMR biopsy if applicable) should be used as the screening creatinine and eGFR 
values to assess AMR severity for stratification. 
i Qualifying renal allograft biopsy for assessment of histologic parameters associated with AMR. In the event that the subject has a new episode of AMR as defined in Section 
7.2.2.4 of the protocol. the subject may be retreated with the same treatment to which they were previously randomized and following the procedures outlined in Table 1, 
beginning at Day 1 with the exception of randomization and limited inclusion/exclusion criteria. For each biopsy, the pathology slides and images are to be submitted. 
j Blood samples for pharmacokinetic/pharmacodynamic analysis will be collected at the time points specified in Table 3. 


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Table 1 Schedule of Assessments (Screening through Day 25) 
Study Procedure 
(Screening)a 
Investigational Product Administration Period 
Post-Treatment 
Evaluations 
1st 
Episode 
Retreatment 
(recurrent AMR) 
within 180 days 
Day 1a 
Day 3 
Day 5 
Day 7 
Day 9 
Day 11 
Day 13 
Day 25  
(±48 hours) 
k If sucrose-free IVIg is administered on the same day as the screening visit, blood samples for immunogenicity should be obtained both prior to and after sucrose-free IVIg administration. Subjects 
where anti-C1 INH antibodies are detected will be followed until negative. 
l DSA antibody will be determined by central and local laboratory analysis at screening (for initial or recurrent episode of AMR), and only by the central laboratory at all other 
time points specified. DSA testing may be performed locally at other time points after screening for all clinical assessments as part of standard of care. Additional serum may 
be collected by the central laboratory for future antibody and titer testing. 
m Subjects will have a minimum of 5 plasmapheresis, plasma exchange, or immune adsorption treatments each followed by sucrose-free IVIg from the time of diagnostic 
biopsy for qualifying episode of acute AMR through Study Day 13. Plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free IVIg may be 
provided as part of standard of care prior to study entry. Protocol-mandated plasmapheresis, plasma exchange, or immune adsorption treatments should be completed by Day 
13. Additional DSA reduction treatments or doses of sucrose-free IVIg may be administered at the discretion of the investigator as part of standard of care. 
n A total of 7 doses of investigational product will be administered: an initial IV infusion of 5000 U CINRYZE or placebo on Day 1, followed by 2500 U of CINRYZE or placebo 
IV on Days 3, 5, 7, 9, 11, and 13. If plasmapheresis, plasma exchange, or immune adsorption treatments therapy occurs on the same day as investigational product dosing, 
investigational product will be administered after completion of the DSA reduction therapy session and administration of sucrose-free IVIg. 
o All medications (and selected blood products) taken from the day of the first dose of investigational product (Day 1) through the day of the last dose of investigational product (Day 13) will be 
recorded. In addition, medications used to treat AEs, SAEs, and adverse events of special interest (AESI) from time of informed consent through 30 days after the last dose of investigational 
product for each treatment period will also be recorded. 
p The following medications will be collected for the duration of the study: Any IV steroids, Rituximab, Muromonab-CD3, Alemtuzumab, Anti-thymocyte globulin (rabbit), 
Lymphocyte immune globulin, anti-thymocyte globulin (equine), any IV immunoglobulin preparation, Daclizumab or basiliximab. See Section 5.5 of the protocol for 
additional medications to record. 
q Adverse events and SAEs will be recorded from the time of Informed Consent through 30 days after the last dose of investigational product regardless of relationship to 
study treatment. Following the 30-day capture period for all AEs and SAEs, only AE/SAEs deemed related to investigational product or other protocol-mandated procedures, 
as well as the following AESIs regardless of relationship to investigational product: any hypersensitivity reaction, any thrombotic or thromboembolic event, any new episode 
of kidney allograft rejection (excluding AMR) even if the event does not qualify for retreatment with investigational product, and any kidney allograft failure, will be collected 
during the long-term follow-up phase of the study. 
r Renal allograft function will be assessed by eGFRMDRD. Allograft failure and need for splenectomy will be assessed at all timepoints. 
s Clinical chemistry includes BUN and serum creatinine 
 


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Table 2 
Schedule of Assessments (Month 3 through Month 48 [End of Study])a 
Study Procedure 
Post-Treatment Evaluations 
Month 3 
(±21 days)b 
Month 6 
(±21 days)b 
Month 12 
(±21 days)b 
Month 18 
(±28 days)b 
Month 24 
(±28 days)b 
Month 30 
(±28 days)b 
Month 36 
(±28 days)b 
Month 42 
(±28 days)b 
Early 
Discontinuation 
Visit Between 
Day 13 & 
Month 6 
EOS/Month 48 
or at patient 
discontinuation 
if after Month 6 
(±28 days)b 
Presence/absence of diabetes 
 
 
 
 
 
 
 
 
 
 
Body Weight 
 
  
 
 
 
 
 
 
 
 
BUN & Serum Cr with eGFR 
(both central and local lab)  c 
 
 
 
 
 
 
 
 
 
 
Central lab Proteinuria: Spot 
urine protein, urine Cr and 
urine protein/urine creatinine 
ratio  
 
 
 
 
 
 
 
 
 
 
Kidney allograft biopsy & 
submission of pathology slides 
& images d 
 
 
 
 
 
 
 
 
 
 
Central lab Immunogenicity 
(anti-C1 INH antibodies) 
 
 
e 
e 
e 
e 
e 
e 
 
e 
Central lab DSA identification 
f 
 
 
 
 
 
 
 
 
 
 
Concomitant medications g 
 
 
 
 
 
 
 
 
 
 
Adverse event monitoring h 
 
 
 
 
 
 
 
 
 
 
Renal allograft assessment 
 
 
 
 
 
 
 
 
 
 
Subject survival status 
 
 
 
 
 
 
 
 
 
 
EQ-5D-5L 
 
 
 
 
 
 
 
 
 
 
Health Resource Utilization 
 
 
 
 
 
 
 
 
 
 
BUN=blood urea nitrogen; C1 INH=C1 inhibitor; Cr=creatinine; DSA=donor-specific antibody; eGFRMDRD=estimated glomerular filtration rate calculated by the Modification 
of Diet in Renal Disease; EOS=End of Study Visit; EQ-5D-5L= EuroQoL Group 5-Dimension 5-Level Self–report Questionnaire; SAE=serious adverse event; TG=transplant 
glomerulopathy 
a The duration of the study will be event driven, and is based upon an assumption that there will be approximately 51 all-cause graft failures including death. The trial will 
continue until 51 such events are accrued and adjudicated by the independent, blinded nephrology EAC. See Section 9.5.1of the protocol for additional details. However the 
maximum amount of time each subject will be followed in the study will be 4 years post initial treatment with investigational product. Subjects will complete visits every 
6 months until the study is ended. If the study is stopped prior to the last enrolled subject completing Month 48, all subjects who have not reached Month 48 will be asked to 
return to the investigational site for their End of Study (EOS) visit. 


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Table 2 
Schedule of Assessments (Month 3 through Month 48 [End of Study])a 
Study Procedure 
Post-Treatment Evaluations 
Month 3 
(±21 days)b 
Month 6 
(±21 days)b 
Month 12 
(±21 days)b 
Month 18 
(±28 days)b 
Month 24 
(±28 days)b 
Month 30 
(±28 days)b 
Month 36 
(±28 days)b 
Month 42 
(±28 days)b 
Early 
Discontinuation 
Visit Between 
Day 13 & 
Month 6 
EOS/Month 48 
or at patient 
discontinuation 
if after Month 6 
(±28 days)b 
b Visit dates for each visit from Month 3 through EOS will reference back to Day 1 of study entry and will be based on calendar months. Visit windows for each visit in Table 2 
will be ±21 days for Months 3, 6, and 12. Visit windows will be ±28 days for Months 18, 24, 30, 36, 42, 48, Early Discontinuation, and End of Study (EOS).  
c In addition to Central laboratory testing, the local laboratory must obtain BUN, and creatinine values and calculate eGFR values for documentation in CRFs for each of the 
time points indicated as well as pre-AMR and  resolution of AMR for all AMR episodes. Subjects who discontinue before 6 months should complete the Early Discontinuation 
Visit Between Day 13 & Month 6.  
d In the event of discontinuation of a fully-dosed subject prior to the Month 6 Visit, every attempt will be made to obtain a biopsy at discontinuation to send to the independent, 
blinded pathology EAC for determination of TG. The required slides and images for the Screening, Month 6, early discontinuation before Month 6 (if applicable), and any other 
unscheduled standard of care biopsies, must be submitted to the Sponsor's designee within 30 days after the biopsy procedure, for subsequent submission to the EAC for review. 
e Subjects where anti-C1 INH antibodies are detected will be followed to measure titers. At Months 12, 18, 24, 36, and 48 the test will be performed ONLY if anti-C1 INH 
antibodies are detected at the previous time point. At Month 3 and Month 6 the test will be performed in each patient. 
f DSA antibody analysis will be performed by the central laboratory and will not be reported back to the investigator. Additional DSA testing at these and other time points may 
be performed by the local laboratory for all clinical assessments as part of standard of care. Additional serum may be collected for the central laboratory for future antibody and 
titer testing. 
g  For the duration of the study, the following concomitant/post-treatment medications will be collected in the case report form: Any IV steroids, Rituximab, Muromonab-CD3, 
Alemtuzumab, anti-thymocyte globulin (rabbit), lymphocyte immune globulin, anti-thymocyte globulin (equine), any IV immunoglobulin preparation, Daclizumab or 
basiliximab. In addition, medications used to treat any related AEs/SAEs or AESIs will also be recorded for the duration of the study as well as those listed in Section 5.5 of the 
protocol 
h Adverse events and SAEs will be collected from the time of Informed Consent through 30 days after the last dose of investigational product regardless of relationship to study treatment. Following 
the 30-day capture period for all AEs and SAEs, only AE/SAEs deemed related to investigational product or other protocol-mandated procedures as well as the following AESIs regardless of relationship 
to investigational product: any hypersensitivity reaction, any thrombotic or thromboembolic event, any new episode of kidney allograft rejection (excluding AMR) even if the event does not qualify 
for retreatment with investigational product, and any kidney allograft failure will be collected during the long-term follow-up phase of the study.   
 
 
 
 


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Table 3: 
Blood Sample Collection Time Points for Pharmacokinetic/ 
  
Pharmacodynamic Testing (All Subjects) 
Sample Day and Time 
C1 INH (antigen and 
function), C3a, and C5a 
Day 1:  Prior to start of DSA reduction therapy, if performed, on Day 1 
X 
Day 1:  Prior to Day 1 investigational product infusion (within 15 min) 
X 
Day 1:  1 h (+ 5 min) after start of Day 1 investigational product infusion 
X 
Day 7:  Prior to start of DSA reduction therapy, if performed, on Day 7 
X 
Day 7:  Prior to Day 7 investigational product infusion (within 15 min) 
X 
Day 7:  1 h (+ 5 min) after start of Day 7 investigational product infusion 
X 
Day 13:  Prior to start of DSA reduction therapy, if performed, on Day 13 
X 
Day 13:  Prior to Day 13 investigational product infusion (within 15 min) 
X 
Day 13:  1 h (+ 5 min) after start of Day 13 investigational product infusion 
X 
C1 INH=C1 inhibitor; C3a= anaphylatoxin split product of C3 activation important in chemotaxis; C5a=anaphylatoxin 
split product of C5 activation important for histamine release and chemotaxis; DSA=donor-specific antibody. 
 
 
 


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2.5 
Determination of Sample Size 
A total of 112 subjects (56 CINRYZE, 56 Placebo) will be randomized in a 1:1 ratio into 2 
treatment groups: CINRYZE or placebo.  Sample size was calculated for the primary endpoint 
and the key secondary endpoint using nQuery Advisor 7.0. 
The primary endpoint in the study is the proportion of subjects with new or worsening TG at 6 
months after treatment initiation. A 43% absolute difference in TG at 6 months between 
treatment groups (3/7 in placebo and 0/7 in CINRYZE) was observed in a subset of subjects 
(14/18) in the completed randomized Phase 2 pilot study (0624-201). For this study, the 
assumed proportion of subjects with new or worsening TG at 6 months will be 50% in the 
placebo group and 10% in the CINRYZE group. A sample size of 60 subjects (30 in placebo 
and 30 in CINRYZE) would be needed to obtain at least 90% power to detect a significant 
treatment difference at an alpha level of 0.025 (1-sided test). 
The key secondary endpoint in the study is the proportion of subjects with all-cause graft failure. 
Assuming the proportions of subjects with graft failure due to AMR are 64% and 25% for 
placebo and CINRYZE, respectively, and all-other-cause graft failure rate is 12% for both 
placebo and CINRYZE, then the proportions of subjects with all-cause graft failure are 68% 
and 34% for placebo and CINRYZE, respectively. A total of 100 subjects will provide 90% 
power to detect an absolute treatment difference of 34% at an alpha level of 0.025 (1-sided test) 
for all-cause graft failure. These assumptions are based on literature (Haririan et al. 2009; Sharif 
et al. 2014; OPTN/STRT Annual Data Report 2012). Considering a 10% drop-out rate during 
the study, 112 subjects will be randomized to the study. Under these assumptions, the 
expectation is that there will be approximately 34 all-cause graft failures on placebo and 
approximately 17 all-cause graft failures on CINRYZE, giving 51 events total. The trial will 
continue until 51 such events are accrued and adjudicated by the nephrology EAC unless 
stopped prematurely based on findings at an interim analysis or until the final subject enrolled 
has been followed for 4 years post initial treatment with investigational product.  
Additional eligible subjects may be enrolled based on the interim data analysis of the first 30 
subjects who complete the Month 6 TG assessment for the re-estimation of sample size. 
2.6 
Multiplicity Adjustments for Type I Error Control 
To control the overall Type I error, the primary and key secondary endpoint will be tested 
hierarchically with a fixed sequence approach. The study will continue to assess the key 
secondary endpoint only if the primary null hypothesis has been rejected. Thus, the significance 
of the key secondary endpoint is contingent, and no adjustment for multiple endpoints is needed.  
The primary endpoint will have 2 analyses (1 interim and 1 final for the primary endpoint). The 
first interim analysis is for futility and sample size recalculation. The second interim analysis, 
which serves as the final analysis for the primary endpoint, is for the assessment of efficacy 
(new or worsening TG at 6 months). The alpha level of 0.0001 is to be spent at the first interim 


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analysis in developing the efficacy boundary of the second interim analysis of TG at 6 months. 
The overall significance level for the efficacy analysis of primary endpoint will be preserved at 
0.025 (1-sided test) by using a significance level of 0.0249 for the second interim analyses. The 
difference between treatments will be evaluated by using the CHW weighted test statistic (Cui 
et al., 1999).   
The key secondary endpoint will have 3 analyses (2 interim and 1 final), at approximately 50% 
(~26 events), 75% (~39 events) and 100% (~51 events) of the targeted all-cause graft failure. 
The Hwang-Shih-DeCani alpha spending function with phi = -4, which is similar to the 
boundaries from the O'Brien-Fleming method, will be used for the unequal spaced timing of 
analysis. Using this approach requires z ≥2.75 (or equivalently p ≤0.0030) to consider stopping 
the study for a positive treatment effect at the first interim analysis (~50% of events), z ≥2.43 
(or equivalently p ≤0.0075) to consider stopping the study for a positive treatment effect at the 
second interim analysis (~75% of events), and z ≥2.01 (or equivalently p ≤0.0221) to claim 
efficacy at the final analysis (~100% of events), as shown in the table below.  This approach 
maintains a fixed sample p-value close to 0.025 (1-sided test) at the final analysis and an overall 
significance level at 0.025. 
Analysis Proportion of Targeted Number of Events  Z Scale p-value (1-sided) 
Interim 3 
50% 
2.751 
0.0030 
Interim 4 
75% 
2.428 
0.0075 
Final 
100% 
2.012 
0.0221 
 


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3. 
OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is to evaluate the efficacy of CINRYZE administered with 
plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free 
immunoglobulin (IVIg) for the treatment of acute AMR of renal allograft in kidney transplant 
recipients as measured by the proportion of subjects with new or worsening transplant 
glomerulopathy (TG) at 6 months after treatment initiation. 
3.2 
Secondary Objectives 
The key secondary objective is to evaluate the efficacy of CINRYZE administered with 
plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free IVIg for 
the treatment of acute AMR of renal allograft in kidney transplant recipients as measured by 
the proportion of subjects with all-cause graft failure at 4 years following treatment initiation 
for the initial qualifying AMR episode. 
 
Secondary objectives from study entry to 6 months are: 
• To assess renal function  
• To assess proteinuria  
• To assess change in histopathology  
• To assess graft outcomes 
 
Secondary objectives from study entry to graft failure or 4 years: 
 
• To assess renal function 
• To assess proteinuria  
• To assess graft outcomes 
• To assess resolution of AMR 
• To assess safety and tolerability of CINRYZE in kidney transplant recipients 
• To assess subject survival status 
 


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3.3 
Exploratory Objectives 


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4. 
SUBJECT POPULATION SETS 
4.1 
All-enrolled Set  
The All-enrolled Set will consist of subjects who have signed informed consent. 
4.2 
Intent-to-Treat Set (ITT) 
The Intent-to-Treat Set will consist of all subjects in the All-enrolled Set for whom a 
randomization number has been assigned. This set will be used for sensitivity analyses of 
efficacy endpoints provided that the ITT set differs by the FAS by at least 10% 
4.3 
Full Analysis Set (FAS) 
The Full Analysis Set will consist of all subjects who have taken at least 1 dose of 
investigational product. The FAS will be used for efficacy analysis according to assigned 
treatment. 
4.4 
Safety Analysis Set (SAF) 
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of 
investigational product. The Safety Analysis Set will be used for safety analysis according to 
actual treatment received. 
4.5 
Per-protocol Analysis Set-1 (PPS1) 
The Per-protocol Analysis Set-1 will consist of all subjects in the FAS who have taken at least 
5 of the 7 planned doses, are assessed for TG at 6 months after initiation of treatment or have 
post-baseline biopsy-proven new or worsening TG within 6 months of initiation of treatment, 
and do not have predefined major protocol deviations that may affect the primary efficacy 
endpoint.  
These protocol deviations will be identified prior to unblinding of the study. 
4.6 
Per-protocol Analysis Set-2 (PPS2) 
The Per-protocol Analysis Set-2 will consist of all subjects in the FAS who have taken at least 
5 of the 7 planned doses, are assessed for graft failure at 4 years, or have shown graft failure 
within 4 years, or died, and do not have predefined major protocol deviations that may affect 
the key secondary endpoint.  
These protocol deviations will be identified prior to unblinding of the study. 
 


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4.7 
Pharmacokinetic and Pharmacodynamic Analysis Set 
• PK Analysis Set: all subjects who have at least 1 reported post dose PK concentration 
value. All PK analyses will be based on the PK Set. The Clinical pharmacology group will 
identify the PK analysis set. 
• PD Analysis Set: all subjects who have at least 1 reported post dose PD value. All PD 
analyses will be based on the PD Set.  The Clinical pharmacology group will identify the 
PD analysis set. 


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5. 
SUBJECT DISPOSITION 
This section describes subject disposition for the analysis sets (i.e., All-enrolled Set, Intent-to-
Treat Set, Safety Analysis Set, FAS, Per Protocol Analysis Sets, and Pharmacokinetic and 
Pharmacodynamic Set) and the study status for All-enrolled Set. 
The number of subjects included in each subject population set will be summarized by treatment 
group and overall. The number of subjects in FAS but without post-dose primary or key 
secondary endpoint assessment will be summarized by treatment group and overall. The 
denominator for the percentage calculation will be the number of subjects in the Intent-to-Treat 
Set. 
The number and percentage of subjects who completed and prematurely discontinued during 
the study will be presented for each treatment group and overall for the Intent-to-Treat Set. 
Primary reasons for premature discontinuation from the study as recorded on the termination 
page of the eCRF will be summarized (number and percentage) by treatment group for the 
Intent-to-Treat Set.  
A listing will also be provided for subject disposition, subjects completing and prematurely 
discontinued during the study, and study analysis sets.  


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6. 
PROTOCOL DEVIATION AND VIOLATION 
All protocol violations and deviations will be recorded on the Protocol Deviation / Violation 
Log.  All protocol violation and deviation data will be summarized by treatment group and 
overall for the Intent-to-Treat Set. A complete listing will also be provided for all protocol 
deviations and violations for the Intent-to-Treat Set.  


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7. 
DEMOGRAPHIC AND OTHER BASELINE 
CHARACTERISTICS 
Demographic and baseline characteristics will be determined for enrolled subjects using the 
screening visit or last observation prior to the first dose of investigational product, whichever 
is later.  
Subject demographics including age, sex, race, ethnicity will be summarized by treatment group 
and overall for the Intent-to-Treat Set, Safety Analysis Set, FAS and Per-protocol Sets.  
Baseline characteristics including, weight, height, BMI, stratification factors, acute AMR 
severity (severe vs. mild to moderate) defined by the screening period eGFRMDRD ≤15 
mL/min/1.73m2 (severe) or >15 mL/min/1.73m2 (mild to moderate) and donor characteristic 
(living vs. deceased donor) will be summarized by treatment group and overall for the Intent-
to-Treat Set, Safety Analysis Set, FAS and Per-protocol Sets.  
Continuous variables will be summarized by descriptive statistics including number of subjects 
(n), mean, standard deviation (SD), median, minimum (min), and maximum (max). Categorical 
variables will be summarized by the number of subjects in each category and the percentage of 
subjects out of the total in the respective analysis set. 
Height and weight will be used to calculate BMI using the formula below: 
 
 
 
BMI =  
 
A listing will be created to show all the demographics and baseline characteristics for each 
subject in the Intent-to-Treat Set. 
7.1 
Medical History 
All medical history findings that have been present/active within 5 years prior to enrollment 
will be recorded regardless of clinical relevance or presence at study start.  Medical history 
findings that have not been active within the 5 years prior to enrollment will be recorded only 
if deemed clinically relevant by the investigator to the conduct of the study.  The medical history 
should include any history of allergic reactions to drugs.  
Medical history data will be summarized by treatment on the Safety Analysis Set.  Medical 
history data will be listed for all subjects in the Safety Analysis Set. 
2
[m])
 
(height
[kg]
 
weight


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7.2 
Transplant History 
The following information associated with Transplant history will be recorded in the eCRF at 
the screening visit: 
• Primary cause of native renal failure: diabetes (type 1 or type 2); hypertension; diabetes 
and hypertension; any glomerulonephritis (e.g., focalsegmental glomerulosclerosis, 
rapidly progressing glomerulonephritis, membrano-proliferative glomerulonephritis); any 
autoimmune nephropathy (e.g., systemic lupus erythematosus, Goodpasture’s syndrome, 
Immunoglobulin A nephropathy); drug toxicity (e.g., lithium, non-steroidal anti-
inflammatory abuse); congenital defect (e.g., posterior urethral valves); Polycystic Kidney 
Disease or other   
• Diabetes (yes/no) 
• Onset date of AMR that qualifies the subject to the study 
• Total number of lifetime kidney transplants 
• Other transplants (e.g., heart, lung, liver, small bowel, pancreas, other)  
• Total number of plasmapheresis, plasma exchange, or immune adsorption treatments in 
the 14 days prior to transplant through 14 days post-transplant 
• Prior splenectomy (yes/no; if yes, then date of splenectomy) 
• Date of current transplant 
• Type of current transplant (deceased donor, living related donor, or unrelated living donor, 
extended criteria donor (per site standard), donor after cardiac death) 
• Confirmation that there is no existing lesion in the transplanted allograft  
• Active treatment of HCV 
• MI or TIA within 6 months prior to study entry 
• ABO incompatible kidney transplant (yes/no) 
• Lowest serum Cr within 30 days after the current transplant (and before the qualifying 
episode of AMR) 
• Highest serum Cr on day of qualifying renal allograft biopsy (±2 days) 
• Need for any dialysis within the first 14 days after the current transplant (yes/no) 
• Need for any dialysis within 14 days prior to first dose of investigational product (yes/no) 
• Specificity of DSA prior to current kidney transplant, if applicable (HLA class I [yes/no; 
if yes, specify antigen] and/or HLA class II [yes/no; if yes, specify antigen]) 
• Specificity of DSA closest to and within ±7 days of the qualifying biopsy (HLA class I 


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[yes/no; if yes, specify antigen] and/or HLA class II [yes/no; if yes, specify antigen]) 
• Use of any of the following medications administered for immunosuppression within the 
period 2 weeks before and 2 weeks after the current transplant (yes/no for each): 
➢ Any IV steroids 
➢ Rituximab  
➢ Muromonab-CD3 
➢ Alemtuzumab 
➢ Anti-thymocyte globulin (rabbit) 
➢ Lymphocyte immune globulin, anti-thymocyte globulin (equine) 
➢ Any sucrose-free IVIg preparation 
➢ Daclizumab or basiliximab 
➢ Other: specify 
Descriptive summaries of transplant history will be presented by treatment group for the Safety 
Analysis Set.  A complete listing for transplant history will be created for all subjects in the 
Safety Analysis Set.  


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8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Exposure to Investigational product  
Exposure to double-blind investigational product for the Safety Analysis Set will be 
summarized in terms of number of treatment periods, number of doses, and total dose.  
Descriptive statistics (n, mean, SD, min, median, and max) will be presented by treatment group 
and by treatment period. 
A listing will be created by subject and treatment period giving the date and time of dose 
administration for each treatment given for the Safety Analysis Set. 
8.2 
Measurement of Treatment Compliance 
Investigational product dosing compliance is defined as the dose administered to a subject 
during the period/study divided by the doses expected to be administered during the same 
period/study multiplied by 100.   
The number of doses administered is calculated by the total number of doses administered on 
investigational product exposure log during the period/study.  The number of doses expected 
to be administered during a treatment period is 7. The number of doses expected to be 
administered during the whole study is calculated as 7 × (1 + number of new qualified acute 
AMR episodes).   
The total dose administered is calculated as sum of dose amount administered during the study. 
The total dose expected to be administered in a treatment period is 20,000 Units. The total dose 
expected to be administered in the whole study is calculated as 20,000 Units × (1 + number of 
new qualified acute AMR episodes).  
Descriptive statistics for investigational product compliance will be presented by treatment 
group, by treatment period (applies to patients with repeat dosing due to recurrent AMRs) and 
overall for the Safety Analysis Set. 


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9. 
CONCOMITANT AND POST-TREATMENT MEDICATION  
The WHO Drug Dictionary will be used to code concomitant and post-treatment medications.   
Concomitant medication is defined as any medications including blood products, 
immunosuppressive agents, or medications used to treat a pre-existing medical history 
condition or AE which are recorded in the CRF if taken/administered during the day of the first 
dose of investigational product (Day 1) through the day of the last dose of investigational 
product (Day 13) for each treatment period (Table 1), inclusive.  Any medication with a start 
date after the date of the last dose of investigational product in each treatment period will not 
be considered a concomitant medication. 
Post-treatment medication is defined as any CRF recorded medication taken/administered after 
first treatment end, or between treatment periods, through year 4.  
Both concomitant and post-treatment medication usage will be summarized by the number and 
percentage of subjects in each treatment group by Anatomical Therapeutic Chemical (ATC) 
classification level 1 (Body System) and preferred term for the Safety Analysis Set.  
Medications can be counted both as concomitant and post-treatment medication.  Multiple 
medication usage by a subject in the same category will be counted only once. The blood 
products will be summarized by preferred term and listed separately from other concomitant 
and post-treatment medications.  
All non-study medications taken/administered during the study will be listed, concomitant 
(taken/administered from the start of the first dose through the last dose in the same treatment 
period) and post-treatment medications (taken/administered after or between each treatment 
periods) will be flagged.   
 


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10. 
EFFICACY ANALYSES 
The type I error for the primary and key secondary analyses will be preserved at the 1-sided 
0.025 level. All confidence intervals will be 2-sided 95% confidence intervals, unless stated 
otherwise.    
The experiment unit for efficacy analyses is each subject during the entire study period. The 
efficacy analysis plan described in this document evaluates the effect of initial treatment.   
The FAS and Per-protocol Analysis Set-1 will be used to report the primary efficacy endpoint 
data.  
The FAS and Per-protocol Analysis Set-2 will be used to report the key secondary efficacy 
endpoint data and FAS will be used to report other secondary efficacy endpoint data.  
Conditional power calculation, sample size re-estimation, claims for futility or efficacy, and 
sensitivity analyses will be based on the analyses using the FAS and Per-protocol Analysis Set-
1.   
If the FAS set deviates from ITT set more than 10%, the robustness of the primary analysis 
results will be demonstrated by the sensitivity analysis using ITT set. In addition, FAS and the 
Per-protocol Analysis Set-1 also will be used for the sensitivity analysis of primary endpoint, 
FAS will also be used for the sensitivity analysis of the key secondary and some other secondary 
efficacy endpoints. 
10.1 
Primary Efficacy Endpoint(s) and Analysis  
The primary efficacy endpoint is defined as the proportion of subjects with new or worsening 
TG at 6 months post-treatment as adjudicated by the pathology EAC based on 2013 Banff 
criteria (standard score). New or worsening TG at 6 months by the standard score is defined as an 
increase of 1 or more between qualifying biopsy and 6-month biopsy. Subjects who do not have 
the TG assessment at 6 months post-dose will be assigned as failures, i.e. having ‘new or 
worsening TG’. 
The primary analysis specified below will be performed based on the FAS for the first and 
second interim analysis of this study. As a sensitivity analysis, the primary analysis will be 
also performed based on Per-protocol Analysis Set-1 in the second interim analysis of the 
study. 
The primary endpoint will be presented as the proportion of subjects with new or worsening 
TG determined at 6 months, and their difference between treatments ( 
) 
is defined as follows: 
Placebo
Cinryze
Placebo
Cinryze

−

=

−
 
Placebo
Cinryze−



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where 
Cinryze

 is the proportion of new or worsening TG at 6 months post treatment in the 
CINRYZE group and 
Placebo

 is the proportion of new or worsening TG at 6 months post 
treatment in the placebo group. 
The analysis will employ a type I error rate of 0.025 to test null hypothesis: 
0
:
0


−

Placebo
Cinryze
H
 
Against the 1-sided alternative: 
0
:


−

Placebo
Cinryze
a
H
 
There will be two interim analyses to assess the primary endpoint.  
The purpose of the first interim analysis is to allow early stopping of the study for futility, 
assessing safety of the treatment, and potentially adjusting the sample size. The trial may be 
stopped for futility at the interim analysis or the sample size of the study may be adjusted up to 
ensure enough power to detect the treatment effect (section 14). The first interim analysis is 
planned to be performed when 30 subjects complete (half of the pre-defined sample size for 
primary endpoint, 15 subjects for each treatment group) the Month 6 visit. A fraction of alpha 
(0.0001) will be spent at the first interim analysis and accounted for in the overall type I error 
rate. Even if the value of test-statistics exceeds the efficacy boundary, the trial will not be 
stopped for efficacy. NOTE: For simplicity, 30 subjects complete the Month 6 visit and 
balanced arms are assumed to demonstrate statistical analyses in this document. 
The futility of the study at the first interim analysis will be determined by calculating the 
conditional power (CP) based on observed trend at interim.  
 
If the CP is < CPmin, the study will be stopped for futility. If the CP is between CPmin and 60%, 
the sample size will be adjusted up to make CP equal to 60%.  The CPmin is the pre-specified 
lower limit of conditional power and will be specified in the DMC SAP before the 1st interim 
analysis. The analysis based on the adjusted number of subjects will be used for the final 
analysis on primary endpoint (i.e. second interim analysis in the study).  The study will continue 
with the original planned sample size if CP is 60% or above. 
The CP at the first interim analysis, assuming that the data that will be observed after the first 
interim analysis will follow the same distribution as seen at interim and the CHW weighted test 
statistic
CHW
Z
 (Cui et al., 1999) as the final test statistic for second interim analysis (also see 
definition below), will be determined by the following formulae: 






−

=
−
2
1
1
1
2
w
Z
w
Z
Z
P
CP

 


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










−
−

−
=
−
−
2
)
1(
2
2
1
1
1
1
n
P
P
w
Z
w
Z

 
Where Z1 and Z2 are the Z test statistics from the first interim stage (from beginning to first  
interim analysis) and second interim stage (from first interim analysis to second interim 
analysis)  respectively,
2
1
2
1
=
= w
w
 , 
2
n  is the sample size at the second interim stage per 
treatment 
group, 
(.)

 
is 
cumulative 
standard 
normal 
distribution 
function, 
Cinryze
Placebo

−

=



, and 
i
Z  (
2
,1
=
i
) is calculated as below: 
)
1
1
)(
1(
,
,
Cinryze
i
Placebo
i
Cinryze
Placebo
i
n
n
P
P
Z
+
−

−

=


 
Placebo


 and 
Cinryze


 are estimated proportions of new or worsening TG at 6 months post 
treatment at the first interim stage for the Placebo group and CINRYZE group, respectively. 
The pooled proportion
Cinryze
i
Placebo
i
Cinryze
Cinryze
i
Placebo
Placebo
i
n
n
n
n
P
,
,
,
,
+

+

=


, where
Placebo
i
n ,
, 
)
2
,1
(
,
=
i
n Cinryze
i
 are 
numbers of subjects for the Placebo group and the CINRYZE group at first or second interim 
stage, respectively. The pre-defined sample size for second interim stage is: 
15
2
,2
,2
=
=
=
n
n
n
Cinryze
Placebo
 
If 
min
2
)
15
(
CP
n
CP

=
, the futility of the study will be claimed.  
If 
%
60
)
15
(
2
min

=

n
CP
CP
, 
2
n will be adjusted to 
*
2
n  satisfy 
%
60
)
(
*
2

n
CP
. 
If 
%
60
)
15
(
2

=
n
CP
, study will continue without sample size adjustment.  
The second interim analysis serves as the final analysis for the primary endpoint. The purpose 
of the second interim analysis is to allow early stopping of the study for futility or for claiming 
of efficacy based on new or worsening TG at 6 months. This analysis will be done using the 
FAS when a required number of subjects (based on the sample size adjustment of first interim 
analysis) complete the Month 6 TG assessments. If the result of the final analysis for primary 
endpoint analysis is statistically significant at 0.0249, the primary null hypothesis will be 
rejected. The difference between treatments will be evaluated by using the CHW weighted test 


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statistic (Cui et al., 1999). The test statistic 
CHW
Z
 at the second interim analysis for TG will be 
derived based on CHW method, i.e., 
2
1
30
15
30
15
Z
Z
ZCHW
+
=
               (Formulae 1) 
where 
1
Z  is the normalized test statistic at first interim stage, and 
2
Z  is the normalized test 
statistic for incremental sample size 
*
2
n  for second interim stage after the sample size 
adjustment. If the number of TG events exceeds 5 for all four cells in the contingency table of 
treatment versus TG event, 
i
Z  (
2
,1
=
i
) will be obtained using normal approximation, 
otherwise 
i
Z  (
2
,1
=
i
) will be calculated from p-value of Fisher’s Exact test as (Lechmacher et 
al., 1999): 
)
1(
1
i
i
p
Z
−

=
−
 
where 
(.)
1
−

 is the function to return a quantile from the standard normal distribution, 
1
p  is 
the p-value from Fisher’s Exact test for the first interim stage,  and 
2
p  is the p-value from 
Fisher’s Exact test for incremental sample size 
*
2
n  for second interim stage after the sample size 
adjustment. 
If 
0249
0
1−
Z
ZCHW
(equivalent to the p-value from the test ≤ 0.0249), the null hypothesis will be 
rejected.  Otherwise, the futility of the study will be claimed.  
The following sensitivity analyses will be conducted for TG assessment by the granular score 
for the FAS and then TG assessment by the standard score and the granular score for Per-
Protocol Analysis Set-1: 
• Sensitivity analysis 1: Primary analysis will be repeated based on Month 6 TG assessment 
by granular score for the Full Analysis Set 
• Sensitivity analysis 2: Primary analysis will be repeated based on Month 6 TG assessment 
by standard score for the Per Protocol Analysis Set-1 
• Sensitivity analysis 3: Primary analysis will be repeated based on Month 6 TG assessment 
by granular score for the Per Protocol Analysis Set-1 
 
The TG assessment by the granular score at 6 months is defined as the following:  
• Worsening TG is defined as an increase of 6.25 in the glomerular capillary double 
contour percentage between qualifying biopsy and 6-month biopsy.  




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(6) AMR free time in months, which defines as (date of Month 6 or early 
discontinuation visit – Date of first dose +1 – number of days with AMR)/30.25 
  
For sensitivity analysis 4, multiple imputation will be used to impute the primary endpoint for 
subjects without TG assessment at 6 months. The p-values from Fisher’s Exact tests will be 
computed for each imputed dataset and transformed to χ2-distribution with degree of freedom 
(df) = 2 using Fisher’s transformation (Fisher, 1932): 
2
2
)
(
)
(
 ~ )
log(
2

m
i
m
i
p
−
=

 
 
(Formulae 2) 
where 
)
(m
ip
 is the p-value from Fisher’s Exact test and 
)
(m
i
 is the transformed χ2-distribution 
for the i-th interim stage 
)
2
,1
( =
i
of the m-th 
)
100
...
2
,1
(
=
m
 imputed dataset. 
Then, Wilson-Helferty transformation (Wilson & Hilferty, 1931; Goria, 1992) will be used to 
transform the χ2-distribution to an asymptotic normal distribution with mean 0 and variance 1, 
as following: 
2
/
1
3
/
1
)
(
)
(
,
9
2
9
2
1














−
−






=
df
df
df
Z
m
i
m
i
WH
  
 (Formulae 3) 
where 
)
(m
i
 is the χ2-distributed statistic from the m-th imputed dataset, 𝑑𝑓 is the number of 
degrees of freedom associated with 
)
(m
i
, and 
)
(
,
m
i
WH
Z
 is the transformed value. 
The transformed normal statistics 
)
(
,
m
i
WH
Z
 will be combined using multiple imputation analysis 
for the first interim stage and the second interim stage, respectively. Then the combined 
statistics 
1,
WH
Z
 and 
2,
WH
Z
 will be used to calculate the CHW weighted test statistic 
CHW
Z
 as:  
2
,
1,
30
15
30
15
WH
WH
CHW
Z
Z
Z
+
=
  
 
(Formulae 4) 
For sensitivity analysis 5, the same approach for handling missing data as for the primary 
analysis will be considered. CMH test will be performed to evaluate the treatment effect with 
controlling for baseline AMR severity and donor characteristic. The p-values from CMH 
general association statistics for the first and second interim stages will be used to yield the 
CHW weighted test statistic 
CHW
Z
 as formulae 1.  


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For sensitivity analysis 6, multiple imputation will be used to impute the primary endpoint 
outcome for subjects without any post-dose TG assessment and those who discontinued prior 
to Month 6 but had TG assessment at time of discontinuation. CMH test will be performed to 
evaluate the treatment effect controlling for baseline AMR severity and donor characteristic. 
The CMH general association statistics will be computed for each imputed dataset and 
transformed to asymptotic normal using Wilson-Helferty transformation as formulae 3. The 
transformed normal statistics 
)
(
,
m
i
WH
Z
 will be combined using multiple imputation analysis for 
first interim stage and second interim stage, respectively. Then the combined statistics 
1,
WH
Z
 
and 
2,
WH
Z
 will be used to calculate the CHW weighted test statistic 
CHW
Z
 as formulae 4.  
Details of transformation and sample SAS code for multiple imputation and Wilson-Helferty 
transformation can be found in Appendix 1 Transformation of CMH Test statistics AND 
Fisher’s Exact p-value for Multiple imputation.  
Descriptive statistics for the primary efficacy outcome will be provided for the following 
subgroups: donor status at transplant, AMR severity at baseline, age, sex, and race.  
10.2 
Key Secondary Efficacy Endpoint(s) and Analysis  
The key secondary endpoint is defined as the proportion of subjects with all-cause graft failure 
at 4 years following treatment of the initial qualifying AMR episode. The graft failure is defined 
as 1 or more of the following: (1) institution of permanent dialysis, (2) current transplant 
nephrectomy, or (3) clinical determination of cessation of kidney graft function in any subject 
that had received a pre-emptive kidney transplant prior to starting dialysis.  The FAS will be 
used for analyzing the key secondary endpoint. Subjects who discontinued prior to 4 years (i.e. 
Month 48) will be considered ‘missing assessment for graft failure at 4 years’ and assigned as 
failures.  
The hypothesis of the key secondary endpoint will only be tested if the testing for the primary 
endpoint of new or worsening TG at 6 months is statistically significant. 
The key secondary analysis specified below will be performed based on the FAS. As a 
sensitivity analysis, the key secondary analysis will be also performed based on Per-protocol 
Analysis Set-2. 
The key secondary endpoint will be presented as the proportion of subjects with all-cause graft 
failure, and their difference between treatments (
) is defined as follows: 
Placebo
Cinryze
Placebo
Cinryze

−

=

−
 
Where 
Cinryze

 is the proportion of all-cause graft failure post-treatment in the CINRYZE group 
and 
Placebo

 is the proportion of all-cause graft failure post-treatment in the placebo group. 
Placebo
Cinryze−





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For multiple imputation for the key secondary endpoint, a monotone missing pattern will be 
assumed. The prediction model will consider treatment group, , AMR severity baseline, donor 
characteristic as factors with available post-dose eGFR results incorporated. The imputation 
seed will be 83789524 and number of imputations will be set as 100.  
For sensitivity analysis 1, multiple imputation will be used to impute the key secondary 
endpoint outcome for all subjects who discontinued prior to 4 years. The p-values from Fisher’s 
Exact tests will be computed for each imputed dataset and transformed to χ2-distribution with 
df = 2 using Fisher’s transformation as: 
 
2
2
)
(
)
(
 ~ )
log(
2

m
m
p
−
=

 
where 
)
(m
p
 is the p-value from Fisher’s Exact test and 
)
(m

 is the transformed χ2-distribution 
for the m-th
)
100
...
2
,1
(
=
m
 imputed dataset. 
Wilson-Helferty transformation (Wilson & Hilferty, 1931; Goria, 1992) will be used to transform 
the χ2-distribution to an asymptotic normal distribution with mean 0 and variance 1, as 
following: 
2
/
1
3
/
1
)
(
)
(
9
2
9
2
1














−
−






=
df
df
df
Z
m
m
WH
 
 
(Formulae 5) 
where 
)
(m

 is the χ2-distributed statistic from the m-th imputed dataset, 𝑑𝑓 is the number of 
degrees of freedom associated with 
)
(m

, and 
)
(m
WH
Z
 is the transformed value. 
Then, the transformed normal statistic 
)
(m
WH
Z
 for each imputed dataset will be combined using 
multiple imputation analysis to yield the combined test statistic 
WH
Z
.  
For sensitivity analysis 2, subjects who discontinued prior to 4 years will be assigned as graft 
failure. The CMH test will be performed to assess the treatment effect with controlling for 
baseline AMR severity and donor characteristic. 
For sensitivity analysis 3, multiple imputation will be used to impute the key secondary 
endpoint outcome for all subjects who discontinued prior to 4 years. The CMH test will be 
performed to assess the treatment effect controlling for baseline AMR severity and donor 
characteristic. The CMH general association statistics will be computed for each imputed 


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dataset and transformed to asymptotic normal as shown in formulae 5.  Then, the transformed 
normal statistic 
)
(m
WH
Z
 for each imputed dataset will be combined using multiple imputation 
analysis to yield the combined test statistic 
WH
Z
.   
Descriptive statistics for the key secondary efficacy outcome will be provided for the following 
subgroups: donor status at transplant, AMR severity at baseline, age, sex, and race.  
 
10.3 
Secondary Efficacy Endpoint(s) and Analysis 
Secondary efficacy endpoints from study entry to 6 months are defined as: 
• Measurement of renal function (eGFRMDRD) at 6 months 
• Change in renal function (eGFRMDRD) from pre-AMR to 6 months 
• Change in renal function (eGFRMDRD ) from screening to 6 months 
• Measurement of proteinuria (spot urine protein, urine creatinine, and urine protein/urine 
creatinine ratio) at 6 months 
• Change in proteinuria (spot urine protein, urine creatinine, and urine protein/urine creatinine 
ratio) from baseline to 6 months 
• Change in histopathology per Banff criteria (Banff 2013 classification) from pre-AMR to 6 
months 
• Proportion of subjects with all-cause graft failure at 6 months 
 
Secondary efficacy endpoints from study entry to 4 years are defined as: 
• Measurement of renal function (eGFRMDRD) and change from pre-AMR baseline and 
screening at 1, 2, 3, and 4 years following the qualifying AMR episode 
• Measurement of proteinuria (spot urine protein, urine creatinine, and urine protein/urine 
creatinine ratio) and change from screening at 1, 2, 3, and 4 years following the qualifying 
AMR episode 
• Time to all-cause graft failure 
• Proportion of subjects with graft failure due to AMR at 4 years 
• Time to graft failure due to AMR 
• Proportion of subjects with resolution of the qualifying AMR episodes 


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• Time to resolution of qualifying AMR episodes 
• Proportion of subjects alive at 4 years 
• Time to all-cause mortality 
 
The proportion of subjects with all-cause graft failure at 6 months, the proportion of subjects 
with graft failure due to AMR at 4 years, the proportion of subjects with resolution of the 
qualifying AMR episodes, the proportion of subjects alive at 4 years will be summarized 
descriptively by treatment group.  
Time to all-cause graft failure, time to graft failure due to AMR, time to resolution of qualifying 
AMR episodes, and time to all-cause mortality for both treatment groups will be summarized 
by Kaplan-Meier estimates. The difference between treatment groups will be assessed by 
proportional hazard regression with treatment group, baseline acute AMR severity, and donor 
characteristic as factors.  Hazard ratio and the 95% confidence interval will be summarized.  
• Date of graft failure will be captured on CRFs as (1) date of return to or institution of 
permanent dialysis, or (2) date of transplant nephrectomy, or (3) date of clinical 
determination. Time to graft failure in months will be calculated as (Date of graft failure 
– Date of first dose + 1)/30.25. Subjects who have not experienced graft failure but still 
on-study will be censored at the last date of graft survival assessment; subjects who 
have completed the study without experiencing graft failure will be censored at the date 
of study completion; subjects who discontinued the study without graft failure will be 
censored at the last date of graft survival assessment. 
• Time to graft failure due to AMR in months will be calculated as (Date of graft failure 
due to AMR – Date of first dose + 1)/30.25. Subjects who have not experienced any 
graft failure and still on-study will be censored at last date of graft survival assessment; 
subjects who have completed the study without experiencing graft failure will be 
censored at the date of study completion; subjects who have experienced graft failure 
due to reasons other than AMR will be censored at the date of graft failure; subjects 
who discontinued from the study without graft failure will be censored at the last date 
of graft survival assessment. 
• Time to resolution of qualifying AMR episodes will be calculated as (Date of qualifying 
AMR resolution – Date of first dose + 1)/30.25. Subjects who have not had resolution 
of qualifying AMR episodes and still on-study will be censored at the date of last visit; 
Subjects who have completed the study without resolution of qualifying AMR will be 
censored at the date of study completion; subjects who discontinued from the study 
without resolution of qualifying AMR will be censored at the date of early 
discontinuation. 
• Time to all-cause mortality will be calculated as (Date of discontinuation due to death 
– Date of first dose + 1)/30.25. Subjects who are alive and still on-study will be censored 


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at the date of last visit; Subjects who have completed the study will be censored at the 
date of study completion; subjects who discontinued from the study but not due to death 
will be censored at the date of early discontinuation. 
Renal function and proteinuria will be evaluated as change from the corresponding baseline 
value. Proteinuria will be log-transformed before analysis. Summary statistics (mean, SD, 
median, min, max) will be provided by treatment group and assessment time points. Difference 
between treatments in change from baseline to 6 months will be assessed by a MMRM model 
including all available scheduled assessments through 6 months. Differences between 
treatments in change from baseline from 1 year through 4 years will be assessed by a separate 
MMRM model. The analysis models will include effects of treatment group, visit, 
treatment*visit, baseline acute AMR severity, donor characteristic as well as the corresponding 
baseline values as covariates. The baseline diabetic status (diabetic vs non-diabetic) may be 
included in the MMRM model as a factor for graft function and serum creatinine if degree of 
freedom allows. The baseline*visit interaction will also be included. An unstructured 
covariance structure shared across treatment groups will be used to model the within-subject 
errors.  Baseline value for renal function is defined as assessment at screening and pre-AMR, 
separately, for different analyses. Baseline value for proteinuria is defined as the last 
measurement prior to the first dose of investigational product during the study.  
The renal function, as measured by eGFRMDRD, will be estimated by the Modification of Diet 
in Renal Disease [MDRD] formula shown below:   
eGFR = 175 × Serum Creatinine -1.154 × Age -0.203 × [1.210 if Black] × [0.742 if female] × [0.808 
if Japanese] 
where Serum Creatinine is from the central laboratory and expressed in mg/dL, and age is 
expressed in years. Note: Age collected at screening visit will be used for all visits before Month 
12 visit and then increase by 1 year at Month 12, by 2 years at Month 24, 3 years at Month 36 
and 4 years at Month 48. 
Number of subjects with all-cause graft failure at 6 months will be summarized by cause of graft 
failure and by treatment group for FAS. 
Number of subjects with resolution of AMR episodes will be summarized by resolution criteria 
(Clinical criteria vs. Histopathology vs. both) and by treatment group for FAS. Summary statistics 
for number of days from the first dose of investigational product to AMR resolution will be 
provided by AMR episode and treatment group.   
. 
10.4 
Exploratory Efficacy Endpoint(s) and Analyses  
Exploratory endpoints are defined as: 


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11. 
SAFETY ANALYSES 
The safety analysis will be performed using the Safety Analysis Set, unless specified otherwise.  
Safety variables include TEAEs, clinical laboratory variables, vital signs, lower extremity 
exam, and C1 INH antibody variables.  For each safety variable, the last value collected prior 
to the first dose of investigational product during the study will be used as baseline for all 
analyses of that safety variable.  
Summary statistics and changes from baseline to post-baseline for clinical laboratory testing, 
vital signs, diabetes status, and lower extremity exam by treatment group will be presented. For 
the clinical laboratory testing results, only the scheduled central lab data will be included in the 
summary tables. All unscheduled or local lab data will only be provided in the listing.  
Number, severity, and causality of AEs will be summarized by treatment group.  
Results of C1 INH antibody testing will be reported for individual subjects and summarized as 
appropriate. 
A Final on-Treatment Assessment (FoTA) is defined as the last valid assessment obtained up 
to 30 days after the last dose of the investigational product during the study. 
11.1 
Adverse Events  
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA)   
Adverse events and SAEs will be recorded from the time the informed consent is signed through 
30 days after the last dose of investigational product regardless of relationship to investigational 
product. This includes events occurring during the screening period, regardless of whether or 
not investigational product has been administered. Following the 30-day capture period for all 
AEs and SAEs, only those AEs/SAEs deemed related to investigational product or other 
protocol mandated procedures will be collected during the long-term follow-up phase of the 
study. If the subject undergoes retreatment with investigational product for a new AMR 
episode, AEs and SAEs will be captured as described above for the treatment of the initial 
occurrence of AMR. In addition, the following events of special interest, both serious and non-
serious, will be closely monitored and reported to Shire GDS via SAE form throughout the 
study, regardless of relationship to investigational product: any thrombotic or thromboembolic 
event, any hypersensitivity reaction, any new episode of kidney allograft rejection (excluding 
AMR), and any kidney allograft failure.  
 
An adverse event that increases in severity will be captured as a new event. Worsening of pre-
treatment events, after initiation of investigational product, will be recorded as new AE. An AE 
(classified by preferred term) that occurs during the study will be considered a treatment-
emergent AE (TEAE) if: 


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• it has a start date and time on or after the first dose of investigational product, or  
• it has a start date and time before the date and time of the first dose of investigational 
product, but increases in severity on or after the date and time of the first dose of 
investigational product.  
 
If more than 1 AE with the same preferred term is reported before the date and time of the first 
dose of investigational product, then the AE with the greatest severity will be used as the 
benchmark for comparison to the AEs occurring during the study under the preferred term.  An 
AE that occurs more than 30 days after the date of the last dose of investigational product in a 
treatment period will not be counted as a TEAE.  For example, an AE occurs more than 30 days 
after the last dose in the initial treatment period, but before the first dose of any new acute AMR 
treatment period will not be counted as a TEAE. 
An overall summary of all AEs/TEAEs in each treatment group and/or treatment period will be 
presented respectively, including the number and percentage of subjects experiencing event, 
and absolute count of events with: 
• Any AE/TEAE 
• Any serious AE/ TEAE 
• Any AE/TEAE related to investigational product in the opinion of the investigator 
• Any AE/ TEAE leading to study drug discontinuation from the study  
• Any severe AE/TEAE. 
• Any AE/TEAE leading to death 
 
The number and percentage of subjects and absolute count of events with AEs/TEAEs in each 
treatment group and/or treatment period will be tabulated respectively in the following ways: 
• By SOC, preferred term  
• By Maximum severity, SOC, and preferred term 
• By SOC, preferred term for serious AE/TEAE   
• By SOC and preferred term for AE/TEAE related to investigational product in the 
opinion of the investigator 
• By SOC and preferred term for AE/TEAE leading to Death 
• By SOC and preferred term for AE/TEAE leading to Study Drug Withdrawal 
 
Total number of subjects on treatment for each treatment group will be given in all table 
headers.  


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For Serious AEs and AEs related to the investigational product, the table by SOC and preferred 
term will only be produced if there are greater than 5 events total. If there are less than or equal 
to 5 events, then only the listing will be provided. 
All information about AEs collected on the CRF will be listed alongside the treatment, preferred 
term, and SOC.  
11.2 
Clinical Laboratory Variables 
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline at 
each assessment time point will be presented by treatment group for the following clinical 
laboratory variables. Baseline is defined as the last measurement prior to the first dose of 
investigational product during the study .   
Chemistry 
albumin, 
alanine 
aminotransferase, 
alkaline 
phosphatase, 
aspartate 
aminotransferase, blood urea nitrogen (BUN),), calcium, spot urine protein, 
carbon dioxide, chloride, creatinine, calculated eGFR, direct bilirubin, 
gamma-glutamyl transferase, glucose, lactate dehydrogenase, phosphorus, 
potassium, sodium, total bilirubin, total cholesterol, total protein, uric acid. 
Includes also creatinine, calculated eGFR and BUN for time points that do 
not include a full chemistry panel. 
Hematology 
 complete blood count with differential, hematocrit, hemoglobin, platelet 
count, red blood cell count, white blood cell count with differential. 
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 4.  The number and percentage of subjects with post-
baseline PCI values will be tabulated by treatment group.  The percentages will be calculated 
relative to the number of subjects with available baseline values and at least 1 post-baseline 
assessment.  The numerator is the total number of subjects with at least 1 post-baseline PCI 
value.  A supportive listing of subjects with post-baseline PCI values will be provided including 
the subject number, site, baseline, and post-baseline values.  
All clinical laboratory data will be listed, including pregnancy. 
 
 
 
 


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Table 4: 
Criteria for Potentially Clinically Important Laboratory Tests 
Parameter 
Lower Limit 
Higher Limit 
Biochemistry 
Alanine aminotransferase (ALT) 
NA 
≥ 3×ULN 
Alkaline phosphatase (ALP) 
NA 
≥ 3×ULN 
Aminotransferase (AST) 
NA 
≥ 3×ULN 
Blood urea nitrogen (BUN) 
NA 
≥ 30 mg/dL 
Creatinine 
NA 
≥ 250 umol/L 
Total bilirubin 
NA 
≥ 2 mg/dL 
Troponin 
NA 
NA 
Hematology 
White blood cell (WBC) 
≤ 2.8×103/mm3 
≥ 16×103/mm3 
Hemoglobin 
8 g/dL 
NA 
Hematocrit 
≤24% 
NA 
platelet count 
≤ 75×103/mm3 
NA 
11.3 
Vital Signs 
Descriptive statistics for vital signs (e.g. systolic and diastolic blood pressure, and pulse) and 
their changes from baseline at each post-baseline visit will be presented by treatment group. 
Baseline is defined as the last measurement prior to the first dose of investigational product 
during the study.   
Vital sign values will be considered PCI if they meet the observed value criteria and the change 
from baseline criteria listed in Table 5.  The number and percentage of subjects with PCI post-
baseline values will be tabulated by treatment group.  The percentages will be calculated 
relative to the number of subjects with baseline and at least 1 post-baseline assessment.  The 
numerator is the total number of subjects with at least 1 PCI post-baseline vital sign value.  A 
supportive listing of subjects with post-baseline PCI values will be provided including the 
subject number, site, baseline, and post-baseline PCI values.   
 
 
 
 


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Table 5: 
Criteria for Potentially Clinically Important Vital Signs 
 
Vital Sign Parameter 
 
Flag 
Criteria Values 
Observed Value 
Change from Baseline 
Systolic blood pressure 
(mmHg) 
High 
180 
Increase of 20 
Low 
90 
Decrease of 20 
Diastolic blood pressure 
(mmHg) 
High 
105 
Increase of 15 
Low 
65 
Decrease of 15 
Pulse rate 
(beats per minute) 
High 
120 
Increase of 15 
Low 
50 
Decrease of 15 
 
11.4 
Electrocardiogram (ECG) 
All ECG data (e.g. heart rate, RR, PR interval, QRS interval, QT interval, and QTc interval) 
including ECG abnormalities as reported by the investigators will be provided in the listings. 
QTc interval will be calculated using both Bazett (QTcB=QT/(RR)1/2) and Fridericia 
(QTcF=QT/(RR)1/3) corrections.  
11.5 
Physical Examinations and lower extremity exam 
Abnormalities identified during the Physical Examination done at the Screening Visit will be 
documented in the subject’s source documents and on the medical history CRF. If the 
abnormality is clearly caused by an event that occurred after the subject signed informed 
consent and before the Physical Examination of the Screening Visit, the event will be captured 
as an AE. Changes after the Physical Examination of the Screening Visit will be captured as 
AEs on the AE CRF page, as deemed by the investigator. 
Additionally, a lower extremity exam will be performed at specified time points (Table 1) and 
will include a determination of presence or absence of unilateral calf tenderness or leg swelling 
that may be new since the previous examination. If a DVT is suspected, a diagnostic study will 
be performed.   
Lower extremity exam results will be provided in the listings. 
11.6 
Immunogenicity (Anti-C1 INH) 
The positive and negative counts of Immunogenicity (Anti-C1 INH) samples will be 
summarized by visit and treatment for the Safety Analysis Set. Baseline is defined as the last 
measurement before first dose of investigational product. All immunogenicity data will be 
listed.  


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11.7 
Coagulation Panel 
In the event that a subject experience an unexplained clinically significant thrombotic or 
thromboembolic event, the coagulopathy panel will be performed at the site’s local laboratory. 
A listing of coagulopathy panel results will be provided for the Safety Analysis Set.  
11.8 
Virology 
A listing for virology results will be provided for the All-enrolled Set.   


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12. 
CLINICAL PHARMACOKINETIC AND 
PHARMACODYNAMIC ANALYSES 
12.1 
Pharmacokinetics Population  
The Pharmacokinetic Set will consist of all subjects who have at least 1 reported post-dose PK 
concentration value. All PK analyses will be based on the PK Set.  
12.2 
Pharmacokinetic Methods 
All summaries and analyses of the pharmacokinetic data will be based on the Pharmacokinetic 
Set. Individual subject listing and descriptive summary of concentrations at nominal sampling 
time points are reported. Additional pharmacokinetic analyses using a population modeling and 
simulation approach and second interim data will be described in Clinical Pharmacology SAP 
and analysis results will be reported separately. 
12.2.1 
Concentration Data 
The concentration of C1-INH antigen in human plasma will be determined using a validated 
sandwich electrochemiluminescent (ECL) assay method and will be expressed in µg/mL.  The 
concentration of C1-INH functional in human plasma will be determined using a validated 
ELISA method and will be expressed in mU/mL.   
12.2.2 
Handling BLQ Values 
The following procedures will be used for plasma PK concentrations below the lower limit of 
quantification (LLOQ):  
• Samples that are below limit of quantification (BLQ) will be reported as <LLOQ in 
the data listings, where LLOQ is replaced by the actual value for LLOQ for specific 
PK assay. 
• Samples that are BLQ are treated as half of the LLOQ value in the calculation of 
summary statistics (e.g. mean, SD, etc.) for the plasma PK concentrations at individual 
time points. Geometric mean and %CV of geometric mean will be set to missing 
where zero values exist. 
• Mean concentrations are reported as zero if all values are BLQ or zero, and no other 
descriptive statistics are reported. If the calculated mean (±SD) concentration is less 
than the LLOQ, the value will be reported as calculated. The mean values derived 
using these conventions will be used to create the mean plasma concentration versus 
time plots. 
• 
Missing values will not be imputed.   


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12.2.3 
Population Pharmacokinetic Analysis  
Additional pharmacokinetic analyses using a population modeling and simulation approach and 
second interim data will be described in Clinical Pharmacology SAP and analysis results will 
be reported separately. 
12.3 
Statistical Analysis of Pharmacokinetic Data 
Descriptive summary statistics including number of observations, mean (SD), median (min, 
max), geometric mean (CV%), 95 % CI for the mean (lower, upper) will be assessed for both 
C1 INH antigen and functional at each nominal time point. 
12.4 
Pharmacodynamic Methods (if applicable) 
All summaries and analyses of the Pharmacodynamic data will be based on the 
Pharmacodynamic Analysis Set who have at least 1 reported post dose PD value. All PD 
analyses will be based on the PD Set. Individual subject listing and descriptive summary of PD 
levels at nominal sampling time points are reported. Additional pharmacodynamic analyses 
using a population modeling and simulation approach and second interim data will be described 
in Clinical Pharmacology SAP and analysis results will be reported separately. 
12.4.1 
C3a and C5a Data 
The levels of C3a complement in human plasma will be determined using a validated 
bioanalytical method.  The levels of C5a complement in human plasma will be determined 
using a validated bioanalytical method 
12.4.2 
Handling BLQ Values 
The following procedures will be used for plasma PD levels below the lower limit of 
quantification (LLOQ): 
• Samples that are below limit of quantification (BLQ) will be reported as <LLOQ in 
the data listings, where LLOQ is replaced by the actual value for LLOQ for specific 
PD assay. 
• Samples that are BLQ are treated as half of the LLOQ value in the calculation of 
summary statistics (e.g. mean, SD, etc.) for the plasma PD levels at individual time 
points. Geometric mean and %CV of geometric mean will be set to missing where 
zero values exist. 


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• Mean levels are reported as zero if all values are BLQ or zero, and no other descriptive 
statistics are reported. If the calculated mean (±SD) levels are less than the LLOQ, the 
value will be reported as calculated. The mean values derived using these conventions 
will be used to create the mean plasma levels versus time plots. 
• Missing values will not be imputed.   
12.4.3 
Population Pharmacodynamic Analysis  
Additional pharmacodynamic analyses using a population modeling and simulation approach 
and second interim data will be described in Clinical Pharmacology SAP and analysis results 
will be reported separately. 
12.5 
Statistical Analysis of Pharmacodynamic Data (if applicable) 
Plasma levels C3a and C5a at each nominal sampling time will be summarized using descriptive 
statistics including number of observations, mean (SD), median (min, max), geometric mean 
(CV%), 95 % CI for the mean (lower, upper) at each nominal time point. 
12.5.1 
Primary Pharmacodynamic Endpoint and Analysis (if applicable) 
Not applicable. 
12.5.2 
Secondary Pharmacodynamic Endpoints and Analysis (if applicable) 
Not applicable. 
12.5.3 
Other Pharmacodynamic Variables and Analysis (if applicable) 
Not applicable. 
12.6 
Analyses of Pharmacokinetic/Pharmacodynamic Relationships (If applicable) 
Not applicable. 


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13. 
OTHER ANALYSES 
13.1 
Quality of Life Analyses 
The EQ-5D-5L is a standardized measure of a subject’s self-reported overall health status.  The 
EQ-5D-5L has two components, the EQ-5D-5L descriptive system and the EQ-Visual 
Analogue Scale (VAS).  The EQ-5D-5L descriptive system comprises the following five 
dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.  Each 
dimension has five levels of severity (states consisting of 5 dimensions no problems/slight 
problems/moderate problems/severe problems/extreme problems.  The EQ-5D VAS records the 
subject’s self-rated health state on a 100-point vertical VAS (0=worst imaginable health state; 
100=best imaginable health state) 
Results of the EQ-5D-5L health status questionnaire will be presented in accordance with the 
EQ-5D-5L User Guide.  EQ-5D-5L will be summarized by the number of subjects and the 
percentage of subjects in each category at each time point for the FAS. Questionnaire 
completion rates at each assessment at each time point will be estimated for both the EQ-5D-
5L VAS and EQ-5D-5L utility index.  Descriptive statistics for EQ-5D-5L results at baseline 
and at each post-dose visit will be presented by treatment. Descriptive statistics for Visual 
analogue scale (VAS) Score and changes from baseline at each post-dose visit will be presented 
by treatment. All randomized subjects who have an EQ-5D-5L assessment at baseline and at 
least 1 subsequent assessment will be included in the analysis describing changes from baseline.  
The baseline for VAS Score is defined as the last value collected prior to the first dose of 
investigational product.   
13.2 
Health Outcomes and Outcomes Research Analyses 
Analysis of healthcare resource utilization (HRU) data will be detailed in a supplemental SAP 
prepared by Outcomes Research and Epidemiology. 
 


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14. 
INTERIM ANALYSIS  
The study is designed to have 2 analyses (interim and final analyses) assessing the primary 
endpoint of new or worsening TG at 6 months after initiation of treatment. In addition, there 
will be 3 analyses (2 interim analyses plus 1 final analysis) assessing proportions of subjects 
with all-cause graft failure, at approximately 50% (~26 events), 75% (~39 events), and 100% 
(~51 events) of the study information. An independent DMC will review the data on 4 interim 
analyses during the course of the study.   
 
The first interim analysis is after 30 subjects complete the Month 6 TG assessment. The purpose 
of the first interim analysis is to allow early stopping of the study for futility, assessing safety 
of the treatment, and potentially adjusting the sample size.  An alpha level of 0.0001 will be 
spent at first interim analysis based on the Haybittle-Peto approach. The trial will not be stopped 
even if the value of test-statistics exceeds the efficacy. The futility of the study at the first 
interim analysis will be determined by calculating the conditional power (CP) based on 
observed trend at interim. If the CP is ≤ CPmin, the study will be stopped for futility.  If the CP 
is between CPmin and 60%, the sample size will be adjusted up to make CP equal to 60%.  The 
study will continue without sample size adjustment if CP is 60% or above. The CPmin is the pre-
specified lower limit of conditional power and will be specified in the DMC SAP before the 1st 
interim analysis. The details for calculating CP can be found in Section 10.1.  
The final analysis for the primary endpoint (i.e. second interim analysis for the study) will be 
done after the required number of subjects (based on the first interim analysis sample size re-
estimation) complete the Month 6 TG assessment. The purpose of the second interim analysis 
for the study is to allow early stopping of the study for futility or for claiming of efficacy based 
on new or worsening TG at 6 months. CHW method (Cui et al., 1999) will be used to evaluate 
the efficacy by using a one-sided alpha significance level of 0.0249. Details of analysis can be 
found in Section 10.1.  
If the result of the final analysis of the primary endpoint (second interim analysis for the 
study) indicates significant treatment effect on TG at 6 months of initiation of treatment, the 
study will continue to assess the long term study outcomes including the key secondary 
endpoint (i.e. proportion of subjects with all cause graft failure). 
 
The third interim analysis of the study will be done when approximately 50% (~26 events) of 
the targeted sample size has experienced all-cause graft failure. The purpose of the third interim 
analysis is to consider early stopping of the study for claiming of efficacy. The evaluation of 
efficacy will use the nominal alpha level based on the Hwang-Shih-DeCani alpha spending 
function with phi = -4, which requires p0.003 to stop the study early for a positive treatment 
effect.   
The fourth interim analysis will be done when approximately 75% (~39 events) of the targeted 
sample size has experienced all-cause graft failure. The purpose of the fourth interim analysis 


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is to consider early stopping of the study for claiming of efficacy. The nominal alpha level for 
evaluating efficacy is based on the Hwang-Shih-DeCani approach. The study may stop early 
for claiming a positive treatment effect if p0.0075. 
 


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15. 
DATA MONITORING/REVIEW COMMITTEE 
An independent Data Monitoring Committee (DMC) will be established to assess safety, 
efficacy, and futility during the study, as well as to ensure the validity and scientific merit of 
the trial. The DMC data review meetings will be held after each interim analysis to review the 
accumulating safety and efficacy data. Additionally, the DMC will review the safety data 
approximately every 6 months for the duration of the study.  
The roles, responsibilities and rules governing operation of the DMC are discussed in full in 
the DMC charter v3.0 dated 06 March 2019, which will be finalized prior to the administration 
of investigational product. The DMC charter will define the primary responsibilities of the 
DMC; guide its activities, its relationship with other study components, its membership, and 
the purpose and timings of its meetings. It will provide the procedures for ensuring 
confidentiality, formal communication, and outline of the content of reports that will be 
provided to  the DMC for each interim analysis. The p-values, conditional power, summary 
statistics, and data listings will be provided to the DMC by an independent statistician supported 
by an independent statistical reporting group not otherwise assigned to the study. The statistical 
analysis details for DMC are discussed in full in the DMC SAP v3.0 dated 06 March 2019.  
 


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16. 
COMPUTER METHODS  
Statistical analyses will be performed using Version 9.3(or newer) of SAS on a suitably 
qualified environment. 


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17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL 
At the first interim, one primary analysis and three sensitivity analyses were conducted for the 
primary endpoint mentioned in DMC SAP v3.0 dated 06 March 2019. Results from the primary 
analysis and two sensitivity analyses suggested very large increase to the sample size making 
it impractical to continue the study. From the result of the other sensitivity analysis, DMC 
members recommended to terminate the study based on the futility criteria specified in SAP. It 
was sponsor’s decision to discontinue the study for futility after 1st interim analysis and produce 
an abbreviated CSR. Due to this decision, final analysis will include selected tables, figures, 
and listings which can be found in section 20. Simple summaries will be provided for the 
primary endpoint data and selected sensitivity analyses of the primary endpoint. Tables, figures, 
and listings presented by timepoint will contain information collected only up to the study 
termination date.  
The followings are the changes from protocol amendment 4 dated 22 November 2017 and SAP.  
• Subject demographic and baseline characteristics for Safety set will not be included.  
• No sensitivity analyses will be done using ITT set. 
• Per Protocol Analysis Set-2 will not be derived.  
• Some Sensitivity analyses for primary efficacy endpoint will not be conducted. 
• Key secondary and other secondary efficacy analyses will not be conducted. 
• Exploratory efficacy analyses will not be conducted. 
• Measurement of healthcare resource utilization (HRU) will not be included. 
 
 


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18. 
DATA HANDLING CONVENTIONS 
18.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics:  n, mean, 
median, standard deviation, minimum, and maximum. Categorical and count variables will be 
summarized by the number of subjects (n) and the percent of subjects in each category.   
When count data are presented, the percentage will be suppressed when the count is zero to 
draw attention to the non-zero counts. A row denoted “Missing” will be included in count 
tabulations where specified on the shells to account for dropouts and missing values.  
Unless specified otherwise, median, min/max will be presented to the same decimal places as 
the raw data. Percentage, mean will be presented to 1 more decimal places than the raw data. 
Standard deviation and standard error will be presented to 2 more decimal places than the raw 
data. 
The p-value for primary endpoint analysis can be presented up to 8 decimal places. Other p-
values will generally be presented to 4 decimal places; values less than 0.0001 will be presented 
as <0.0001.  
18.2 
Derived Efficacy Endpoints  
Graft function, defined as eGFR ≥40 mL/min/1.73m2  at 3 months post-transplant, will be 
estimated by the Modification of Diet in Renal Disease [MDRD] formula for Serum 
Creatinine in mg/dL shown below:   
 
For standardized (IDMS-calibrated) serum creatinine assays: 
eGFRMDRD = 175 × (standardized serum Cr) -1.154 × (Age) -0.203 × [1.210 if Black] × [0.742 if 
female] ×   [0.808 if Japanese] 
 
For non-standardized (non-IDMS-calibrated) serum creatinine assays: 
eGFRMDRD = 186 × (serum Cr) -1.154 × (Age) -0.203 × [1.210 if Black] × [0.742 if female] ×   
[0.808 if Japanese] 
 
eGFR is expressed in mL/min1.73m2, serum creatinine is expressed in mg/dL, and age is 
expressed in years.  
 


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18.3 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the date and time of dose of investigational product, 
then the results from the last assessment made prior to the date and time of dose of 
investigational product will be used as baseline.  If clinical discharge assessments are repeated 
or unscheduled, the latest assessment will be used as the clinical discharge assessment for 
generating descriptive statistics.  However, all post-baseline assessments will be used for post-
baseline overall PCI value determination, and all assessments will be presented in the data 
listings.  
In the following sections, where missing times are seen on the database, they are handled using 
the same underlying assumptions as for missing dates. 
18.4 
Missing Date of Investigational Product  
When the date of the last dose of investigational product is missing for a subject in the Safety 
Analysis Set, all efforts should be made to obtain the date from the investigator.  If it is still 
missing after all efforts, then the last visit date when investigational product was administrated 
will be used in the calculation of treatment duration.   
18.5 
Missing Date Information for Concomitant or Post-Treatment Medications  
For concomitant or post-treatment medications, including rescue medications, original missing 
or partial values of start date and/or stop date will be presented in listings, and imputations will 
be performed when descriptive summaries are needed.  When the start date and the stop date 
are both incomplete for a subject, impute the start date first.     
18.5.1 
Incomplete Start Date  
The following rules will be applied to impute the missing numerical fields.  If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date. 
Missing day and month 
• 
If the year of the incomplete start date is the same as the year of the date of the first dose 
of investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields 
• 
If the year of the incomplete start date is before the year of the date of the first dose of 
investigational product, then December 31 will be assigned to the missing fields 
• 
If the year of the incomplete start date is after the year of the date of the first dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 


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• 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
• 
If the month and year of the incomplete start date are the same as the month and year of 
the date of the first dose of investigational product, then the day of the date of the first 
dose of investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the first dose of investigational product 
or if both years are the same but the month is before the month of the date of the first 
dose of investigational product, then the last day of the month will be assigned to the 
missing day 
• 
If either the year is after the year of the date of the first dose of investigational product or 
if both years are the same but the month is after the month of the date of the first dose of 
investigational product, then the first day of the month will be assigned to the missing 
day.  
18.5.2 
Incomplete Stop Date  
The following rules will be applied to impute the missing numerical fields.  If the date of the 
last dose of investigational product is missing, then replace it with the last visit date.  If the 
imputed stop date is before the start date (imputed or non-imputed start date), then the imputed 
stop date will be equal to the start date. 
Missing day and month 
• 
If the year of the incomplete stop date is the same as the year as of the date of the last 
dose of investigational product, then the day and month of the date of the last dose of 
investigational product will be assigned to the missing fields 
• 
If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields 
• 
If the year of the incomplete stop date is after the year of the date of the last dose of 
investigational product, then 01 January will be assigned to the missing fields. 
Missing month only 
• 
The day will be treated as missing and both month and day will be replaced according to 
the above procedure. 
Missing day only 
• 
If the month and year of the incomplete stop date are the same as the month and year of 
the date of the last dose of investigational product, then the day of the date of the last 
dose of investigational product will be assigned to the missing day 
• 
If either the year is before the year of the date of the last dose of investigational product 
or if both years are the same but the month is before the month of the date of the last dose 


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of investigational product, then the last day of the month will be assigned to the missing 
day 
• 
If either the year is after the year of the last dose of investigational product or if both years 
are the same but the month is after the month of the date of the last dose of investigational 
product, then the first day of the month will be assigned to the missing day. 
18.6 
Missing Date Information for Adverse Events  
For AEs, the default is to only impute incomplete (i.e., partially missing) start dates.  Incomplete 
stop dates may also be imputed when calculation of the duration of an AE is required per the 
protocol.  If imputation of an incomplete stop date is required, and both the start date and the 
stop date are incomplete for a subject, impute the start date first. 
18.6.1 
Incomplete Start Date  
Follow same rules as in Section 18.5.1. 
18.6.2 
Incomplete Stop Date  
When required per the protocol, follow the same rules as in Section 18.5.2.  
18.7 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “Mild” will be assigned.  If the severity is missing for an AE starting 
on or after the date of the first dose of investigational product, then a severity of “Severe” will 
be assigned.  The imputed values for severity assessment will be used for incidence summaries, 
while the actual values will be used in data listings. 
18.8 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting on or after the date 
of the first dose of investigational product, a relationship of “Related” will be assigned.  The 
imputed values for relationship to double-blind investigational product will be used for 
incidence summaries, while the actual values will be presented in data listings. 


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19. 
REFERENCES 
Cui L, Hung HM, Wang SJ. 1999. Modification of sample size in group sequential clinical 
trials. Biometrics; 55: 853-7. 
Fisher RA. 1932, Statistical Methods for Research Workers, 4th Ed. Oliver and Boyd, London. 
Goria MN. 1992. On the forth root transformation of chi-square. Australian Journal of Statistics, 
34 (1), 55-64 
Haririan A, Kiangkitiwan B, Kukuruga D, et al. 2009. The impact of C4d pattern and donor-
specific antibody on graft survival in recipients requiring indication renal allograft biopsy. Am 
J Transplant; 9(12): 2758-67. 
Lechmacher W, Wassmer G. 1999. Adaptive Sample Size Calculations in Group Sequential 
Trials. Biometrics; 55(4):1286-1290. 
Ratitch B, Lipkovich I, O’Kelly M. 2013. Combining Analysis Results from Multiply Imputed 
Categorical Data. The Pharmaceutical Industry SAS Users Group 2013, Paper SP03. 
Rubin DB. 1987. Multiple Imputation for Nonresponse in Surveys. New York: John Wiley and 
Sons. 
Sharif A, Kraus ES, Zachary AA, et al. 2014. Histologic phenotype on 1-year 
posttransplantation biopsy and allograft survival in HLA-incompatible kidney transplants. 
Transplantation; 97: 541-7. 
United States Organ Transplantation SRTR & OPTN Annual Data Report, 2012. 
Wilson E, Hilferty MM. 1931. The distribution of chi-squared. Proceedings of the National 
Academy of Sciences, Washington, 17, 684–688. 


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20. 
TABLE OF CONTENTS FOR FIGURES, TABLES, AND 
LISTINGS 
The shell of tables, figures, and listings are contained in a separate document and will serve as 
guidance. Modifications of shells might be made if needed. 
Table 
Title 
Final 
analysis for 
abbreviated 
CSR 
14.1.1.1 
Disposition by Treatment Group (All-enrolled Set) 
Y 
14.1.1.2 
Protocol Deviation and Violation by Site and by Treatment Group 
(Intent-to-Treat Set) 
Y 
14.1.2.1 
Demographic Characteristics by Treatment Group (Intent-to-Treat 
Set) 
Y 
14.1.2.2 
Demographic Characteristics by Treatment Group (Safety Analysis 
Set) 
N 
14.1.2.3 
Demographic Characteristics by Treatment Group (Full Analysis 
Set) 
Y 
14.1.2.4 
Demographic Characteristics by Treatment Group (Per Protocol 
Analysis Set-1) 
Y 
14.1.2.5 
Demographic Characteristics by Treatment Group (Per Protocol 
Analysis Set-2) 
N 
14.1.2.6 
Baseline Characteristics by Treatment Group (Intent-to-Treat Set) 
Y 
14.1.2.7 
Baseline Characteristics by Treatment Group (Safety Analysis Set) 
N 
14.1.2.8 
Baseline Characteristics by Treatment Group (Full Analysis Set) 
Y 
14.1.2.9 
Baseline Characteristics by Treatment Group (Per Protocol Analysis 
Set-1) 
Y 
14.1.2.10 
Baseline Characteristics by Treatment Group (Per Protocol Analysis 
Set-2) 
N 
14.1.3.1 
Summary of Transplant History by Treatment Group (Safety 
Analysis Set) 
Y 
14.1.3.2 
Medical History by System Organ Class, Preferred Term, and 
Treatment Group (Safety Analysis Set) 
Y 
14.1.3.3 
Medical History by Body System and Treatment Group (Safety 
Analysis Set) 
Y 
14.1.4.1 
Concomitant Medication by Treatment Group (Safety Analysis Set) 
Y 
14.1.4.2 
Concomitant Blood Product by Treatment Group (Safety Analysis 
Set) 
Y 
14.1.4.3 
Post-Treatment Medication by Treatment Group (Safety Analysis 
Set) 
Y 
14.1.4.4 
Post-Treatment Blood Product by Treatment Group (Safety Analysis 
Set) 
Y 


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Table 
Title 
Final 
analysis for 
abbreviated 
CSR 
14.2.1.1a 
Summary and Analysis of Month 6 TG Assessment by Standard 
Score and Treatment Group 
(Full Analysis Set) 
Y 
14.2.1.1b 
Summary and Analysis of Month 6 TG Assessment by Granular 
Score and Treatment Group 
(Full Analysis Set) 
Y 
14.2.1.1c 
Summary of Month 6 TG Assessment by Standard Score and 
Treatment Group 
(Per Protocol Analysis Set-1) 
Y 
14.2.1.1d 
Summary of Month 6 TG Assessment by Granular Score and 
Treatment Group 
(Per Protocol Analysis Set-1) 
Y 
14.2.1.2 
Sensitivity Analysis of Month 6 TG Assessment by Treatment 
Group (Fisher’s Exact with MI) (Full Analysis Set) 
N 
14.2.1.3 
Sensitivity Analysis of Month 6 TG Assessment by Treatment 
Group (CMH) (Full Analysis Set) 
N 
14.2.1.4 
Sensitivity Analysis of Month 6 TG Assessment by Treatment 
Group (CMH with MI) (Full Analysis Set) 
N 
14.2.1.5 
Summary and Analysis of Month 6 TG Assessment by Treatment 
Group (Fisher’s Exact) (Per Protocol Analysis Set-1) 
N 
14.2.1.6 
Summary of Month 6 TG Assessment by Treatment Group and 
Subgroup (Full Analysis Set) 
N 
14.2.1.7 
Summary of Month 6 Biopsy Assessment Data Availability by 
Treatment Group 
(Full Analysis Set) 
Y 
14.2.2.1 
Summary and Analysis of All-Cause Graft Failure at 4 Years by 
Treatment Group (Fisher’s Exact) (Full Analysis Set) 
N 
14.2.2.2 
Sensitivity Analysis of All-Cause Graft Failure at 4 Years by 
Treatment Group (Fisher’s Exact with MI) (Full Analysis Set) 
N 
14.2.2.3 
Sensitivity Analysis of All-Cause Graft Failure at 4 Years by 
Treatment Group (CMH test) (Full Analysis Set) 
N 
14.2.2.4 
Sensitivity Analysis of All-Cause Graft Failure at 4 Years by 
Treatment Group (CMH test with MI) (Full Analysis Set) 
N 
14.2.2.5 
Summary and Analysis of All-Cause Graft Failure at 4 Years by 
Treatment Group (Fisher’s Exact) (Per Protocol Analysis Set-2) 
N 
14.2.3.1.1 
Summary and Analysis of Renal Function (eGFRMDRD) at 6 Months, 
Change from pre-AMR to 6 Months by Treatment Group (Full 
Analysis Set) 
N 


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CONFIDENTIAL 
 
 
Table 
Title 
Final 
analysis for 
abbreviated 
CSR 
14.2.3.1.2 
Summary and Analysis of Renal Function (eGFRMDRD) at 6 Months, 
Change from Screening to 6 Months by Treatment Group (Full 
Analysis Set) 
N 
14.2.3.1.3 
Summary and Analysis of Renal Function (eGFRMDRD) and Change 
from pre-AMR at 1, 2, 3 and 4 Years and Treatment Group (Full 
Analysis Set) 
N 
14.2.3.1.4 
Summary of Renal Function (eGFRMDRD) and Change from 
Screening at 1, 2, 3 and 4 Years and Treatment Group (Full Analysis 
Set) 
N 
14.2.3.2.1 
Summary and Analysis of Proteinuria (Spot Urine Protein/Creatinine 
Ratio) at 6 Months and Change from Baseline to 6 Months by 
Treatment Group (Full Analysis Set) 
N 
14.2.3.2.2 
Summary and Analysis of Proteinuria and Change from Baseline at 
1, 2, 3 and 4 Years and by Treatment Group (Full Analysis Set) 
N 
14.2.3.3.1 
Summary of Histopathology Parameter per Banff Score at 6 Months, 
Change from pre-AMR to 6 Months by Treatment Group (Full 
Analysis Set) 
N 
14.2.3.3.2 
Summary of Histopathology Parameters per Banff Score Shift from 
Pre-AMR to 6 Mont’s by Treatment Group (Full Analysis Set) 
N 
14.2.3.4.1 
Summary and Analysis of All-Cause Graft Failure at 6 Months by 
Treatment Group (Full Analysis Set) 
N 
14.2.3.4.2 
Kaplan-Meier Analysis of Time to All-Cause Graft Failure by 
Treatment Group (Full Analysis Set) 
N 
14.2.3.4.3 
Proportional Hazards Regression Analysis of Time to All-Cause 
Graft Failure by Treatment Group (Full Analysis Set) 
N 
14.2.3.5.1 
Summary of Graft Failure due to AMR at 4 Years by Treatment 
Group (Full Analysis Set) 
N 
14.2.3.5.2 
Kaplan-Meier Analysis of Time to Graft Failure Due to AMR by 
Treatment Group (Full Analysis Set) 
N 
14.2.3.5.3 
Proportional Hazards Regression Analysis of Time to Graft Failure 
Due to AMR by Treatment Group (Full Analysis Set) 
N 
14.2.3.6.1 
Summary of Resolution of Qualifying AMR by Treatment Group 
(Full Analysis Set) 
N 
14.2.3.6.2 
Kaplan-Meier Analysis of Time to resolution of qualifying AMR by 
Treatment Group (Full Analysis Set) 
N 
14.2.3.6.3 
Proportional Hazards Regression Analysis of Time to resolution of 
qualifying AMR by Treatment Group (Full Analysis Set) 
N 
14.2.3.7.1 
Summary of Subjects Alive at 4 Years by Treatment Group (Full 
Analysis Set) 
N 


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CONFIDENTIAL 
 
 
Table 
Title 
Final 
analysis for 
abbreviated 
CSR 
14.2.3.7.2 
Kaplan-Meier Analysis of Time to All-Cause Mortality by 
Treatment Group (Full Analysis Set) 
N 
14.2.3.7.3 
Proportional Hazards Regression Analysis of Time to All-Cause 
Mortality by Treatment Group (Full Analysis Set) 
N 
14.2.4.1.1 
Summary of Resolution of AMR Episodes by Episode and by 
Treatment Group (Full Analysis Set) 
N 
14.2.4.1.2 
Summary of Recurrent AMR Episodes and Their Resolution by 
Treatment Group (Full Analysis Set) 
N 
14.2.4.2 
Summary and Analysis of Acute Cellular Rejection Episodes by 
Treatment Group (Full Analysis Set) 
N 
14.2.4.3.1 
Summary of HLA DSA Presence by Treatment Group (Full Analysis 
Set) 
N 
14.2.4.3.2 
Summary of PRA by Treatment Group (Full Analysis Set) 
N 
14.2.4.4 
Summary of Rescue Medication Usage by Treatment Group (Full 
Analysis Set) 
N 
14.2.4.5 
Summary and Analysis of Incidence of Splenectomy by Treatment 
Group (Full Analysis Set) 
N 
14.2.4.6.1 
Summary of Electron Microscopy Analysis at 6 Months by 
Treatment Group (Full Analysis Set) 
N 
14.2.4.6.2 
Summary of New or Worsening TG at 6 Months Evident Only on 
EM and Graft Failure Status by Treatment Group (Full Analysis Set) 
N 
14.2.5.1.1 
Summary of EQ-5D-5L by Dimension, Time Point and Treatment 
Group (Full Analysis Set) 
N 
14.2.5.1.2 
Summary of EQ-5D-5L Utility Index and Change from Baseline by 
Time Point and Treatment Group (Full Analysis Set) 
N 
14.2.5.1.3 
Summary of VAS Scores and Change from Baseline by Time Point 
and Treatment Group (Full Analysis Set) 
N 
14.2.5.1.4 
Summary of EQ-5D-5L Completion Rates for Utility Index and 
VAS by Time Point and Treatment Group (Full Analysis Set) 
N 
14.2.6.1 
Summary of C1 INH Antigen Plasma Concentration and Functional 
Activity Parameters by Treatment (Pharmacokinetic Analysis Set) 
Y 
14.2.6.2 
Summary of C3a and C5a Plasma Levels by Treatment Group 
(Pharmacodynamic Analysis Set) 
Y 
14.3.1.1.1 
Overall All Adverse Events by Treatment Group (Safety Analysis 
Set) 
Y 
14.3.1.1.2 
Overall Treatment-Emergent Adverse Events by Treatment Group 
(Safety Analysis Set) 
Y 


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CONFIDENTIAL 
 
 
Table 
Title 
Final 
analysis for 
abbreviated 
CSR 
14.3.1.2.1 
All Adverse Events by System Organ Class, Preferred Term, and 
Treatment Group (Safety Analysis Set) 
Y 
14.3.1.2.2 
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Treatment Group (Safety Analysis Set) 
Y 
14.3.2.1.1 
All Adverse Events by Maximum Severity, System Organ Class, 
Preferred Term, and Treatment Group (Safety Analysis Set) 
Y 
14.3.2.1.2 
Treatment-Emergent Adverse Events by Maximum Severity, System 
Organ Class, Preferred Term, and Treatment Group (Safety Analysis 
Set) 
Y 
14.3.2.2.1 
All Adverse Events Considered Related to Investigational Product 
by System Organ Class, Preferred Term, and Treatment Group 
(Safety Analysis Set) 
Y 
14.3.2.2.2 
Treatment-emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term, and 
Treatment Group (Safety Analysis Set) 
Y 
14.3.3.1.1 
All Serious Adverse Events by System Organ Class, Preferred Term, 
and Treatment Group (Safety Analysis Set) 
Y 
14.3.3.1.2 
Treatment-emergent Serious Adverse Events by System Organ 
Class, Preferred Term, and Treatment Group (Safety Analysis Set) 
Y 
14.3.3.2.1 
All Adverse Events leading to Death by System Organ Class, 
Preferred Term, and Treatment Group (Safety Analysis Set) 
Y 
14.3.3.2.2 
Treatment-emergent Adverse Events leading to Death by System 
Organ Class, Preferred Term, and Treatment Group (Safety Analysis 
Set) 
Y 
14.3.3.3.1 
All Adverse Events Leading to Study Drug Withdrawal by System 
Organ Class, Preferred Term, and Treatment Group (Safety Analysis 
Set) 
Y 
14.3.3.3.2 
Treatment-emergent Adverse Events Leading to Study Drug 
Withdrawal by System Organ Class, Preferred Term, and Treatment 
Group (Safety Analysis Set) 
Y 
14.3.4.1 
Quantitative Clinical Laboratory Results by Treatment Group:  
Biochemistry (Safety Analysis Set) 
Y 
14.3.4.2 
Normal Ranges and PCI Criteria:  Biochemistry 
Y 
14.3.4.3 
Quantitative Clinical Laboratory Results by Treatment:  Hematology 
(Safety Analysis Set) 
Y 
14.3.4.4 
Normal Ranges and PCI Criteria:  Hematology (Safety Analysis Set) 
Y 
14.3.4.5 
Potentially Clinically Important (PCI) Laboratory Results for 
Biochemistry and Hematology by Treatment Group (Safety Analysis 
Set) 
Y 


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CONFIDENTIAL 
 
 
Table 
Title 
Final 
analysis for 
abbreviated 
CSR 
14.3.5.1 
Actual Values and Change from Baseline in Vital Signs by 
Treatment Group (Safety Analysis Set) 
Y 
14.3.5.2 
Potentially Clinically Important (PCI) Vital Signs by Treatment 
Group (Safety Analysis Set) 
Y 
14.3.6.1 
Immunogenicity (Anti-C1 INH) by Visit and Treatment Group 
(Safety Analysis Set) 
Y 
14.3.7.1 
Investigational Product Exposure by Treatment Group by Treatment 
Period (Safety Analysis Set) 
Y 
 
Figure 
Title 
 
14.2.2.1 
Kaplan-Meier Analysis of Time to All-Cause Graft Failure by Treatment 
Group (Full Analysis Set) 
N 
14.2.2.2 
Kaplan-Meier Analysis of Time to Graft Failure Due to AMR by 
Treatment Group (Full Analysis Set) 
N 
14.2.2.3.1 
Kaplan-Meier Analysis of Time to resolution of qualifying AMR episodes 
by Treatment Group (Full Analysis Set) 
N 
14.2.2.3.2 
Kaplan-Meier Analysis of Time to resolution of qualifying AMR episodes 
by Treatment Group and Donor Type (Full Analysis Set) 
N 
14.2.2.3.3 
Kaplan-Meier Analysis of Time to resolution of qualifying AMR episodes 
by Treatment Group and Severity of Acute AMR (Full Analysis Set) 
N 
14.2.2.4 
Kaplan-Meier Analysis of Time to All-Cause Mortality by Treatment 
Group (Full Analysis Set) 
N 
 
 
 
Listing 
Title 
 
16.2.1.1 
Subjects Disposition (All-enrolled Set) 
Y 
16.2.1.2 
Subjects Who Prematurely Terminated from the Study (All-enrolled Set) 
Y 
16.2.1.3 
Study Analysis Set Classification (All-enrolled Set) 
Y 
16.2.2.1 
Listing of Protocol Deviations and Violations (Intent-to-Treat Set) 
Y 
16.2.4.1 
Subject Demographic and Baseline Characteristics (Intent-to-Treat Set) 
Y 
16.2.4.2.1 
Transplant Medical History (Safety Analysis Set) 
Y 
16.2.4.2.2 
General Medical History (Safety Analysis Set) 
Y 
16.2.4.3.1 
Concomitant and Post-Treatment Medication (Safety Analysis Set) 
Y 
16.2.4.3.2 
Concomitant and Post-Treatment Blood Product (Safety Analysis Set) 
Y 
16.2.4.3.3 
DSA Reduction Therapy (Safety Analysis Set) 
Y 
16.2.5.1 
Investigational Product Administration (Safety Analysis Set) 
Y 
16.2.5.2 
Pharmacokinetic Blood Draw Times and Concentration Data 
(Pharmacokinetic Analysis Set) 
Y 


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CONFIDENTIAL 
 
 
16.2.5.3 
Pharmacodynamic Blood Draw Times and Levels (Pharmacodynamic 
Analysis Set) 
Y 
16.2.6.1.1 
Determination of Transplant Glomerulopathy Status (Full Analysis Set) 
Y 
16.2.6.1.2a 
Histopathology Results from Individual Pathologist Scoring 
Worksheet (Full Analysis Set) 
Y 
16.2.6.1.2b 
Histopathology Results from Final EAC Biopsy Assessment (Full 
Analysis Set) 
Y 
16.2.6.1.3 
Electron Microscopy Analysis (Full Analysis Set) 
Y 
16.2.6.1.4 
Pathology EAC Biopsy Assessment 
(Full Analysis Set) 
Y 
16.2.6.2.1 
Renal Allograft Assessment (Full Analysis Set) 
Y 
16.2.6.2.2 
Nephrology EAC Assessment 
(Full Analysis Set) 
Y 
16.2.6.3 
eGFR and Serum Creatinine (Full Analysis Set) 
Y 
16.2.6.4 
Proteinuria (Full Analysis Set) 
Y 
16.2.6.5 
Recurrent AMR Episodes and Resolution of AMR Episodes (Full 
Analysis Set) 
Y 
16.2.6.6 
Patient Survival (Full Analysis Set) 
Y 
16.2.6.7 
Donor-specific Antibody (DSA) Identification and Titer (Full Analysis 
Set) 
Y 
16.2.6.8 
Salvage Splenectomy (Full Analysis Set) 
N 
16.2.6.9 
EQ-5D-5L (Full Analysis Set) 
Y 
16.2.7.1 
Adverse Events (Safety Analysis Set) 
Y 
16.2.7.1a 
Adverse Event Special Interest (Safety Analysis Set) 
Y 
16.2.7.1b 
Thrombotic and Thromboembolic Events (Safety Analysis Set) 
Y 
16.2.7.2 
Serious Adverse Events (Safety Analysis Set) 
Y 
16.2.8.1.1 
Clinical Laboratory Test Results (Safety Analysis Set) 
Y 
16.2.8.1.2 
 Subjects with Potentially Clinically Important Laboratory Test Results 
(Safety Analysis Set) 
Y 
16.2.8.2.1 
 Vital Signs (Safety Analysis Set) 
Y 
16.2.8.2.2 
Subjects with Potentially Clinically Important Vital Signs (Safety 
Analysis Set) 
Y 
16.2.8.3 
12-Lead Electrocardiogram Results (All-enrolled Set) 
Y 
16.2.8.4 
Lower Extremity Exam (Safety Analysis Set) 
Y 
16.2.8.5 
Immunogenicity (Anti-C1 INH antibody) Results (Safety Analysis Set) 
Y 
16.2.8.6 
Diabetes Status (Safety Analysis Set) 
Y 
16.2.8.7 
Coagulopathy Panel Results (Safety Analysis Set) 
Y 
16.2.8.8 
Virology Results (All-enrolled Set) 
Y 
 


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CONFIDENTIAL 
 
 
APPENDIX 1 TRANSFORMATION OF CMH TEST STATISTICS AND 
FISHER’S EXACT P-VALUE FOR MULTIPLE IMPUTATION 
Rubin’s pooling methodology to combine inference from multiple imputation assumes the test 
statistic estimates are asymptotically normally distributed. In order to satisfy Rubin’s rule 
(Rubin, 1987), transformation is needed to convert the test statistics to asymptotic normal.  
CMH general association statistic, under the null hypothesis of no association, has an 
asymptotic chi-square distribution. The p-value of Fisher’s exact test can be transformed to a 
chi-square distribution with degree of freedom (df) = 2 using Fisher’s transformation (Fisher, 
1932): 
2
2
 
~
 )
log(
2

p
−
=

  
 
where p  is the p-value from Fisher’s Exact test. 
The chi-square distributed statistic obtained from Fisher’s Exact test or CMH test can be 
transformed to an asymptotic normal by using Wilson-Hilferty transformation (Wilson & 
Hilferty, 1931; Lechmacher, 1992; Ratitch et al. 2013 ) as: 
3
)
(
)
(
/
_
df
wh
m
m

=

 
where 
)
(m

 is the chi-square distributed test statistic computed from the m-th imputed dataset, 
𝑑𝑓 is the number of degrees of freedom associated with 
)
(m

, and 
)
(
_
m
wh

 is the transformed 
value. The transformed statistic is approximately normally distributed with mean 1 − 2/(9 × 𝑑𝑓) 
and variance 2/(9 × 𝑑𝑓) under the null hypothesis. We can standardize this transformed statistic 
to obtain a variable that is normally distributed with mean 0 and variance 1:  
2
3
)
(
_
9
2
9
2
1
)
(
df
df
df
Z
m
cmh
wh
m








−
−

=
 
This transformed statistic can now be passed to PROC MIANALYZE in order to perform a 
combined test. 
A sample code to impute missing data using logistic regression, perform Fisher’s Exact test, 
transform Fisher’s Exact p-value, perform CMH test, transform the CMH statistic, and perform 
PROC MIANALYZE for the combined normal score: 
/*impute missing data using logistic regression*/ 
proc mi data=TG out=datain mi seed=83789524 nimpute=100; 
   var treatment AMR donor response; 


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   class treatment AMR donor response; 
   monotone logistic; 
run; 
 
/*perform Fisher's exact test*/ 
proc freq data=datain mi; 
 
tables Treatment*Response /fisher; 
 
ods output FishersExact=FishersExact; 
 
by _imputation_; 
run; 
 
/*perform transformation of p-value from Fisher's exact test to normal*/ 
Data Fisher WH; 
 
set FishersExact(Where=(Label1="Right-sided Pr >= F")); 
 
 /*transform fisher's p to chi-square with df=2*/ 
 
fisher chi=-2*log(nValue1); 
 
/*transform chi-square with df=2 to standard normal*/ 
 
fisher_value_wh=((fisher_chi/2)**(1/3) - (1-2/(9*2)))/SQRT(2/(9*2));  
  
fisher_sterr_wh = 1.0; 
run; 
/*perform CMH test*/ 
proc freq data=datain mi; 
 
tables AMR*Donor*Treatment*Response / cmh;  
 
ods output CMH=CMH; 
 
by _imputation_; 
run; 
/*perform WH transformation of p-value from CMH to normal*/ 
Data CMH WH; 
 
set cmh(Where=(AltHypothesis="General Association")); 
 
cmh_value_wh=((VALUE/DF)**(1/3) - (1-2/(9*DF)))/SQRT(2/(9*DF)); 
  
cmh_sterr_wh = 1.0; 
run; 
/*MI analysis to combine statistics from each imputed dataset, take 
Fisher’s for example. CMH is similar*/ 
PROC MIANALYZE DATA=Fisher_wh; 
 ODS OUTPUT PARAMETERESTIMATES=mian_Fisher_wh; 
 MODELEFFECTS Fisher value_wh; 
 STDERR Fisher_sterr_wh; 
RUN;