Clinical trial NCT02134314
Conditions: End Stage Renal Disease Kidney Failure Delayed Graft Function Ischemic Reperfusion Injury
Keywords: ESRD (End Stage Renal Disease) CKD (Chronic Kidney Disease) Kidney Transplant ECD delayed graft function chronic kidney disease expanded-criteria donor end stage renal disease
Sponsor: Cedars-Sinai Medical Center
Start date: 2014-09-01; Completion date: 2017-03-13
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The use of C1INH (Berinert) in patients receiving deceased donor kidney transplants with high risk for delayed graft function (DGF) may show significant improvement in outcomes post transplant compared with patients that do not receive C1INH treatment. Complement activation has been detected in animal models and human kidneys with ischemic reperfusion injury (IRI) and inflammatory cell infiltrates. By blocking complement activation the investigators hope to improve kidney graft function post transplant in these recipients.

Detailed description:
Early graft function has a long-term effect on graft survival. Poor early graft function and delayed graft function (DGF) contributes to decreased short- and long-term patient and graft survival, increased incidence of acute rejection, prolonged hospitalization, and higher costs of transplantation. Although multiple factors contribute to the impaired graft function, ischemia-reperfusion injury (IRI) is the underlying pathophysiology leading to poor early graft function and DGF. A \>35% incidence of DGF has remained constant over time despite significant improvements in immunosuppressive strategies and patient management. This may be due to increased use of kidneys from "extended-criteria" and/or non-heart-beating donors, where even greater rates (\>60%) of DGF have been reported.

More than 96,680 people are currently waiting for a kidney transplant in the United States (United Network for Organ Sharing (UNOS); UNOS.org 3/22/13). Of the 15,092 kidney transplants performed in the US in 2011, \~11,000 (62%) were from deceased donors. Of these, approximately 17% were from expanded-criteria donors. The USRDS reports that more than 50% of patients on the waiting list are willing to accept a kidney from an expanded-criteria donor (ECD) or donors after cardiac death (DCD).

From the investigators previous studies with C1INH (Berinert®) for prevention of antibody mediated rejection (ABMR), the investigators noted that no patients developed ABMR during treatment with C1INH, the investigators also noted a near significant reduction in DGF due to IRI (ClinicalTrials.gov(NCT01134510), FDA Investigational New Drug (IND#): 14363). These findings suggest an important role for complement in the mediation of IRI and that inhibition of early complement activation using C1INH in patients receiving at risk kidneys for IRI should reduce this costly and often devastating complication of kidney transplantation. In addition, numerous other studies in animal models have shown dramatic improvements in IRI models with the use of C1INH. Complement activation is detectable in animal and in human kidneys models after IRI and experimental data suggests that use of C1INH prior to induction of IRI significantly reduces IRI as well as inflammatory cell infiltrates. Based on this, the investigators hypothesize that the use of C1INH in patients receiving deceased donor (DD) kidney transplants with high risk for DGF will show significant reductions in DGF and improved outcomes post-transplant compared with patients receiving DD transplants who do not receive C1INH treatment. Here, the investigators propose to investigate the application of pre-operative and post-transplant doses of C1INH (Berinert®) vs. placebo in adult subjects receiving a DD renal allograft considered at high-risk for IRI and DGF. The investigators hypothesize that C1INH treated patients will demonstrate improved function of the kidney allograft compared to placebo, with equivalence in safety. The primary objectives of this study are: Using a double blinded, placebo controlled format, the investigators will:

1\. Evaluate and compare the safety of C1INH (50 units/kilogram, round to the nearest 500 unit) administered pre-transplant and 24 hrs post-transplant in recipients of kidney allografts from high risk for IRI deceased donors.

The secondary objectives are to:

1. On the basis of safety and efficacy, determine appropriate Berinert® study dose for Phase III investigation, and
2. Determine appropriate endpoint choice for Phase III investigation.

Arms: arm 1: 35 patients will receive C1 esterase inhibitor in addition to standard of care immunosuppressive therapy. arm 2: 35 patients will receive placebo in addition to standard of care immunosuppressive therapy.
Interventions: intervention 1: C1 Esterase Inhibitor intervention 2: Placebo
Intervention descriptions: intervention 1: C1 Esterase Inhibitor 50 units per kilogram intravenous infusion administered on day of transplant, and another dose at 24 hours post-operatively. Total: 2 doses intervention 2: Placebo medication identical to study drug (C1 esterase inhibitor) volume will be administered on day of transplant, and another dose at 24 hours post-operatively. Total: 2 doses

Protocol documents:
Prot_SAP_000.pdf: 
CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
1
  
 
CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase I/II, Double-Blind, Placebo-
Controlled Study: Assessing Safety 
and Efficacy of Preoperative and 
Post-Transplant C1 Inhibitor 
(Berinert®) (Human) (C1INH) vs. 
Placebo Administration in Recipients 
of a Renal Allograft from Deceased 
High Risk Donors and its impact on 
Delayed Graft Function (DGF) and 
Ischemia/Reperfusion Injury (IRI) 
 
Test Drug: 
C1INH (Berinert®) CSL Behring Inc. 
Sponsor’s Name and 
Address: 
Stanley Jordan, MD 
8900 Beverly Blvd  
Los Angeles, CA 90048 
 
Sponsor’s Telephone 
Number: 
 
Sponsor’s FAX: 
 
310-423-2641 
310-423-6369 
 
Collaborator:  
 
Study Number and Protocol 
Version Number/Date: 
 
CSL Behring Inc.  
 
Version 7.0, November 25, 2014 
 
Development Phase: 
 
 
PIs:  
 
Phase I/II  
 
 
Stanley C. Jordan, M.D., FASN 
Director, Nephrology & Transplant 
Immunology 
Department of Medicine & Pediatrics 
Cedars-Sinai Medical Center 
8900 Beverly Blvd  
L.A., CA. 90048 
Telephone: 310-423-2641 
Fax: 310-423-6369 
e-mail: sjordan@cshs.org 
 
 
 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
2
 
 
 
Ashley A. Vo, Pharm.D 
Director, Transplant Immunotherapy 
Program 
Cedars-Sinai Medical Center 
8900 Beverly Blvd  
L.A., CA. 90048 
Telephone: 310-423-4021 
Fax: 310-423-6369 
e-mail: Ashley.vo@cshs.org 
 
 
 
 
Clinical Trial 
Coordinator: 
Jua Choi, Pharm.D 
Research Pharmacist 
Transplant Immunotherapy Program 
Cedars-Sinai Medical Center 
8900 Beverly Blvd  
L.A., CA. 90048 
Telephone: 310-248-8186 
Fax: 310-423-6369 
e-mail: jua.choi@cshs.org 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
3
 
Table of Contents 
1. 
Introduction ............................................. 1 
2. 
Hypothesis .............................................. 13 
2.1 
Study Objectives ........................................ 13 
2.2  Study Synopsis.......................................... 13 
3. 
Investigator(s) And Other Study Participants ............ 20 
4. 
Investigational Plan .................................... 20 
4.1 
Study Design And Plan ................................... 20 
4.1.1 Study Drug Administration Timing ........................ 21 
4.2 
Selection Of Study Population ........................... 22 
4.2.1 Inclusion Criteria ...................................... 22 
4.2.2 Exclusion Criteria ...................................... 23 
4.3 
Removal Of Subjects From Study .......................... 24 
4.4 
Premature Termination Of Study/Closure Of Center ........ 25 
4.5 
Treatments .............................................. 25 
4.5.1 Treatments To Be Administered ........................... 25 
4.5.2 Identity Of Investigational Product(s) .................. 25 
4.5.3 Method Of Assigning Subjects To Treatment Groups ........ 26 
4.5.4 Selection Of Doses In The Study ......................... 26 
4.5.4.1 
C1INH Dosing........................................ 26 
4.5.4.2 
Placebo Dosing...................................... 26 
4.5.5 Immunosuppression ....................................... 27 
4.5.5.1 
Induction Antibody Therapy.......................... 27 
4.5.5.2 
Maintenance Immunosuppression....................... 27 
4.5.5.2.1 Calcinurine Inhibitors.............................. 27 
4.5.5.2.2 Mycophenolate Mofetil............................... 27 
4.5.5.2.3 Corticosteroids..................................... 27 
4.5.6 Anti-infective Prophylaxis .............................. 28 
4.5.7 Selection And Timing Of Dose For Each Subject ........... 28 
4.5.8 Blinding ................................................ 28 
4.5.9 Treatment Compliance .................................... 29 
4.6 
Study Variables ......................................... 29 
4.6.1 Efficacy Variables ...................................... 29 
4.6.1.1 
Primary Efficacy Endpoints.......................... 29 
4.6.1.2 
Secondary Efficacy Endpoints........................ 30 
4.6.2 Safety Variables ........................................ 30 
4.6.2.1 
Adverse Drug Reactions.............................. 30 
4.6.2.2 
Assessment of Risk for Thrombotic Events with  C1INH 
Administration .......................................... 31 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
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4.6.2.3 
Evidence of a Thrombotic Effect of C1INH 
Administration when Given in Supraphysiologic Dosages to 
Humans .................................................. 31 
4.6.2.4 
Evidence of a Thrombotic Effect of C1INH 
Administration when Given in Supraphysiologic Dosages to 
Animals ................................................. 33 
4.6.2.5 
Therapy Stopping Points............................. 33 
4.6.2.6 
Primary Saftey Endpoints............................ 33 
4.6.2.7 
Secondary Safety Endpoints.......................... 33 
4.6.3 Assessment Periods ...................................... 33 
4.6.3.1 
Screening Procedure – Day -30 to Day 0.............. 33 
4.6.3.2 
Day 0 - Day of Transplantation...................... 34 
4.6.3.3 
Day 1-7 Assessments measured daily through day 7 or 
until discharge ......................................... 35 
4.6.3.4 
Days 14 ± 2 days & 28 ± 2 days...................... 36 
4.6.3.5 
Days 60 ± 5 days & 90 ± 5 days...................... 36 
4.6.4 Observations And Measurements ........................... 36 
4.6.4.1 
Physical Examination................................ 37 
4.6.4.2 
Clinical Assessment................................. 37 
4.6.4.3 
Vital Signs......................................... 37 
4.6.4.4 
Serum Creatinine.................................... 37 
4.6.4.5 
Calculated Creatinine Clearance / Calculated GFR...... 
 37 
4.6.4.6 
Serum Creatinine Reduction Ratio.................... 37 
4.6.4.7 
Urine Output........................................ 37 
4.6.4.8 
PT, PTT and INR Tests............................... 38 
4.6.4.9 
Hematology and Chemistry Profile.................... 38 
4.6.4.10 ECG Testing......................................... 38 
4.6.4.11 ACR Assessment...................................... 38 
4.6.4.12 Rate and Duration of Dialysis....................... 38 
4.6.5 Drug Concentration Measurements ......................... 38 
4.7 
Data Quality ............................................ 38 
4.8 
Documentation ........................................... 39 
5. 
Ethical And Legal Aspects ............................... 39 
5.1 
Ethics Committee (EC) Or Institutional Review Board (IRB)39 
5.2 
Ethical Conduct Of The Study ............................ 39 
5.3 
Regulatory Authority Approvals/Authorizations ........... 40 
5.4 
Subject Information And Consent ......................... 40 
5.5 
Confidentiality ......................................... 40 
6. 
Statistical Methods And Determination Of Sample Size .... 41 
6.1 
Statistical And Analytical Plans ........................ 41 
6.2 
Determination of Sample Size ............................ 41 
7. 
Adverse Events (AEs) .................................... 43 
7.1 Adverse Event (AE) Monitoring............................. 43 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
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7.2 
Adverse Event (AE) Definitions .......................... 43 
7.2.1 Adverse Events (AEs) .................................... 43 
7.2.2 Serious Adverse Event (SAE) ............................. 43 
7.2.3 Unexpected Adverse Event (AE) ........................... 45 
7.2.4 Relationship Of Adverse Event To Investigational Product 45 
7.2.5 Severity Of The Adverse Event (AE) ...................... 46 
7.2.6 Adverse Event (AE) Documentation ........................ 46 
7.3 
Reporting of Serious Adverse Events (SAEs) or Pregnancy . 46 
8.0 
References .............................................. 48 
9. 
Appendices .............................................. 53 
9.1 
Calculation of GFR ...................................... 79 
 
 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
6
Glossary and Abbreviations 
 
AE 
Adverse Event 
CRF 
Case Report Form (either paper or electronic) 
EC 
Ethical Committee 
GCP 
Good Clinical Practice 
IRB 
Institutional Review Board 
MRR 
Medical Research Report 
SAE 
Serious Adverse Event 
SOC 
Standard of Care 
DGF 
Delayed Graft Function 
EGF 
Early Graft Function 
CVA 
Cerebral Vascular Accident 
DCD 
Donation after Cardiac Death 
ECD 
Extended Criteria Donor 
GFR 
Glomerular Filtration Rate 
UNOS 
United Network for Organ Sharing 
SCD 
Standard Criteria Donor 
OPTN 
National Organ Procurement and Transplantation 
Network 
ACR 
Acute Cellular Rejection 
C1INH 
C1 inhibitor (Berinert®) 
CMV 
Cytomegalovirus 
IRI 
Ischemia-Reperfusion Injury 
USRDS 
The United States Renal Data System 
WFI 
Water for Injection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
7
Introduction 
Over the past decade, improvements in immunosuppressive 
regimens, surgical techniques, and organ procurement have 
resulted in a significant increase in renal transplantation 
success (Oniscu et al, 2005). Currently, the worldwide rates for 
1- and 5-year graft survival are 95% and 80%, respectively, with 
death with a functioning graft being the most common reason for 
renal graft loss after 1 year (Daly et al, 2005). Studies on 
renal transplantation outcomes have traditionally focused on 
patient and graft survival, with little to no consideration of 
graft function (Boom et al, 2000). Although graft loss is the 
worst type of graft dysfunction, grafts with an impaired 
function require the most intense follow-up, are economically 
most costly and require rigorous clinical management to preserve 
life-expectancy of the graft (Boom et al, 2000). For these 
reasons, parameters of graft function are being increasingly 
included as outcome measures in renal transplantation studies, 
including delayed graft function (DGF). Indeed, the new UNOS 
allocation policies 
(http://optn.transplant.hrsa.gov/policiesAndBylaws/policies.asp) 
scheduled for implementation in 2014 will tend to give higher 
risk kidneys to older diabetic recipients. This is likely to 
increase the risk significantly for DGF and poorer allograft 
function. 
Despite a decline in the number of patients experiencing 
allograft rejection episodes over the past decade, the incidence 
of patients with DGF has remained steady and was reported in 2.6 
percent of transplants from living donors, compared to 22, 28, 
and 41 percent of SCDs, ECDs, and donations after cardiac death 
patients respectively.  
 
Figure 1: Data obtained from United States Renal Data Systems 
Report Transplantation  2012 Vol 2, pp 283-294. 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
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Most deceased donor and some live donor organ transplants 
manifest a degree of early dysfunction (Halloran and Hunsicker, 
2001). Delayed graft function (DGF) is a term used to describe 
the lack of acceptable function in a kidney after 
transplantation (Daly et al, 2005). DGF has been well described 
in association with an inferior functioning kidney at 1 and 2 
years post-transplant (Halloran et al, 1988; Hariharan et al, 
2003). Typical histological findings of DGF are dilatation of 
tubules, loss of proximal epithelial cell brush border, 
epithelial cell necrosis/apoptosis, and cellular casts (Smith et 
al, 2003). In the presence of DGF, kidneys are more likely to 
have adverse outcomes including decreased functional graft 
survival and 6-month patient survival, and increased acute 
rejection (Daly et al, 2005; Halloran and Hunsicker, 2000). It 
is interesting to note that analyses of the UNOS scientific 
renal transplant registry (United States) showed DGF was 
associated with increased probability of patient death in the 
first 6 months (Halloran and Hunsicker, 2000), whereas analyses 
in the Netherlands found DGF to be an independent risk factor 
for acute rejection and suboptimal renal function at 1 year, but 
not survival (Boom et al, 2000). The use of kidneys from 
extended criteria deceased donors (ECD) are also associated with 
higher rates of DGF and poorer long-term survival. These ﬁndings 
are especially important in view of recent publications which 
showed compromised outcomes in patients receiving kidneys from 
suboptimal donors. A recent analysis of outcomes from 9134 
recipients of cardiac-death and brain-death donor kidneys, donor 
age ≥60 years was identiﬁed as a risk factor for graft failure 
and reduced long-term renal function. (Summers et al, 2010).  
These investigators found that graft survival and renal function 
decrease as the age of the donor increases, with recipients of 
these ECD kidneys having twice the risk of graft failure 
compared with recipients of younger donor kidneys. Another group 
performed a comprehensive systematic review of kidney 
transplants from ECDs and concluded that management protocols 
for this patient population need to be based on nephron-
protecting strategies (Pascual et al, 2008). Thus strategies to 
reduce IRI and DGF are critical to increasing the number and 
long-term outcomes of marginal kidneys.  
 
Historically DGF has been defined as the requirement for 
dialysis during the first week after renal transplantation, 
however the postoperative requirement of hemodialysis or 
peritoneal dialysis is not standardized and the decision to 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
9
dialyze varies from center to center and among consultants (Daly 
et al, 2005). More recently, efforts have been made to 
scientifically quantify DGF in a more stringent manner with 
various alternative definitions of DGF including; (1) the number 
of days to achieve a creatinine clearance of >10 mL/min, 
calculated by the Gault-Cockroft formula (Giral-Classe et al, 
1998), (2) a serum creatinine level of >3 mg/dL on the fifth day 
post-transplant (Humar et al, 2000), (3) the need for dialysis 
within 72 hours after transplantation (Hetzel et al, 2002), (4) 
serum creatinine level changes, including an increase, remaining 
unchanged, or decreasing by less than 10% per day immediately 
after surgery during three consecutive days for >1 week (Boom et 
al, 2000), (5) a rising serum creatinine level above that before 
surgery, or urine output of <300 mL within 6 hours of 
transplantation, despite diuretics and adequate volume (Gonwa et 
al, 2002), (6) urine output of <1 L in the first 24 hours or a 
decrease in serum creatinine of <20-30% reflected in a poor 
glomerular filtration rate (GFR) (Halloran and Hunsicker, 2001), 
and (7) calculating the creatinine reduction ratio on day two 
following surgery (Salahudeen et al, 2004). However despite 
these alternative suggestions, the conventional definition of 
“requirement for dialysis in the first week post-transplant” 
remains the most utilized and published definition for DGF, with 
“need for dialysis” being easily measured and clinically 
relevant. 
 
The reported incidence of DGF varies widely depending on the 
source of the graft, with DGF estimated to occur in 
approximately 20-35% of all patients who receive a deceased 
donor graft (Koning et al, 1997; Halloran and Hunsicker, 2001), 
and rates varying up to 80% in association with extended 
criteria (ECD) donor grafts (SCJ personal data from CSMC). The 
risk factors for DGF are the same as those that influence graft 
survival and include donor tissue quality (age), brain death and 
other components of cadaver donation, preservation variables 
particularly cold ischemia time, immune variables, and recipient 
variables (Halloran and Hunsicker, 2001). The duration of cold 
ischemia time has been shown to have a direct effect on the 
presence of DGF and graft survival with durations longer than 28 
hours associated with increased risk (Lechevallier et al, 1998; 
Jacobs et al, 1996; Peters et al, 1995; Kahan et al, 1987), and 
a 23% increase for every 6 hours of cold ischemia time (Ojo et 
al, 1997). Additionally, DGF is significantly associated with 
the use of kidneys from older donors, particularly donors of 
more than 50 years of age (Boom et al, 2000). In the United 
States, in the last decade, the proportion of deceased donors 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
10
older than 50 years of age has increased from 21% to 30% (Nathan 
et al, 2003; Ojo et al, 2001), however the kidney waiting list 
has increased by 260% and the number of deceased donor kidney 
transplants has increased by only 16% (Metzger et al, 2003; 
Port, 2001; Nathan et al, 2003). Due to the increasing disparity 
between organ supply and demand, the use of kidneys from “older” 
expanded criteria donors (ECDs) has become generally accepted 
and increasingly common (Metzger et al, 2003). 
In the United States, the United Network for Organ Sharing 
(UNOS) (www.unos.org) which administers the national Organ 
Procurement and Transplantation Network (OPTN) (www.optn.org) 
defines two types of deceased donor kidneys, namely “standard 
criteria donors” (SCD) and “expanded criteria donors” (ECD). 
Using pre-transplant variables to identify increased risk of 
graft loss, an ECD donor kidney is defined as a kidney donated 
for transplantation from (1) a brain-dead donor over the age of 
60 years, or (2) from a donor between the ages of 50-59 with at 
least two of the following: a history of hypertension, a 
terminal serum creatinine greater than or equal to 1.5 mg/dl 
(normal range 0.8-1.4 mg/dl), or death from a cerebral vascular 
accident (CVA) (stroke or aneurysm). In comparison, an SCD donor 
kidney is defined as a kidney donated for transplantation by a 
donor who has suffered brain death and does not fit the criteria 
for ECD. With the growing demand for first-time and repeat 
deceased donor renal transplants, ECD donor kidneys are being 
increasingly considered by transplant programs. As a consequence 
of the utilization of marginal kidneys, DGF is a major 
complication following transplantation with ECD donor kidneys. 
 
 
Complement as a Mediator of Ischemia Reperfusion Injury (IRI) 
 
The complement system in humans exists as a system of 
recognition molecules, proteolytic enzymes and receptors for 
activated complement components that are responsible for host 
defense. The complement system can be activated in at least 3 
separate ways; first, the classical pathway which depends on 
antibody binding to antigen targets and binding complement 
components (i.e. C1q) to ultimately activate C3 and initiate 
terminal complement component activation of C5b-C9 (see figure 
1). Binding of lectins (i.e. mannose binding lectin and mannose 
binding lectin serine protease (MBLSP) activate the C3 
convertase without activation of C1->4->2 (C3 convertase). In 
addition, the alternative pathway is activated by interaction 
with H20 or activating surfaces. The deposition of complement on 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
11
bacteria or sites of injury signal initiation of an inflammatory 
response and tags complement bound targets for elimination 
through apoptosis or phagocytosis by macrophages. The complement 
system also contains a number of receptors that modify or abate 
complement-mediated inflammation. Complement also exists in two 
distinct compartments (central and local). The central 
compartment of complement is produced in the liver and is 
responsible for all circulating complement factors. The 
peripheral compartment included complement generated locally in 
organs such as the CNS and kidneys (Sacks et Zhou 2012. 
Activation of complement in the peripheral compartments appears 
to be regulated primarily by IRI. Figure 2 below describes the 
importance of complement activation in initiation of renal 
tubular cell (RTC) injury with reference to induction by IRI. 
Briefly, IRI stimulates C3 production in the RTCs that is 
subsequently cleaved by the MBL/MBLSP or alternative pathway 
(Sacks et Zhou 2012). C3b generated then activates C5 to C5a and 
C5b. C5b forms the C5b-C9MAC which induces cell death and 
cytokine (IL-6) release. C5a interacts with the C5aR to induce 
apoptosis and cell death. Data from (Sacks et Zhou 2012) have 
also shown that kidneys from C3 deficient mice are resistant to 
IRI. Other investigators have also shown that expression of C3 
and other complement components in human donor kidneys before 
transplantation had a negative impact on graft outcome at 2-3 
years (Naesens et al 2009). Thus there is significant support 
for a role of complement activation in inducing RTC injury and 
ultimately DGF and it would be reasonable to assume that 
administration of complement inhibitors would be of potential 
benefit in prevention or amelioration of RTC injury and possibly 
improve outcomes in kidneys at high risk for development of DGF. 
 
 
IschemiaReperfusionInjury
C3
C3b
MBSP
C5
C5b
C5b-9MAC
IL-6
Prostaglandins
Collagen
C5a
C5aR
Ac va onInducedCellDeath
RenalTubularCells
C5a


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
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Figure 2 shows complement activation by I/R injury (from Sachs & 
Zhou 2012). 
 
Evidence for Use of C1INH to Prevent IRI and DGF 
 
Although limited, there are recent investigations which show 
dramatic results in prevention of IRI after C1INH treatment. 
(Dalle Lucca et al 2012) investigated the ability of recombinant 
C1INH (rC1INH) to alter tissue injury in a porcine model of 
controlled hemorrhage. In this model, the administration of 
100U/kg or 250U/kg rC1INH significantly reduced IRI injury to 
kidneys, lungs, intestine and liver. The animals treated with 
250U/kg also showed significant reductions in TNF- levels and 
severity of metabolic acidosis. The significant beneficial 
effects of rC1INH administration were found to be related to the 
ability of C1INH to reduce IRI induced complement activation in 
tissue. All treated animals also showed reduced immune cell 
infiltration and cytokine production. The authors felt that the 
use of rC1INH would have significant benefits in patients with 
hemorrhagic shock in prevention of IRI and organ failure 
(Castellano et al, 2010). In a comprehensive analysis of rC1INH 
use in an IRI model of kidney injury in the swine model found 
that IRI was associated with significant C3 activation, 
primarily through the MBL/MBLSP-2 pathway. The infusion of 
rC1INH led to significant reductions in peritubular capillary 
C4d deposition, and C5b-C9MAC. Complement inhibition with rC1INH 
also reduced the numbers of infiltrating CD163+, CD4+ and CD8+ 
T-cells. Animals treated with rC1INH had significantly less RTC 
injury and renal damage. The authors conclude that the use of 
C1INH may represent a novel therapeutic approach in the 
prevention of DGF that would have particular relevance to kidney 
transplantation.  
 
2.0 Hypothesis 
Since complement activation is detectable in animal models of 
IRI and in human kidneys after IRI and since experimental data 
suggests that use of C1INH prior to induction of IRI shows 
significant beneficial effects on reducing IRI as well as 
inflammatory cell infiltrates, we hypothesize that the use of 
C1INH in patients receiving deceased donor (DD) kidney 
transplants with high risk for DGF will show significant 
reductions in DGF and improved outcomes post-transplant compared 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
13
with patients receiving DD transplants who do not receive C1INH 
treatment.  
 
2.1 Study Objectives 
In this study, we propose to investigate the application of pre-
operative and post-transplant doses of C1INH (Berinert®)vs. 
placebo in adult subjects receiving a deceased donor renal 
allograft considered at high-risk for IRI and DGF. We 
hypothesize that C1INH treated patients will demonstrate 
improved function of the kidney allograft compared to placebo, 
with equivalence in safety. We will also evaluate biopsies at 
transplant in all entered patients. 
The primary objectives of this study are: Using a double 
blinded, placebo controlled format, we will:  
1. Evaluate and compare the safety of C1INH (50 U/kg, round to 
the nearest 500unit)administered pre-transplant and 24 hrs post-
transplant in recipients of  kidney allografts from high risk 
deceased donors. The secondary objectives are to:  
1. On the basis of safety and efficacy, determine appropriate 
Berinert® study dose for Phase III investigation, and  
2. Determine appropriate endpoint choice for Phase III 
investigation. 
 
2.2 Study Synopsis 
 
TITLE 
A Phase I/II, Double-Blind, Placebo-
Controlled Study: Assessing Safety and 
Efficacy of Intraoperative and Post-
Transplant C1 Inhibitor(Human) 
(C1INH)vs. Placebo in Recipients of a 
Kidney Allograft from Deceased High Risk 
Donor and its impact on Risk for  
Delayed Graft Function (DGF) 
INVESTIGATIONAL 
AGENT 
C1INH (Berinert® [human][C1INH]) 
HYPOTHESIS 
Pre-operative, infusion of C1INH before 
allograft reperfusion and 24 hour post-
transplant will improve early graft 
function and reduce the rate of DGF in 
patients receiving kidney allografts 


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Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
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from high risk deceased donor compared 
to placebo. 
RATIONALE  
Early graft function has a long-term 
effect on graft survival. Poor early 
graft function and DGF contributes to 
decreased short- and long-term patient 
and graft survival, increased incidence 
of acute rejection, prolonged 
hospitalization, and higher costs of 
transplantation.  Although multiple 
factors contribute to the impaired graft 
function, ischemia-reperfusion injury 
(IRI) is the underlying pathophysiology 
leading to poor early graft function and 
DGF.  A >35% incidence of DGF has 
remained constant over time despite 
significant improvements in 
immunosuppressive strategies and patient 
management.  This may be due to 
increased use of kidneys from “extended-
criteria” and/or non-heart-beating 
donors, where even greater rates (>60%) 
of DGF have been reported.  
 
More than 96,680 people are currently 
waiting for a kidney transplant in the 
United States (UNOS.org 3/22/13).  Of 
the 15,092 kidney transplants performed 
in the US in 2011, ~11,000 (62%) were 
from deceased donors.  Of these, 
approximately 17% were from expanded-
criteria donors.  The USRDS reports that 
more than 50% of patients on the waiting 
list are willing to accept a kidney from 
an expanded-criteria donor (ECD) or DCD 
donor.  
 
NUMBER OF 
PATIENTS AND 
CENTERS 
70 patients will be enrolled into the 
study (35 C1INH and 35 Placebo). The 
study will be initiated at Cedars-Sinai 
Medical Center and extended to 
collaborators with completion of 
contractual agreements.  
INVESTIGATOR / 
CLINICAL 
TRIAL LOCATION 
Stanley C. Jordan, M.D. 
Cedars-Sinai Medical Center 


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STUDY OBJECTIVES 
 To evaluate and compare the safety of 
Berinert® 50U/kg in recipients of a 
kidney allograft from a high risk 
deceased donors receiving one IV dose 
of Berinert® 50U/kg (round to the 
nearest 500unit) or placebo pre-
operatively and a repeat dose 
(Berinert® 50U/kg v. Placebo) 24 hrs. 
post-transplant.  
 To evaluate early kidney function in 
recipients of a kidney allograft from 
a high risk deceased donors following 
the administration of two IV doses of 
Berinert® pre-operatively and 24 hrs 
later as compared to placebo. 
 
STUDY DESIGN 
 
Patients who fulfill all I/E criteria 
will be enrolled into Study 
I Study Group (70 patients):  
      Treatment Arm I - Patients will be 
administered one IV dose of 50U/kg of 
Berinert® (round to the nearest 
500unit)on-call to OR for kidney 
transplant. 
    Control Arm – Patients will be 
administered one IV dose of normal 
saline (NS) approximately on-call to 
the OR for kidney transplant in a 
volume identical to the volume of the 
IV dose of Berinert®. Berinert® 
(50U/kg) round to the nearest 
500unit)or placebo will be 
administered to study subjects again 
at 24 hrs post-transplant. 
 
  
STUDY POPULATION 
 
Inclusion Criteria: 
 Adult men or women (18-70 years of 
age) who are on chronic dialysis 
therapy and acceptable candidates 
for receipt of a kidney transplant. 
 Recipients of kidney allograft from 
ECD donors 
 Recipients of kidney allograft from 
DCD donors 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
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 Recipients of kidney allograft 
other than ECD and DCD who have 
risk index of 3-8 (minimum 3 and 
maximum 8) for DGF, based on the 
criteria in the risk index detailed 
in the table below  
 Recipients who are ABO compatible 
with donor allograft 
 Pre-transplant vaccination with 
Menactra® meningococcal vaccine 
 Understand and sign a written 
inform consent prior to any study 
specific procedure 
Women of childbearing potential must 
have a negative pregnancy test prior to 
randomization, and must be on an 
acceptable form of birth control. 
Characteristic 
Risk Index 
Donor Age (years) 
<40 
0 
41-49 
1 
50-54 
2 
55-59 
3 
>60 
6 
Cold Ischemia time 
0-12 
0 
13-18 
1 
19-24 
2 
24-30 
3 
31-36 
4 
>37 
6 
Recipient Race 
Non-Black 
0 
Black 
1 
Recipient with Diabetes 
 
Has diabetes 
1 
No diabetes 
0 
Donor Death due to CVA 
Donor age < 50 years 
0 
Donor age >50 years 
3 
 
Exclusion Criteria: 
 Patients with a known pro-
thrombotic disorder. (eg. Factor V 
Leiden) 


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 Patients with a history of 
thrombosis or hypercoagulable 
state, excluding access clotting. 
 Patients with a history of 
administration of C1INH containing 
products or recombinant C1INH 
within 15 days prior to study 
entry. 
 Patients with a known 
hypersensitivity to treatment with 
C1INH. 
 Patients with an abnormal 
coagulation function. (INR >2, PTT> 
50, PLT<80,000) who are not on 
anti-coagulation. 
 Patients with known active presence 
of malignancies. 
 Patients who are PCR positive for 
Hep B, Hep C, or HIV. 
 Recipients of pre-emptive kidney 
transplantation. 
 Recipients of multi-organ 
transplants. (kidney and any other 
organ) 
 Recipients of kidney allograft from 
DD who: CIT < 18 hours, terminal 
serum creatinine ≤ 1mg/dl. 
 Recipients of kidney allograft that 
was on pump preservation for any 
period prior to transplantation. 
 Recipients of kidney allograft from 
a living donor. 
 Female subjects who are pregnant or 
lactating.   
 
 
STUDY ENDPOINTS  
SAFETY:  
 Overall incidence of adverse events 
and serious adverse events and 
relationship of AE and SAEs to the 
study treatment 
 Evaluation of blood chemistry, 
hematology, and coagulation 
parameters 


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 Patient and graft survival at Day 
90 
 Rate of acute cellular rejection 
(ACR) and antibody mediated 
rejection at Day 90 
 
EFFICACY ASSESSMENTS: 
 
Primary Endpoints  
For patients who do not require 
dialysis in the first 7 days: 
 
Proportion of patients enrolled 
with serum creatinine >3mg/dL 
on postoperative day 5. 
 
Proportion of patients with 
serum creatinine reduction 
ratio of < 30% from 24 to 48 
hours post-transplant. 
For patients who require dialysis in 
the first 7 days: (Excluding patients 
who get dialysis for hyperkalemia) 
 
The proportion of patients 
enrolled who require at least 
one session of dialysis in the 
first 7 days post transplant.  
 
Number of dialysis sessions per 
patient in the first 7 days 
post transplant.  
 
Secondary Endpoints 
 
Daily serum creatinine for 
seven days post transplant or 
until discharge. 
 
Daily Calculated Creatinine 
Clearance for seven days post 
transplant or until discharge. 
 
Serum creatinine at 14, 28, 60, 
and 90 days post transplant. 
 
Total 24 hr urine output days 
1-7 post-transplant. 
 
Rate of dialysis use at 14, 28, 
60, and 90 days post 
transplant. 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
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 
Dialysis duration at 14, 28, 
60, and 90 days post 
transplant. 
 
Rate of acute cellular and 
antibody mediated rejection 
episodes by day 90.  
 
Patient and graft survival by 
day 90.  
 
Calculated creatinine clearance 
at 14, 28, 60, and 90 days post 
transplant. 
 Incidence of DGF as categorized 
by a DGF scale of increasing 
severity as follows:  
 
Grade 1 - immediate urine 
production and no need for 
dialysis with creatinine 
reduction ratio (CRR) between 
time 0 of transplantation and 
day 7 post-transplantation >70% 
 
Grade 2 - creatinine reduction 
ratio (CRR) between time 0 of 
transplantation and day 7 post-
transplantation of >70% with 
need for dialysis 
 
Grade 3 - creatinine reduction 
ratio (CRR) between time 0 of 
transplantation and day 7 post-
transplantation <70% with no 
need for dialysis 
 
Grade 4 - creatinine reduction 
ratio (CRR) between time 0 of 
transplantation and day 7 post-
transplantation of <70% with 
need for dialysis. 
 
 Protocol biopsies will be performed 
at the time of implantation. 
Pathological analysis will be done 
to determine if there is an 
increase in interstitial 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
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20
fibrosis/tubular atrophy (IFTA), 
glomerulosclerosis, transplant 
glomerulopathy, and other markers 
of ischemic injury.  
IMUNOSUPPRESSION  
REGIMEN  
 Induction therapy using 
Thymoglobulin in divided doses for 
a total of 6mg/kg or Campath 1H 
30mg SQ x 1. 
 Calcineurin inhibition (Tacrolimus 
or Cyclosporine) will be delayed 
for minimum 24 hours post 
transplant.  
 MMF will be started and used per 
standard of care (SOC). 
 Corticosteroids will be used per 
SOC. 
 Valgancyclovir will be used as the 
prophylaxis for CMV for a minimum 
of 6 months.  
 Prophylaxis for bacterial and 
fungal infection will be per 
institutional SOC.  
 Diagnosis and treatment of acute 
cellular or antibody-mediated 
rejection will be per institutional 
SOC. 
STATISTICAL 
ANALYSIS 
Descriptive and comparative statistics 
will be used to evaluate results 
DURATION OF STUDY 
90 days 
 
3.Investigator(s) And Other Study Participants  
Information regarding additional key personnel involved in the 
conduct of the study, including names and contact details of 
participating investigators, monitors, clinical laboratories, 
technical departments and/or institutions, as well as 
information on members of additional study committees, will be 
found in the study files of the sponsor and on site if 
requested. 
A Data Safety Monitoring Board (DSMB) committee will review 
safety data. Quarterly assessment of AEs & SAEs will be 
performed and reported to CSL Behring, FDA and Cedars-Sinai IRB. 
In addition, DSMB must be informed and may be convened at any 
time questions about safety arise and/or thromboembolic events 


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
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21
occur. Please see appendix E for DSMB charter and FDA Guidance 
for Clinical Trial Sponsors.   
  
4. Investigational PlanStudy Design And Plan 
This is a Phase I/II double-blind, randomized, placebo-
controlled study assessing safety and limited efficacy of 
intraoperative C1INH (50U/kg) vs. Placebo administered prior to 
graft reperfusion in adult subjects receiving a deceased donor 
kidney allograft considered high-risk for development of DGF. 
Patients will also receive an additional dose 24 hrs. post-
transplant (C1INH (50U/kg vs. placebo). Once eligible patients 
are identified, consented, and have an acceptable kidney 
transplant offer, they will be randomized by the Cedars-Sinai 
Research Pharmacy to receive study drug vs. placebo. Drug and 
placebo will be prepared by the Cedars-Sinai Research Pharmacy 
and conveyed to the operating room in a blinded manner. 
 
4.1.1 
Study Drug Administration Timing 
In consideration of the latest time point of treatment 
application before graft reperfusion (ie. beginning of renal 
vein anastomosis),study treatments will be administered pre-
operatively at any one point in time, from time of admission up 
to the beginning of renal vein anastomosis before graft 
reperfusion. Due to the biologic half-life of C1INH 
(approximately 2.5 to 3.8 days), the time difference between 
early and late intraoperative treatment application, is thought 
to be negligible.  In addition, the patients will receive study 
treatments at 24 hrs. post-transplant. This will constitute the 
entirety of C1INH vs. placebo administration. The study format 
is shown below in figure 3. 
 


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Figure 3: Study format to evaluate C1INH in DGF. 
 
4.2 
Selection Of Study Population 
 
Persons legally incompetent to provide informed consent 
 
include, but may not be limited to, minors (children), 
individuals who are mentally incapable of understanding the 
implications of the PI/IC, and those who are physically unable, 
by any written, physical or verbal means, to confirm their 
understanding and consent to take part in the study.  Our policy 
is not to enter adult patients who are mentally incompetent to 
give informed consent.  Exceptions must be approved by the Study 
Director. 
 
Up to 70 adult men and women (18-70 years of age) who are 
recipients of a kidney transplant and recipients of only a 
kidney allograft from a deceased donor who is high risk for DGF 
will be enrolled in the study.  
 
Screening&
Consent
C1INH(50U/kg)
@Transplant&
@24hrs.post-transplant
Placebo(0.9NS)
@Transplant&
@24hrs.post-transplant
-6M




Transplant







3M 









Randomiza on
Rou neLabs(CBC,CMP,CNILevels)
PT,PTTD-Dimers,C3,C4C1INHlevels
Rou nePEtoassessforevidenceof
DVT(WellsCriteria,EGFRdetermina ons)
Transplanta onwithDGFcriteria+
Kidneytransplant.Induc ontherapy
Campath-1H30mgSQorThymoglobulin1.5mg/kgX4doses
Post-TxImmunosuppression:Prograf/Cellcept/Prednisone
PhaseI/IIStudyofSafety&LimitedEfficacyofBerinert®toPreventIschemia/Reperfusion
InjuryandDelayedAllogra Func oninKidneyAllogra Recipients


CONFIDENTIAL                         C1INH (Berinert®) IRI Study in Kidney Transplant 
Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
23
4.2.1 
Inclusion Criteria 
Recipient Inclusion Criteria 
1). Adult men or women (18-70 years of age) who are on chronic 
dialysis therapy and acceptable candidates for kidney 
transplant. 
2). Understand and sign a written informed consent prior to 
study specific procedures. 
3). Recipients who are ABO compatible with donor allograft. 
4). Recipients of kidney allograft from ECD* donors. 
5). Recipients of kidney allograft from DCD** donors. 
6). Recipients of kidney allograft other than ECD and DCD who 
have risk index of 3-8 (minimum 3 and maximum 8) for DGF, based 
on the criteria in the risk index detailed in Table 1. 
7). Women of childbearing potential must have a negative 
pregnancy test prior to randomization, and must be on an 
acceptable form of birth control. 
 
 
Table 1: Risk factors for Delayed Graft Function 
 
Characteristic 
Risk Index
Donor Age (years) 
<40 
0 
41-49 
1 
50-54 
2 
55-59 
3 
>60 
6 
Cold Ischemia time 
0-12 
0 
13-18 
1 
19-24 
2 
24-30 
3 
31-36 
4 
>37 
6 
Recipient Race 
Non-Black 
0 
Black 
1 
Recipient with Diabetes 
 
Has Diabetes 
1 
No Diabetes 
0 
Donor cause of death due 
to CVA
Donor age < 50 years 
0 
Donor age >50 years 
3 
 


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*ECD Kidney: An ECD allograft is defined as a renal allograft 
donated for transplantation from a brain-dead donor over the age 
of 60 years or from a donor aged 50 to 60 years with two of the 
following: a history of hypertension, a pre-retrieval terminal 
serum creatinine greater than or equal to 1.5 mg/dl, or death 
from a cerebral vascular accident (stroke or aneurysm) (Cecka, 
2004). 
 
**DCD Kidney: Recovery of organs and or tissues from a donor 
whose heart has irreversibly stopped beating, previously 
referred to as non-heart-beating or asystolic donation (UNOS). 
 
4.2.2 
Exclusion Criteria 
1) Patients with a known pro-thrombotic disorder. (eg. Factor V 
Leiden) 
2) Patients with a history of thrombosis or hyper-coagulable 
state, excluding access clotting. 
3) Patients with a known hypersensitivity to treatment with C1INH 
or blood products. 
4) Patients with an abnormal coagulation function. (INR >2, PTT> 
50, PLT<80,000) who are not on anti-coagulation. 
5) Patients with known active presence of malignancies. 
6) Patients who are positive for Hep B, Hep C, or HIV PCR test. 
7) All zero mismatch kidneys. 
8) Recipients of multi-organ transplants. (kidney and any other 
organ)Recipients of kidney allograft from donors who:  < 40 
years of age, CIT < 18 hours, serum creatinine ≤ 1mg/dl. 
9) Recipients of kidney allograft that was on pump preservation 
for any period prior to transplantation. 
11)Recipients of kidney allograft from a living donor. 
12)Female subjects who are pregnant or lactating.   
 
  
4.3 
Removal Of Subjects From Study 
A subject who is withdrawn is one who discontinued in the 
clinical study for any reason. 
Subjects may be withdrawn from the study for the following 
reasons: 
 At their own request or at the request of their 
legally acceptable representative. 
 If, in the investigator's opinion, continuation in the 
study would be detrimental to the subject's well 
being. 
 At the specific request of the sponsor. 


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In all cases, the reason for withdrawal must be recorded in the 
case report form and in the subject's medical records.  
Patients have the right to withdraw from the study at any time 
for any reason without penalty or prejudice.  The Investigator 
also has the right to withdraw patients from the study if he/she 
feels it is in the best interest of the patient or if the 
patient is uncooperative or non-compliant.  It is understood by 
all concerned that an excessive rate of withdrawals can render 
the study un-interpretable; therefore, unnecessary withdrawal of 
patients should be avoided.  Should a patient decide to 
withdraw, all efforts will be made to complete and report the 
observations, and early withdrawal procedures, as thoroughly as 
possible. 
The Investigator should contact the patient either by telephone 
or through a personal visit to determine as completely as 
possible the reason for the withdrawal.  A complete final 
evaluation at the time of the patients withdrawal should be made 
with an explanation of why the patient is withdrawing from the 
study.  If the reason for removal of a patient from the study is 
an adverse event or an abnormal laboratory test result, the 
principal specific event or test will be recorded on the CRF.  
For all patients who are withdrawn pre-maturely, every attempt 
should be made to assess the patient’s status (i.e. patient and 
graft survival, malignancies, etc.) at 30 days after 
administration of the last dose of study medication. 
 
4.4 
Premature Termination Of Study/Closure Of Center 
The sponsor has the right to close this study, and the 
investigator/sponsor has the right to close a center, at any 
time, although this should occur only after consultation between 
involved parties. The Ethics Committee/Institutional Review 
Board (EC/IRB) must be informed. Should the study/center be 
closed prematurely, all study materials (except documentation 
that has to remain stored at site) must be returned to the 
sponsor. The investigator will retain all other documents until 
notification given by the sponsor for destruction. 
 
4.5 
Treatments 
4.5.1 
Treatments To Be Administered 
This study is designed with two blinded treatment groups (C1INH 
vs. Placebo). Each group will include 35 patients in a treatment 
arm and 35 patients in a placebo arm.  


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This design is statistically powered to show significant 
differences if there is a 30-50% reduction in the treatment 
group and may trend towards positive treatment effect since 
extensive DGF (40-50%)is expected in ECD and DCD recipients. The 
dose of C1INH chosen is (50U/kg)(round to the nearest 500unit) 
X2 (high-dose treatment) which should increase serum C1INH 
levels significantly above physiologic levels. This is based on 
our observations from our experience using C1INH vs. placebo to 
prevent antibody-mediated rejection in humans.  In those 
randomized to placebo, an equivalent volume of placebo (0.9% 
normal saline) will be administered prior to graft reperfusion. 
Patients who fulfill all I/E criteria will be enrolled into this 
Phase I/II study.  
 
4.5.2 
Identity Of Investigational Product(s) 
Medication will be labeled according to the requirements of 
local law and legislation.  Label text will be approved 
according to agreed CSL-Behring procedures, and a copy of the 
labels will be made available to the study site upon request. 
Product name: Berinert® / C1INH (Human) 
Chemical name: Complement Factor 1 Inhibitor (C1INH) 
Study Medication & Dosing: Berinert® is available in a single-
use vial that contains 500 units of C1 esterase inhibitor as a 
lyophilized concentrate.  Each vial must be reconstituted with 
10 mL of diluent (sterile water) provided.  Prior to 
reconstitution, Berinert® should be stored at 2° to 25°C.  After 
reconstitution, administration may begin within 8 hours provided 
the solution has been stored at up to 25°C.  Berinert® is dosed 
at 50 units per kg body weight (round to the nearest 500units) 
and is administered by slow IV injection at a rate of 
approximately 4 mL per minute.  Participation patients will 
receive 50U/kg C1 INH vs placebo (0.9% NS) on days 0 and day 1 
post-transplant, (see Appendix A). 
 
 
4.5.3 
Method Of Assigning Subjects To Treatment Groups 
Patients will be randomized into treatment/placebo arms in a 1:1 
ratio.  Randomization will be completed prior to patient 
entering the operating room for transplantation. 
This study is a double-blind, placebo-controlled study. The 
clinical pharmacist will maintain the randomization assignment. 


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The Investigators, other study personnel, patients, and the 
Sponsor will be blinded to treatment assignment.   
4.5.4 Selection Of Doses In The Study 
4.5.4.1 Berinert® (C1INH Dosing) 
For the planned study, subjects will receive C1NH 50U/kg (round 
to the nearest 500units) (maximum dose: 4000U) pre-operatively 
over a period of 10-20 minutes at any one point in time, from 
time of induction of anesthesia up to the beginning of renal 
vein anastomosis before graft reperfusion. For all dose 
reconstitution, Berinert® is provided in single dose vials of 
500 units. Each vial will be reconstituted in 10 ml sterile 
water for injection).  Placebo will be administered in an 
identical volume. An additional dose of Berinert® (50U/kg,actual 
body weight, maximum dose 4000U) vs. placebo will be 
administered at 24 hours post-surgery.  
4.5.4.2 Placebo Dosing 
The placebo used in this study will be 0.9% normal saline 
administered as a single intravenous infusion intra-operatively 
over a period of 10-20 minutes pre-operatively at any one point 
in time, from time of induction of anesthesia up to the 
beginning of renal vein anastomosis before graft reperfusion. 
The total volume will be identical to that calculated for 
Berinert® infusions.  
 
4.5.5 Immunosuppression 
Immunosuppression regimen is an important part of the 
care for recipients of kidney transplantation. The 
regimen to be used in this study is reflecting the 
fact that the patients enrolled into this study are 
at high risk for developing poor or delayed graft 
function.  
 
4.5.3.1 
4.5.5.1 Induction Antibody Therapy 
All patients enrolled into this study will be treated with 
induction antibody therapy with Thymoglobulin® OR Campath 1H. 
For Thymoglobulin®, the first dose will be given immediately 
after the transplantation procedure to follow with additional 
doses so that patients receive up to 6 mg/kg (1.5mg/kg/dose) 
using standard institutional treatment guidelines for use of 
this agent in this patient population. Campath 1H will be 
administered in a single 30 mg subcutaneous dose post-


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transplant. No induction administration of IL-2 receptor 
inhibitors is permitted in this protocol.  
 
4.5.5.2 Maintenance Immunosuppression 
4.5.5.2.1 Calcineurin Inhibitors (Tacrolimus or Cyclosporine) 
Tacrolimus (Prograf) and Cyclosporine (Neoral) are indicated for 
the prophylaxis of organ rejection in patients receiving 
allogeneic kidney transplants. Tacrolimus or Cyclosporine will 
be held in this study for a minimum of 24 hours post transplant 
and will be initiated and monitored with trough levels using 
standard institutional treatment guidelines for use of these 
agents in this patient population. 
 
4.5.5.2.2 Mycophenolate Mofetil(MMF) 
Mycophenolate mofetil (MMF, CellCept), the morpholinoethylester 
of mycophenolic acid, has been shown to have antiproliferative 
effects on lymphocytes by blocking proliferation of T- and B-
lymphocytes. MMF will be dosed using standard institutional 
treatment guidelines for use of these agents in this patient 
population. Myfortic can be used instead of CellCept and will be 
dosed using standard institutional treatment guidelines for use 
of these agents in this patient population. 
 
4.5.5.2.3 Corticosteroids 
Corticosteroids will be administered using standard institutional 
treatment guidelines for use of these agents in this patient 
population.  
 
4.5.6 Anti-infective Prophylaxis 
Valgancyclovir for the prophylaxis of CMV infection will be use 
for a minimum of 6 months.  
 
Ciprofloxacin will be administered at 250mg/daily X30 days for 
meningococcal prophylaxis. 
 
Local standards of care for post-transplant bacterial and fungal 
prophylaxis will be applied using standard institutional 
treatment guidelines for use of these agents in this patient 
population.  
 
C O N F I D E N T I A L  


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4.5.7 Selection And Timing Of Dose For Each Subject 
The active treatment arm (Berinert® 50U/kg, maximum dose 4000U) 
will be compared to a placebo control treatment arm, with a 
total of 35 adult subjects in each study group. A total of 70 
adult subjects will be enrolled in the study and additional 
subjects will not be enrolled to replace dropouts. This design 
is statistically powered to show differences in DGF with a 30-
50% reduction in DGF predicted for the Berinert® study group. 
Treatment effect will be investigated following intravenous 
treatment with two doses of Berinert® or an equivalent volume of 
placebo (0.9% normal saline) pre-operatively prior to graft 
reperfusion and repeated 24 hours post-transplantation. 
 
4.5.8 Blinding 
The pharmacist will be contacted by the study staff and informed 
of a patient’s eligibility.  The pharmacist will prepare the 
blinded study medication or placebo. The study treatment will be 
prepared according to a pharmacist-supplied randomization code 
(blinded from all other study personnel). The study treatment 
will be prepared in an IV syringe (total volume up to 70 ml 
Berinert® {4000U} for 80kg individual) and labeled with: 
 Protocol Number 
 Screening number  
 Randomization number. 
The blinded intravenous syringe of study treatment labeled as 
stated above will be transported to the surgical suite and 
matched with the matching patient chart. 
In case of a medical emergency, the study drug assignment for a 
particular patient may be unblinded. Unblinding study drug 
assignment will only be necessary if knowledge about treatment 
is needed for the medical management of the patient. The 
patient’s treatment assignment can be identified for unblinding 
purposes by calling the Investigational Pharmacist (310-423-
6580). When this is necessary, the investigator must immediately 
notify the Sponsor’s Medical Monitor, and document the reason 
and date of the un-blinding. The event must also be documented 
on the study termination record, the AE page of the CRF, and in 
source documents. Additionally, the Principal Investigator will 
submit to the Sponsor a written explanation describing the event 
within 5 working days. The procedures for un-blinding study drug 
treatment will be provided to the Principal Investigators prior 
to study implementation.  


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4.5.9 Treatment Compliance 
There are only two application of the drug, which takes place 
approximately 60-120 minutes prior to graft reperfusion 
administered pre-operatively and 24 hours post-transplant.  
 
4.6 
Study Variables 
4.6.1 
Efficacy Variables 
4.6.1.1 
Primary Efficacy Endpoints  
For patients who do not require dialysis in the first 7 
days: 
 Proportion of patients enrolled with serum 
creatinine >3mg/dL on postoperative day 5. 
 Proportion of patients with serum creatinine 
reduction ratio of < 30% from 24 to 48 hours post-
transplant. 
For patients who require dialysis in the first 7 days: 
(Excluding patients who get dialysis for hyperkalemia) 
 The proportion of patients enrolled who require at 
least one session of dialysis in the first 7 days 
post transplant.  
 Number of dialysis sessions per patient in the first 
7 days post transplant.  
 
4.6.1.2 
Secondary Efficacy Endpoints 
 
 Daily serum creatinine for seven days post 
transplant or until discharge. 
 Daily Calculated Creatinine Clearance for seven days 
post transplant or until discharge. 
 Serum creatinine at 14, 28, 60, and 90 days post 
transplant. 
 Total urine output in hours 16-24, 40-48 post 
transplant. 
 Rate of dialysis use at 14, 28, 60, and 90 days post 
transplant. 
 Dialysis duration at 14, 28, 60, and 90 days post 
transplant. 
 Calculated creatinine clearance at 14, 28, 60, and 90 
days post transplant. 


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 
Rate of acute cellular and antibody mediated rejection 
episodes by day 90.  
 
Patient and graft survival by day 90.  
 
 Protocol renal transplant biopsy at time of  
implantation. 
 Incidence of DGF as categorized by a DGF scale of 
increasing severity as follows:  
 
Grade 1 - immediate urine production and no need for 
dialysis with creatinine reduction ratio (CRR) between 
time 0 of transplantation and day 7 post-
transplantation >70% 
 
Grade 2 - creatinine reduction ratio (CRR) between 
time 0 of transplantation and day 7 post-
transplantation of >70% with need for dialysis 
 
Grade 3 - creatinine reduction ratio (CRR) between 
time 0 of transplantation and day 7 post-
transplantation <70% with no need for dialysis 
 
Grade 4 - creatinine reduction ratio (CRR) between 
time 0 of transplantation and day 7 post-
transplantation of <70% with need for dialysis 
 
4.6.2 
Safety Variables 
4.6.2.1 Adverse Drug Reactions: The most serious adverse 
reaction reported in subjects in clinical studies who received 
Berinert® was an increase in the severity of pain associated 
with hereditary angioedema.  In a placebo controlled clinical 
study, the incidence of adverse events occurring in more than 4% 
of subjects (n = 43) receiving Berinert® up to 72 hours after 
infusion was nausea (7%), headache (7%), abdominal pain (7%), 
dysgeusia (4.7%), vomiting (2.3%), pain (2.3%), and muscle 
spasms (2.3%).   Adverse reactions can persist 7-9 days after 
infusion and have been reported to be abdominal pain (6.5%), 
diarrhea (4.6%), nausea (6.5%), vomiting (4.6%), headache 
(11.1%), hereditary angioedema recurrence (11.1%), muscle spasm 
(5.6%), and pain (5.6%).  Subjects were tested at baseline and 
after 3 months for exposure to parvovirus B19, HBV, HCV, and 
HIV-1 and HIV-2. No subject who underwent testing evidenced 
seroconversion or treatment-emergent positive polymerase chain 
reaction testing for the above pathogens.  Post-marketing 
reports from Europe since 1979 in patients receiving Berinert® 


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for treatment of HAE include hypersensitivity/anaphylactic 
reactions, a few suspected cases of viral transmission, 
including cases of acute hepatitis C, injection-site pain, 
injection-site redness, chills, and fever. See Novation Drug 
Monograph for Berinert® (Appendix B). 
 
 
4.6.2.2 Assessment of Risk for Thrombotic Events with C1INH 
Administration: Patients with known risk factors for thrombotic 
events will be monitored for signs and symptoms of thrombosis, 
such as new onset swelling and pain in the limbs or abdomen, new 
onset chest pain, shortness of breath, loss of sensation or 
motor power, or altered consciousness, vision, or speech.  To 
address the increased risk of TE, we will apply the Well’s 
criteria for diagnosis of DVT (http://www.mdcalc.com/wells-
criteria-for-dvt)(Wells, 2003,2006,2006). Patients will be 
assessed with each infusion for evidence of DVT or other TEs. 
Those receiving a high-risk score will have lower-extremity 
Doppler venous ultrasounds to rule-out the presence of DVTs.  In 
addition, routine measurements of coagulation factors to 
evaluate DIC (D-Dimers, fibrinogen, PT, PTT) will be performed 
(See Appendix A). 
 
 
4.6.2.3 Evidence of a Thrombotic Effect of C1INH Administration 
when Given in Supraphysiologic Dosages to Humans: The German 
Medical Profession’s Drugs Committee (AkdÅ) reported on 13 cases 
of severe thrombus formation after Berinert® infusions 
Arzteblatt, 2000). These infusions were given to neonates 
undergoing cardiac surgery and doses of Berinert® were given at 
exceedingly high doses (~500U/kg) without control studies(see 
Appendix C). Nine of these infants died of this complication. 
The conclusions from this report are as follows:   
 There are no studies to support the use of C1INH outside of 
those with hereditary angioneurotic edema.  
 The use of C1INH in patients who do not have C1INH 
deficiency may result in abnormal coagulation parameters 
with propensity to thrombosis. 
 There are no controlled studies that suggests a benefit of 
C1INH therapy in conditions other than C1INH deficiency.  
 Any proposed uses outside of C1INH deficiency should be 
conducted in a controlled manner to monitor for unexpected 
or unanticipated side effects of C1INH therapy. 
 
Clearly, this is a serious and unanticipated complication of 
C1INH therapy that could potentially limit its use in patients 


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with other conditions where complement inhibition would be 
desirable. This is the case with our proposal.  Inhibition of 
complement activation post-transplant has great potential for 
prevention of complement-dependent DGF. In addition, there is an 
important unmet need for new therapeutics in the prevention and 
treatment of DGF. Despite this, it is important to assess the 
tolerability and safety of C1INH therapy in this patient 
population. Although the C1INH dosing proposed in our study is 
much less than that reported to be associated with TE (50U/kg 
twice, Days 0 & 1), there is still a possibility that increasing 
C1INH levels above normal baseline could have deleterious 
effects and induce coagulation abnormalities. Recent safety data 
from clinical trials of C1INH for use in C1INH deficiency 
(Cicardi 2010, 2010 and Zuraw 2010) have not reported TE with 
one exception of a basilar artery thrombosis in a patient 
treated for C1INH deficiency (Appendix C). This event was deemed 
unrelated to C1INH therapy. For that reason, the study will be 
randomized and patients will be monitored for DVT using the 
Wells Criteria. In addition, C1INH levels will be obtained at 
every visit and D-Dimers as well as PT/PTT will be monitored. As 
previously indicated if significant coagulation abnormalities or 
TE events are seen in any study patient, the study will be 
terminated. However, data from our recently completed study of 
C1INH in prevention of antibody-mediated rejection 
(NCT01134510)in a randomized placebo controlled study showed no 
evidence of thrombotic events in any patient treated with 
Berinert® at 20U/kg x 8 doses given during the first month post-
transplant. In addition, recent reports from the FDA (Gandhi et 
al 2012) suggests that thrombotic events do occur with C1INH 
therapy, but most cases are associated with the product 
(Cinryze®). Thus, continued surveillance will be part of this 
study.  
 
 
4.6.2.4 Evidence of a Thrombotic Effect of C1INH Administration 
when Given in Supra-physiologic Dosages to Animals:  Data on 
C1INH transgenic mice show that blood levels as high as 2mg/ml (NL 25 g/ml) are produced without reported effects 
(Vinci,2002)(Appendix D). Other investigators have shown that 
ischemia-reperfusion injury is reduced in animals transgenic for 
C1INH expression (Vinci, 2002) (Appendix D).   Data provided by 
CSL Berhing (Appendix D) shows that administration of Berinert® 
up to 200U/kg daily for 14 days had no deleterious effects and 
did not induce coagulation abnormalities.   
 
 


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4.6.2.5 Therapy Stopping Points 
As indicated previously, the study will be halted and re-
evaluated by the DSMB if any patient in the study group develops 
thrombosis of the allograft, thromboembolic events (TE) or 
evidence of coagulation abnormalities that would suggest 
impending TE. In addition, the study will be halted or stopped 
if any other known or unexpected AEs attributable to C1-
inhibitor occur.  Reassessment of the study goals and 
complications will be done and discussed with CSL Behring, the 
DSMB and FDA prior to proceeding.  
 
1.1.1.6 
Primary Safety Endpoints 
 Overall incidence of adverse events and serious adverse 
events and relationship to the study treatment 
including but not limited to, occurrence of infections, 
thrombosis of the allograft, vascular thromboses, 
bleeding, death, vital signs, and abnormal lab values. 
 
4.6.2.1 
Secondary Safety Endpoints 
 Chemistry and coagulation parameters 
 Patient survival at day 90. 
 Graft survival at day 90. 
 Rate of acute cellular and antibody mediated rejection 
episodes at day 90. 
 
4.6.3 
Assessment Periods 
4.6.3.1 
Screening Procedure – Day -30 to Day 0 
Prior to screening activities, each patient must be given an 
opportunity to ask questions and to understand the details of 
study participation. This consent process must be documented in 
the patient’s source documents and evidenced by the patient 
signing the informed consent form. 
After signing the ICF, each patient will be assigned a patient 
identifier number that will be used on all subject 
documentation. Numbers will be assigned in ascending sequential 
order. This number will also correspond to the patient number 
entered on study materials. 


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The Principal Investigator or qualified and assigned Sub-
investigator will review the inclusion and exclusion criteria 
and laboratory test data to confirm eligibility of each subject. 
The screening procedures will include the following:  
 Informed consent 
 Medical history 
 Inclusion/Exclusion criteria review 
 Vital signs/weight 
 Complete physical examination (including DVT exam) 
 12-lead ECG (w/in 6 months) 
 Chest X-ray (w/in 6 months) 
 Hematology & chemistry profile 
 PT, PTT, D-Dimer, Fibrinogen 
 Review historical serologies for HIV, HBV, HCV, CMV and EBV 
 Pregnancy test (for WOCP) 
 Urine output measurement 
 Urinalysis 
 Concomitant medications 
 Pneumococcal vaccine & Neisseria menigitides 
 
4.6.3.2 
Day 0 – Day of Transplantation 
 Inclusion/Exclusion criteria (pre-transplant) 
 Vital signs (pre- and post-transplant) 
 Physical examination (pre- and post-transplant) 
 Randomization (pre-transplant) 
 Hematology & chemistry profile (pre- and post-transplant) 
 PT, PTT and INR (pre- and post-transplant) 
 Concomitant medications (pre- and post-transplant) 
 ECG (pre-transplant) 
 Chest x-ray (pre-transplant) 


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 Serum Creatinine (pre-and post-transplant, within 4-hours 
of surgery) 
 Clinical Assessment (post-transplant) 
 Berinert vs. Placebo infusion (on call to OR) 
 C1 inhibitor, C3, C4 levels (prior to dose #1 of C1INH or 
placebo) 
 Campath 1H or Thymoglobulin administration 
  
4.6.3.3 
Day 1-7 Assessments measured daily through day 7 or 
until discharge 
 Berinert vs. Placebo infusion (24hrs post-transplant) 
 C1 inhibitor, C3, C4 levels (prior to second dose of C1INH 
or placebo) 
 
 Urine output between hours of 16-24, 40-48 post transplant 
 Concomitant medications 
 Serum creatinine measurements daily through Day 7 or until 
discharge.   
 Dialysis assessment 
 Vital Signs 
 Clinical Assessment 
 Calculated Creatinine / Calculated GFR 
 Urine output measurement 
 Adverse event assessment 
 Hematology & chemistry profile 
 PT, PTT and INR (day 1 and day 7 only) 
  
4.6.3.4 
Days 14 ± 2 days & 28 ± 2 days 
 Concomitant medications 
 Serum creatinine measurement 
 Vital Signs 


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 Dialysis assessment  
 Adverse Event Assessment 
 Clinical Assessment  
 Calculated Creatinine / Calculated GFR 
   Hematology & chemistry profile 
 
4.6.3.5 
Days 60 ± 5 days & 90 ± 5 days 
 Concomitant medications  
 Serum creatinine measurement 
 Dialysis assessment  
 Vital Signs 
 ACR assessment on Day 90 
 Adverse Event Assessment 
 Clinical Assessment  
 Calculated Creatinine / Calculated GFR 
   Hematology & chemistry profile 
 
 
4.6.4 
Observations And Measurements—see Appendix A. 
 
4.6.4.1 
Physical Examination 
A complete physical examination will include; body weight and the 
examination of the following body systems: general appearance, 
skin, HEENT (head, ears, eyes, nose, throat), cardiovascular, 
pulmonary, 
abdomen, 
neurological, 
lymph 
nodes, 
spine 
and 
extremities (skeletal). In addition, Wells Criteria Assessment 
will be done for presence of DVTs.   
 
4.6.4.2 
Clinical Assessment 
A clinical assessment will be preformed and will include a limited 
physical examination, the evaluation of the patient for clinical 
signs of infection, possible rejection, adverse events, and change 
in renal function.  Any abnormalities will be recorded on the CRF. 


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4.6.4.3 
Vital Signs 
Vital signs; including blood pressure, heart and respiratory 
rate will be measured using clinically acceptable methods and 
devices at each clinic visit. Height will be measured at the 
screening visit only. 
 
4.6.4.4 
Serum Creatinine 
Serum creatinine levels will be measured per institutional SOC. 
 
4.6.4.5 
Calculated Creatinine Clearance / Calculated GFR 
Calculated creatinine clearance and GFR will be calculated using 
the MDRD or Cockroft & Gault formula.  
 
4.6.4.6 
Serum Creatinine Reduction Ratio 
Serum creatinine reduction ratio will be calculated at 48 hours 
post transplant, using the formula described by Govani et al 
(2002).   
 
4.6.4.7 
Urine Output 
Urine output will be collected and recorded for the first 5-7 
days post-transplant. 
 
4.6.4.8 
PT, PTT and INR Tests 
PT, PTT and INR tests will be performed per institutional SOC. 
 
4.6.4.9 
Hematology and Chemistry Profile 
Hematology and Chemistry profile performed per institutional SOC 
and will include measurements of WBC, RBC, platelets, 
electrolytes, BUN, glucose, T Bili, Alb, Alk Phos, AST, ALT, BUN 
and Albumin. 
 
4.6.4.10 
ECG Testing 
An ECG will be performed per institutional SOC. 
 


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4.6.4.11 
ACR Assessment 
An acute rejection assessment will be recorded on patients who 
were diagnosed with an ACR grade ≥ Grade 2 per the Banff grading 
system and received anti-rejection therapy. 
 
4.6.4.12 
Rate and Duration of Dialysis 
Duration of dialysis will be measured by the number of sessions 
of dialysis treatment needed in the first 7 days post 
transplant.  As for rate of dialysis, one dialysis session will 
represent the need for dialysis treatment. 
 
4.6.5 
Drug Concentration Measurements 
Complement levels (C3, C4, C1INH-Function, and C1INH % activity) 
will be measured during the first week of the study period. 
 
4.7 
Data Quality 
Monitoring and auditing procedures defined/agreed by the sponsor 
will be followed, in order to comply with Good Clinical Practice 
(GCP) guidelines. Our center will be monitored at quarterly to 
ensure compliance with the study protocol, GCP and legal 
aspects. This will include on-site checking of the case report 
forms (CRF) for completeness and clarity, cross checking with 
source documents, and clarification of administrative matters. 
 
4.8 
Documentation 
Entries made in the CRF must be either verifiable against source 
documents, or have been directly entered into the CRF, in which 
case the entry in the CRF will be considered as the source data.  
The source data parameter to be verified and the identification 
of the source document must be documented. The study file and 
all source data should be retained until notification given by 
the sponsor for destruction. 
 
5 
Ethical And Legal Aspects 
5.1 
Ethics Committee (EC) Or Institutional Review Board (IRB) 
Documented approval from appropriate Ethics Committee(s)/IRBs 
will be obtained prior to study start, according to GCP, local 
laws, regulations and organizations. When necessary, an 
extension, amendment or renewal of the Ethics Committee approval 


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must be obtained and also forwarded to the sponsor.  The Ethics 
Committees must supply to the sponsor, upon request, a list of 
the Ethics Committee members involved in the vote and a 
statement to confirm that the Ethics Committee is organized and 
operates according to GCP and applicable laws and regulations. 
 
5.2 
Ethical Conduct Of The Study 
The procedures set out in this protocol, pertaining to the 
conduct, evaluation, and documentation of this study, are 
designed to ensure that the sponsor and investigator abide by 
GCP Guidelines and under the guiding principals detailed in the 
1989 version of the Declaration of Helsinki.  The study will 
also be carried out in keeping with applicable local law(s) and 
regulation(s).  This may include an inspection by the sponsor 
representatives and/or Regulatory Authority representatives at 
any time.  The investigator agrees to the inspection of study-
related records by the Regulatory Authority/sponsor 
representatives, and must allow direct access to source 
documents to the Regulatory Authority/sponsor representatives.   
Modifications to the study protocol will not be implemented by 
either the sponsor or the investigator without agreement by both 
parties. However, the investigator may implement a deviation 
form, or a change of, the protocol to eliminate an immediate 
hazard(s) to the trial subjects without prior EC/IRB/Sponsor 
approval/favorable opinion. As soon as possible, the implemented 
deviation or change, the reasons for it and if appropriate the 
proposed protocol amendment should be submitted to the 
EC/IRB/Sponsor. Any deviations from the protocol must be fully 
explained and documented by the investigator. 
 
5.3 
Regulatory Authority Approvals/Authorizations 
Regulatory Authority approvals/authorizations/ notifications, 
where required, must be in place and fully documented prior to 
study start. 
 
5.4 
Subject Information And Consent 
A core information and Informed Consent Form will be provided. 
Prior to the beginning of the study, the investigator must have 
the EC/IRB written approval/favorable opinion of the written 
Informed Consent Form and any other written information to be 
provided to subjects.  The written approval of the EC/IRB 


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together with the approved subject information/Informed Consent 
Forms must be filed in the study files. 
Written informed consent must be obtained before any study 
specific procedure takes place.  Participation in the study and 
date of informed consent given by the subject should be 
documented appropriately in the subject’s files. 
 
5.5 
Confidentiality 
All records identifying the subject will be kept confidential 
and, to the extent permitted by the applicable laws and/or 
regulations, will not be made publicly available. 
Subject names will not be supplied to the sponsor. Only the 
subject number and subject initials will be recorded in the case 
report form, and if the subject name appears on any other 
document (e.g., pathologist report), it must be obliterated 
before a copy of the document is supplied to the sponsor.  Study 
findings stored on a computer will be stored in accordance with 
local data protection laws.  The subjects will be informed in 
writing that representatives of the sponsor, EC/IRB, or 
Regulatory Authorities may inspect their medical records to 
verify the information collected, and that all personal 
information made available for inspection will be handled in 
strictest confidence and in accordance with local data 
protection laws. 
If the results of the study are published, the subject’s 
identity will remain confidential.  
The investigator will maintain a list to enable subjects’ 
records to be identified. 
 
6 
Statistical Methods And Determination Of Sample Size 
6.1 
Statistical And Analytical Plans 
6.2 
Determination of Sample Size 
 
The sample size calculations were based on a conservative 
assessment aimed to show ~50% reduction in DGF rates with C1INH 
application. Data from the Cedars-Sinai Medical Center Renal 
Transplant Program for DGF rates are shown below: 


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Briefly, the DGF rates at our center for the proposed study 
groups are >70% compared to 33% for SCD donors. Thus, a 
conservative proposal is explored below. The sample size 
calculations showing 35 subjects per group would sufficiently 
power the study (80%) to show 50% reduction when an anticipated 
DGF rate of 50% for the study group is anticipated. 
 
 
 
 
 
 
 
 
 
The “proportion” below is the proportion with DGF. 
A 2-sided test (to be more conservative) was performed. 
We assumed a 50% DGF rate in the Placebo group. 
Treated group DGF rate vary: 20%, 25%, and 30%. 
sample size per group for 80% and 90% power are shown. 
 
Two group continuity corrected 2 test of equal proportions (odds 
ratio = 1) (equal n's) 
1
2 
3
4
5
6
Test significance level, 
 
  0.050   0.050   0.050   0.050   0.050   0.050
1 or 2 sided test? 
   2
   2 
   2
   2
   2
   2
Treated Group 
proportion, 1 
 0.200
 0.250  0.300
 0.200
 0.250
 0.300
Placebo Group 
proportion, 2 
 0.500
 0.500  0.500
 0.500
 0.500
 0.500
Odds ratio,  
 = 2 (1 - 1) / [1 (1 - 
2)] 
4.000
 
3.000 
2.333
4.000
3.000
2.333
Power ( % ) 
     80      80      80      90      90      90
n per group 
 45
 66 
 103
 58
 85
 134
 
A two group continuity corrected 2 test with a 0.05 two-sided 
significance level will have 80% power to detect the difference 
between a Treated Group proportion, 1, of 0.20 and a Placebo 
Group proportion, 2, of 0.50 (odds ratio of 4.00) when the 
sample size in each group is 45. 
 


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Note: The odds ratio (OR) is the OR for DGF.  In Column 1, OR = 
4, so the odds of DGF in the Placebo group is 4 times the odds 
of DGF in the Treated group. 
 
One-sided tests: 
 
Two group continuity corrected 2 test of equal proportions (odds 
ratio = 1) (equal n's) 
1
2 
3
4
5
6
Test significance level, 
 
  0.050   0.050   0.050   0.050   0.050   0.050
1 or 2 sided test? 
   1
   1 
   1
   1
   1
   1
Treated Group 
proportion, 1 
 0.200
 0.250  0.300
 0.200
 0.250
 0.300
Placebo Group 
proportion, 2 
 0.500
 0.500  0.500
 0.500
 0.500
 0.500
Odds ratio,  
 = 2 (1 - 1) / [1 (1 - 
2)] 
4.000
 
3.000 
2.333
4.000
3.000
2.333
Power ( % ) 
     80      80      80      90      90      90
n per group 
 37
 54 
 83
 48
 71
 111
 
Statistical Assumptions 
 
 Since this study is a Phase I/II, we will primarily explore 
the safety of the proposed dose in the renal transplant 
population receiving high-risk ECD and DCD kidneys. Our 
previous experience in a population of highly-HLA 
sensitized renal allograft recipients showed that 
administration of 20U/kg (8 doses in 1 month) was safe and 
without AE or SAE when compared to placebo (NCT01134510). 
Based  on the calculations above, we propose a randomized, 
placebo controlled trial of C1INH vs. placebo entering 35 
eligible patients into both arms of the study. 
7 
Adverse Events (AEs) 
7.1 
Adverse Event (AE) Monitoring 
7.2 
Adverse Event (AE) Definitions 
7.2.1 
Adverse Events (AEs) 
An AE is any untoward medical occurrence in a subject or 
clinical investigation subject administered with a 
pharmaceutical product. The AE does not necessarily have to have 
a causal relationship with this treatment.  An AE can therefore 


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be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated 
with the use of an investigational product, whether or not 
considered related to the medicinal product. 
Adverse events associated with the use of a drug in humans, 
whether or not considered drug related, include the following:  
 An AE occurring in the course of the use of a drug 
product in professional practice, 
 An AE occurring from an overdose whether accidental or 
intentional, 
 An AE occurring from drug abuse,  
 An AE occurring from drug withdrawal.  
 An AE where there is a reasonable possibility that the 
event occurred purely as a result of the subjects 
participation in the study (e.g. adverse event or 
serious adverse event due to discontinuation of anti-
hypertensive drugs during wash-out phase) must also be 
reported as an adverse event even if it is not related 
to the investigational product. 
The clinical manifestation of any failure of expected 
pharmacological action is not recorded as an AE if it is already 
reflected as a data point captured in the CRF.  If, however, the 
event fulfills any of the criteria for a “serious” AE (SAE), it 
must be recorded and reported as such. 
 
7.2.2 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose:  
 results in death 
 is life-threatening 
 requires in-patient hospitalization or prolongation of 
existing hospitalization 
 results in persistent or significant disability or 
incapacity 
 is a congenital anomaly or birth defect 
 is an important medical event 
Life-threatening: The term “life-threatening” in the definition 
of “serious” refers to an adverse event in which the subject was 
at risk of death at the time of the event. It does not refer to 
an adverse event which hypothetically might have caused death if 
it were more severe. 


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Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
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Hospitalization: Any AE leading to hospitalization or 
prolongation of hospitalization will be considered as Serious, 
UNLESS at least one of the following exceptions are met  : 
 The admission is pre-planned (i.e., elective or 
scheduled surgery arranged prior to the start of the 
study)    
OR 
 The admission is not associated with an adverse event 
(e.g., social hospitalization for purposes of respite 
care)   
However it should be noted that invasive treatment during any 
hospitalization may fulfill the criterion of ‘medically 
important’ and as such may be reportable as an SAE dependent on 
clinical judgment.  In addition where local regulatory 
authorities specifically require a more stringent definition, 
the local regulation takes precedent. 
Disability:  a substantial disruption of a person’s ability to 
conduct normal life’s functions. 
Important medical event: Any adverse event may be considered 
serious because it may jeopardize the subject and may require 
intervention to prevent another serious condition. As guidance 
for determination of important medical events refer to the “WHO 
Adverse Reaction Terminology – Critical Terms List”. These terms 
either refer to or might be indicative of a serious disease 
state.  
Such reported events warrant special attention because of their 
possible association with a serious disease state and may lead 
to more decisive action than reports on other terms. 
SAE medwatch reports WILL NOT be filled out for any prolonged 
hospital admissions or readmissions that are related to expected 
complications of the patients’ primary disease (ESRD).  For 
example, prolonged admissions for dialysis or readmission for 
fluid overload as a consequence of ESRD since this this is an 
expected complication of the patients’ disease state and not 
related to study drug. These events will be adjudicated by the 
PI. Otherwise, all SAEs medwatch reports will be submitted to 
the IRB, study sponsor and FDA.  
 
 
7.2.3 
Unexpected Adverse Event (AE) 
An unexpected AE is any adverse drug event, the specificity or 
severity of which is not consistent with the current 


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Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
46
Investigator Brochure (or Package Insert for marketed products). 
Also, reports which add significant information on specificity 
or severity of a known, already documented adverse event 
constitute unexpected AEs. For example, an event more specific 
or more severe than described in the Investigator Brochure would 
be considered “unexpected”. Specific examples would be; (a) 
acute renal failure as a labeled adverse event with a subsequent 
new report of interstitial nephritis and (b) hepatitis with a 
first report of fulminant hepatitis. 
 
7.2.4 
Relationship Of Adverse Event To Investigational Product 
The assessment of the relationship of an AE to the 
administration of study drug is a clinical decision based on all 
available information at the time of the completion of the case 
report form. 
An assessment of ‘No’ would include: 
1. The existence of a clear alternative explanation, e.g., 
mechanical bleeding at surgical site; or 
2. Non-plausibility, e.g., the subject is struck by an 
automobile when there is no indication that the drug caused 
disorientation that may have caused the event; cancer developing 
a few days after the first drug administration.  
An assessment of ‘Yes’ indicates that there is a reasonable 
suspicion that the adverse event is associated with the use of 
the investigational drug. 
Factors to be considered in assessing the relationship of the 
adverse event to study drug include:  
 The temporal sequence from drug administration: The 
event should occur after the drug is given.  The length 
of time from drug exposure to event should be evaluated 
in the clinical context of the event 
 Recovery on discontinuation (de-challenge), recurrence 
on reintroduction (re-challenge): Subject’s response 
after drug discontinuation (de-challenge) or subjects 
response after drug re-introduction (re-challenge) 
should be considered in the view of the usual clinical 
course of the event in question 
 Underlying, concomitant, intercurrent diseases: Each 
report should be evaluated in the context of the 
natural history and course of the disease being treated 
and any other disease the subject may have 


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 Concomitant medication or treatment: The other drugs 
the subject is taking or the treatment the subject 
receives should be examined to determine whether any of 
them may be suspected to cause the event in question 
 The pharmacology and pharmacokinetics of the test drug: 
The pharmacokinetic properties (absorption, 
distribution, metabolism and excretion) of the test 
drug(s), coupled with the individual subject’s 
pharmacodynamics should be considered. 
 
7.2.5 
Severity Of The Adverse Event (AE) 
The following classification should be used: 
The severity of AEs should be graded as follows: 
Mild – usually transient in nature and generally not interfering 
with normal activities 
Moderate – sufficiently discomforting to interfere with normal 
activities 
Severe – prevents normal activities. 
 
7.2.6 
Adverse Event (AE) Documentation 
All AEs occurring after the subject has signed the informed 
consent must be fully recorded in the subject’s case record 
form. 
Documentation must be supported by an entry in the subject’s 
file.  A laboratory test abnormality considered clinically 
relevant, e.g., causing the subject to withdraw from the study, 
requiring treatment or causing apparent clinical manifestations, 
or judged relevant by the investigator, should be reported as an 
AE.  Each event should be described in detail along with start 
and stop dates, severity, relationship to investigational 
product, action taken and outcome. 
 
7.3 
Reporting of Serious Adverse Events (SAEs) or Pregnancy 
Serious adverse events (SAEs), including laboratory test 
abnormalities fulfilling the definition of serious, after 
signing the informed consent and during follow-up period must 
immediately (within 24 hours of the investigator’s awareness) be 
reported to the person detailed in the study file.  A Serious 
Adverse Event Form must also be completed within 24 hours of the 


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Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
48
investigator awareness and forwarded to the designated person as 
detailed in the study file. Each SAE must be followed up until 
resolution or stabilization by submission of updated reports to 
the designated person. 
When required, and according to local law and regulations, SAEs 
must be reported to the EC/IRB and Regulatory Authorities. 
All AEs, SAEs, and SUSARs believed or possibly attributable to 
the investigational product must be reported to CSL-Behring in 
accord with the signed Pharmacovigilance Agreement, which will 
also be included in the study file and regulatory binder.  
Pregnancy occurring during a clinical investigation, although 
not considered an SAE, must be reported to CSL-Behring Inc. 
within the same timelines as an SAE on a Pregnancy Monitoring 
Form. The outcome of a pregnancy should be followed up carefully 
and any abnormal outcome of the mother or the child should be 
reported. This also applies to pregnancies following the 
administration of the investigational product to the father 
prior to sexual intercourse. 


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Berinert® Ischemia/Reperfusion Study: V3 March 14, 2014 
49
8 
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2010 Aug 5;363(6):513-22 
 
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9 
Appendices 
Appendix A 
Study  visit 
 
Screening 
 
Transplant 
Day 0 
(Infusion #1 
C1INH vs 
Placebo) 
 
Day 1±6 
hrs 
(Infusion 
#2 C1INH 
vs 
Placebo) 
 
 
Day 
2±6 
hrs 
 
 
 
Day 
3±6 
hrs 
 
 
Day 
4±6 
hrs 
 
 
Day 
5±1 
days 
 
 
Day 
6±2 
days 
 
 
Day 
7 ±3 
days
* 
 
Day 
14 
±3 
days 
Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
Inclusion/exclusi
on criteria review 
X 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
Complete 
Physical Exam 
(Including DVT 
Exam) (1)   
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital 
signs/weight 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-lead ECG 
(w/in 6M)  
X 
 
 
 
 
 
 
 
 
 
Chest X-ray (w/in 
6M) 
X 
 
 
 
 
 
 
 
 
 
Safety laboratory 
tests (CBC, CMP) 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
PT, PTT, D. 
Dimer, 
Fibrinogen 
X 
X 
X 
 
 
 
 
 
X 
 
Review Historical 
Serologies for 
HIV, HBV, HCV, 
CMV and EBV 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test 
(for WOCP) 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
X 
Urine Output 
Measurement 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Estimated GFR 
(using MRDR or 
Cockroft & Gault 
equation) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 


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(1) DVT exam will be done on day 0 and day1  (days Berinert vs.Placebo are given)  
(2) For scores indicating high risk for DVT, patient will have Doppler ultrasound. 
*Day 4-7 assessments should be performed daily until the 
patient is discharged. 
**If patient is discharged prior to day 7, day 7 lab assessments 
should be performed.  
Allograft biopsy 
 
X 
 
 
 
 
 
 
 
 
 
Dialysis 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
x 
X 
Assessment for 
DVT (Using Wells 
Criteria Score) 
(2) 
 
X 
X 
 
 
 
 
 
X 
 
Pneumococcal 
Vaccine & 
Neiserria 
Menigitides 
X 
 
 
 
 
 
 
 
 
 
Berinert® vs 
Placebo Infusion 
 
 
X 
X 
 
 
 
 
 
 
 
 
C3, C4 Levels 
 
X 
X 
 
 
 
 
 
X  
 
C1 Inhibitor 
Level (Prior to 
each infusion)  
 
X 
X 
 
 
 
 
 
X 
 
Campath  or 
Thymoglobulin 
administration 
 
X 
 
 
 
 
 
 
 
 
Concomitant 
medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Monitoring 
 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Acute Rejection 
Assessment