Clinical trial NCT04696146
Conditions: End Stage Renal Disease Chronic Kidney Diseases
Sponsor: Cedars-Sinai Medical Center
Start date: 2021-03-03; Completion date: 2024-10-31
Enrollment: 45 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase I/II double-blind, randomized, placebo-controlled study assessing safety and limited efficacy of intraoperative C1INH (500U/kidney) vs. Placebo administered into the graft renal artery 1-2 hours prior to implantation in adult subjects receiving a deceased donor kidney allograft considered high-risk for development of DGF (KDPI\>80). 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. The drug will be administered by the transplant surgeon in the OR in a blinded manner.

Detailed description:
Pre-operative, infusion of C1INH into the renal allograft artery 1-2 hours prior to implantation will improve early graft function and reduce the rate of DGF, requirements for dialysis, graft survival and eGFR in patients receiving kidney allografts from high risk deceased donor compared to placebo.

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 94,653 people are currently waiting for a kidney transplant in the United States (UNOS.org 9/30/2019). Of the 19,360 kidney transplants performed in the US in 2018, 20% were from DCD donors and 9% from donors of KDPI\>85. The USRDS reports that more than 50% of patients on the waiting list are willing to accept a kidney from an expanded-criteria donor (KDPI \>85). This study will seek to expand the use of high KDPI kidneys and reduce wastage by showing improved function after C1INH treatment.

Patients who fulfill all I/E criteria will be eligible to be enrolled into Study

I Study Group (40 patients):

Treatment Arm I - KDPI \>80 kidneys will be infused with one intrarenal dose of 500U of Berinert® in OR prior to implantation into the recipient.

Control Arm - KDPI \>80 kidneys will be administered one intrarenal dose of normal saline (NS) in the OR in a volume identical to the volume of the dose of Berinert® before implantation of kidney into the patient.

Drug v. placebo administration will be randomized 1:1. Drug preparation and randomization will be carried out in a blinded fashion by research pharmacist.

Arms: arm 1: Berinert 500 units arm 2: Normal Saline in identical volume to Berinert
Interventions: intervention 1: Berinert intervention 2: Placebo
Intervention descriptions: intervention 1: Intrarenal dose of 500 U of Berinert intervention 2: Normal Saline placebo

Protocol documents:
Prot_SAP_000.pdf: 
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CLINICAL STUDY PROTOCOL 
Protocol Title: 
A Phase I/II, Double-Blind, Placebo-Controlled Study: 
Assessing Safety and Efficacy of Preoperative Renal 
Allograft Infusions of 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: 
 
OneLegacy 
 
IRB#469. FDA IND 15806. Version 5.0, January 26, 2022 
 
 
Incorporate Amendment: 
 
Development Phase: 
 
 
PI:  
 
 
 
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 
 
 
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 
 
 
 
 
 


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Clinical Trial Coordinator: 
Noriko Ammerman, 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: noriko.ammerman@cshs.org 
 
 
 
 
 
 
 
 
 

 


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Table of Contents 
1. 
Introduction .................................................. 7 
2. 
Hypothesis ................................................... 16 
2.1 
Study Objectives ............................................. 13 
2.2  Study Synopsis.......................................... 13 
3. 
Investigator(s) And Other Study Participants ................. 20 
4. 
Investigational Plan ......................................... 21 
4.1 
Study Design And Plan ........................................ 21 
4.1.1 Study Drug Administration Timing ............................. 21 
4.2 
Selection Of Study Population ................................ 22 
4.2.1 Inclusion Criteria ........................................... 23 
4.2.2 Exclusion Criteria ........................................... 24 
4.3 
Removal Of Subjects From Study ............................... 24 
4.4 
Premature Termination Of Study/Closure Of Center ............. 25 
4.5 
Treatments ................................................... 26 
4.5.1 Treatments To Be Administered ................................ 26 
4.5.2 Identity Of Investigational Product(s) ....................... 26 
4.5.3 Method Of Assigning Subjects To Treatment Groups ............. 27 
4.5.4 Selection Of Doses In The Study .............................. 27 
4.5.4.1 
C1INH Dosing ............................................ 27 
4.5.4.2 
Placebo Dosing .......................................... 27 
4.5.5 Immunosuppression ............................................ 27 
4.5.5.1 
Induction Antibody Therapy .............................. 27 
4.5.5.2 
Maintenance Immunosuppression ........................... 28 
4.5.5.2.1 Calcinurine Inhibitors .................................. 28 
4.5.5.2.2 Mycophenolate Mofetil ................................... 28 
4.5.5.2.3 Corticosteroids ......................................... 28 
4.5.6 Anti-infective Prophylaxis ................................... 28 
4.5.7 Selection And Timing Of Dose For Each Subject ................ 29 
4.5.8 Blinding ..................................................... 29 
4.5.9 Treatment Compliance ......................................... 30 
4.6 
Study Variables .............................................. 30 
4.6.1 Efficacy Variables ........................................... 30 
4.6.1.1 
Primary Efficacy Endpoints .............................. 30 
4.6.1.2 
Secondary Efficacy Endpoints ............................ 30 
4.6.2 Safety Variables ............................................. 31 
4.6.2.1 
Adverse Drug Reactions .................................. 32 
4.6.2.2 
Assessment of Risk for Thrombotic Events with  C1INH 
Administration ............................................... 32 
4.6.2.3 
Evidence of a Thrombotic Effect of C1INH Administration when 
Given in Supraphysiologic Dosages to Humans ............. 32 
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 ................................. 34 
4.6.2.6 
Primary Saftey Endpoints ................................ 34 
4.6.2.7 
Secondary Safety Endpoints .............................. 34 


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4.6.3     Assessment Periods ....................................... 34 
4.6.3.1 
Screening Procedure ..................................... 34 
4.6.3.2 
Day 0 - Day of Transplantation .......................... 35 
4.6.3.3 
Day 1-7 Assessments measured daily through day 7 or until 
discharge ............................................... 36 
4.6.3.4 
Day 30 ± 5 days ......................................... 37 
4.6.3.5 
Days 90, 180 ± 15 days .................................. 37 
4.6.4     Observations And Measurements ............................ 37 
4.6.4.1 
Physical Examination .................................... 37 
4.6.4.2 
Vital Signs ............................................. 38 
4.6.4.3 
Serum Creatinine ........................................ 38 
4.6.4.4 
Calculated Creatinine Clearance / Calculated GFR ........ 38 
4.6.4.5 
Urine Output ............................................ 38 
4.6.4.6 
PT, PTT and INR Tests ................................... 38 
4.6.4.7 
Hematology and Chemistry Profile ........................ 38 
4.6.4.8 
ECG Testing ............................................. 39 
4.6.4.9 
ACR Assessment .......................................... 39 
4.6.4.10 
Rate and Duration of Dialysis ........................... 39 
 
4.7 
Data Quality ................................................. 39 
4.8 
Documentation ................................................ 39 
5. 
Ethical And Legal Aspects .................................... 40 
5.1 
Ethics Committee (EC) Or Institutional Review Board (IRB) .... 40 
5.2 
Ethical Conduct Of The Study ................................. 40 
5.3 
Regulatory Authority Approvals/Authorizations ................ 40 
5.4 
Subject Information And Consent .............................. 41 
5.5 
Confidentiality .............................................. 41 
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) ......................................... 44 
7.1  Adverse Event (AE) Monitoring ................................ 44 
7.2 
Adverse Event (AE) Definitions ............................... 44 
7.2.1   Adverse Events (AEs) ....................................... 44 
7.2.2   Serious Adverse Event (SAE) ................................ 44 
7.2.3   Unexpected Adverse Event (AE) .............................. 46 
7.2.4 Relationship Of Adverse Event To Investigational Product ..... 46 
7.2.5 Severity Of The Adverse Event (AE) ........................... 47 
7.2.6 Adverse Event (AE) Documentation ............................. 47 
7.3 
Reporting of Serious Adverse Events (SAEs) or Pregnancy ...... 48 
8.0 
References ................................................... 49 
9. 
Appendices ................................................... 54 
9.1 
Calculation of GFR ........................................... 80 

 


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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 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 


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1.0 Introduction 
Delayed graft function (DGF), defined as the need for dialysis in the first 
week after kidney transplant, is estimated to occur in over 20% of deceased 
donor kidney transplants (1).  Its development is associated with an 
increased risk of rejection, poorer long-term kidney allograft function, and 
lower patient and graft survival (2,3).  This association is modified by the 
severity of DGF, as indicated by the duration of dialysis-dependence after 
transplant, where longer periods of dialysis-dependence are associated with 
progressively higher risks  of rejection and graft failure (4).  Not 
surprisingly, kidneys at higher risk for DGF are more likely to be discarded 
in the United States despite the well-documented shortage in donor organ 
supply (5,6). 
 
The predominant mechanism of DGF is ischemia-reperfusion injury.  This is 
marked by an alloantigen-independent inflammatory response, characterized by 
influx of pro-inflammatory cells early after ischemic injury (7).  
Additionally, the complement cascade can be activated in response to 
ischemia-induced membrane changes (8).  Although the alternative pathway has 
historically been thought to play the major role in ischemia-reperfusion 
injury, evidence suggests that the classical and mannose binding lectin 
(MBL) pathways are also important (9,10).  Damage-associated molecular 
patterns (DAMPs), polysaccharides, and intracellular antigens exposed during 
ischemic injury can activate both the classical and MBL pathways (11).  C4-
deficient mice, who cannot activate the classical pathway C3 convertase 
(C2aC4b), were less susceptible to ischemia-induced injury compared to wild-
type mice and antibodies against mannan-binding lectin-associated serine 
protease (MASP)-2 were protective against  ischemia-reperfusion injury in 
the murine gastrointestinal tract and myocardium (11,12).  Recent data from 
an animal model of heart transplant ischemia-reperfusion injury demonstrated 
that ischemia-reperfusion injury was largely prevented in animals that were 
genetic knockouts for the MBL collectin-11 but not for Factor B (alternative 
pathway) knockouts (10).  In addition, wild-type mice treated with C1 
esterase inhibitor were protected from ischemia-reperfusion injury, similar 
to collectin-11 (-/-). Thus, mounting experimental evidence suggests 
blockade of the classical and MBL complement pathways is a potentially 
attractive approach for prevention or mitigation of DGF caused by ischemia-
reperfusion injury. Of interest is recent data linking IRI/DGF to induction 
of B-cell injury and DSA generation post-transplant. This is discussed 
below: 
 
Evidence for B-cell Activation in Allografts Experiencing IRI/DGF 
Cippa et al (13) in an elegant article published in Nature demonstrated a 
causal relationship between IRI/DGF and subsequent B-cell activation in the 
allografts. This clearly differed from allografts not experiencing IRI/DGF 
as no B-cell signals were demonstrated on protocol biopsies. The authors 
showed that production of DSAs post-transplant was a late event reflecting 
irreversible organ damage due to IRI/DGF. The authors conclude that their 
findings point to new opportunities for early diagnosis and novel 
therapeutic interventions that could prevent or alter IRI/DGF induced immune 


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activation events in the allograft. Here, early ischemic events incite 
innate immune systems (complement activation) that ultimately leads to 
chronic injury and activation of B-cells through exposure to cryptic 
antigens resulting in DSAs. Prevention of this early IRI/DGF damage should 
limit immune activation of B-cells and DSA inducted injury later post-
transplant. See Figures 1A and 1B for the data presented in this manuscript.  
 
Fig. 1A Chronic kidney injury and B cell immunity in human allografts. Heatmap 
showing the gene expression correlation of the 120 most variably expressed genes 
across kidney biopsies collected at 3 and 12 months after transplantation (N =80). 
The names of the genes included in the cluster in the bottom right corner are 
shown. b, c RPKM values of MS4A1 (CD20) and IGKC over time in human kidney 
allograft biopsies. BL: baseline. N= 39–42 for each time point. Wilcoxon matched-
pairs signed rank test, ****P < 0.0001, **P < 0.01, *P < 0.05. d Semi-quantitative 
evaluation of immune cell infiltrates in the kidney at different time points after 
transplantation as determined by CIBERSORT analysis on RNAseq data. N = 39–42 for 
each time point. Wilcoxon matched-pairs signed rank test, **P < 0.01. e Cluster 
analysis based on the expression of B cell-associated genes including kidney 
biopsies collected at 12 months after transplantation (N= 39). Patients classified 
in the CKI group are indicated on the left. f t-SNE analysis on RNAseq data from 
kidney biopsies collected 12 months after transplantation defining the 
classification of patients in the CKI group. The boundary was determined by visual 
examination of the t-SNE plot. N = 39. g RPKM values of COL1A1 and MMP2 shown as 
examples of genes differentially expressed in CKI and non-CKI. Mean value and 
standard error (SE) are shown. Mann–Whitney test, ****P < 0.0001. (13) 
 
Data presented in this manuscript also demonstrated increased allo- and 
auto-antibody production in microarray analysis of blood from patients 
experiencing IRI/DGF post-transplant.  


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Figure 1B: Volcano plot comparison of signal-to-noise ratio in IgG reactivity in 
plasma samples collected 16–18 months after IRI (n = 6) and in age-matched controls 
(n= 6) on microarray of autoantigens, with indication of log2-fold change on the x-
axis (>0 indicates higher in IRI) and significance level. (13)  
 
1.1
Criteria for Defining IRI/DGF in Human Kidney Transplants 
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 dialyze varies from center to center and among consultants 
(14). Efforts have been made to scientifically quantify DGF in a more 
stringent manner with various alternative definitions of DGF including; (14) 
the number of days to achieve a creatinine clearance of >10 mL/min, 
calculated by the Gault-Cockroft formula (15) a serum creatinine level of >3 
mg/dL on the fifth day post-transplant (16) the need for dialysis within 72 
hours after transplantation  (17) 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 (18) 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 (19) 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) (20) and calculating the creatinine reduction ratio on day two 
following surgery  (21). 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. However, 
recent data from the FDA indicate that more relevant end points for clinical 
trials of agents aimed at reducing IRI/DGF would be need for dialysis in the 
first month post-transplant and eGFR at 1year  
(https://www.fda.gov/media/103928/download. 
 
1.2 The Kidney Donor Profile Index (KDPI) 
Key to the success of any study aimed at evaluating efficacy against IRI/DGF 
is the reasonable stratification of risk for said event. In recent years 
this has been codified using the KDPI index. The Kidney Donor Profile Index 
(KDPI) is a numerical measure that combines ten donor factors, including 
clinical parameters and demographics, to summarize into a single number the 


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quality of deceased donor kidneys relative to other recovered kidneys. The 
KDPI is derived by first calculating the Kidney Donor Risk Index (KDRI) for 
a deceased donor.  
Kidneys from a donor with a KDPI of 90%, for example, have a KDRI (which 
indicates relative risk of graft failure) greater than 90% of recovered 
kidneys. The KDPI is simply a mapping of the KDRI from a relative risk scale 
to a cumulative percentage scale. The reference population used for this 
mapping is all deceased donors in the United States with a kidney recovered 
for the purpose of transplantation in the prior calendar year. Lower KDPI 
values are associated with increased donor quality and expected longevity. 
This is shown in  figure 2 below: 
 
 
 
Figure 2: This figure shows the outcomes of kidney transplants performed 2007-2017 
based on KDPI scores. Here, the patients with the highest scores (86-100%) 
experienced the worst outcomes over time. This would suggest that kidneys donated 
from patients with high risk for IRI/DGF are unlikely to provide long-term benefits 
to patients, thus may be discarded.  
 
1.3 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 3). 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 H2O or 
activating surfaces. The deposition of complement on 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 


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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 (22) 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 (22). 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 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 
(23). 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.  
 
As previously mentioned, this field has evolved considerably in the past 2-3 
years. Recent data from a small consortium trial examined the utility of 
eculizumab (anti-C5) for prevention of IRI/DGF in a protocol similar to the 
one we previously reported with C1INH.(24)  Here, the investigators showed 
no benefit on prevention of IRI/DGF and no long term benefit in improving 
eGFR in treated v. placebo patients. This would seem to challenge the 
findings of our larger study with C1INH v. placebo where significant 
benefits in reducing IRI/DGF were seen early that translated into long-term 
benefits in graft survival and renal function (24, 25). The differences seen 
in the two trials may be explained by two important papers recently 
published. Data summarizing this information is shown below. Briefly, data 
from Sacks et al (26) (27) have recently demonstrated that the lectin 
pathway of complement activation is critical to IRI/DGF injury in animal 
models. This finding implicated IRI induced expression of fucose on renal 
tubular cells that directly binds to the MASP collectin-11. The binding of 
this serine protease activates complement through the lectin pathway 
resulting in C5b-C9MAC and C5a induced ischemic injury to tubules. This is 
shown in Figure 4 below. These authors also found that collectin-11 was 
critical to the induction of interstitial fibrosis and tubular atrophy in 
experimental models. The conundrum regarding the differences in complement 
inhibitors used in the two studies discussed above may be resolved by a 
study reported by (10)  Using a heart transplant model of IRI/DGF injury, 
these investigators examined the role of complement using specific knock-out 
mice. Here, Factor B (-/-) animals showed no benefit in prevention of 
IRI/DGF suggesting that the omission of the alternative complement 
activating pathway had no impact on prevention of IRI/DGF (10). This is 
important since the alternative pathway is best inhibited by eculizumab. In 
addition, the investigators performed similar experiments using collectin-11 
(-/-) mice. Here dramatic differences were seen with knock-out of the 
collectin-11 gene expression resulting in a significant inhibition of 


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IRI/DGF injury to allografts. This data would tend to confirm the importance 
of the interactions of collectin-11 with fucose moieties on ischemic cells 
as a critical pathway for IR injury. Further support for this contention was 
shown when the investigators used C1INH treatment in this model. Here, 
results recapitulated those seen in the collectin-11 (-/-) experiments 
suggesting that C1INH treatment may have unique benefits in preventing 
IRI/DGF injury to allografts (10). The complement activation pathways and 
their roles in IRI/DGF are shown in Figure 4 below. In addition, Figure 4 
shows the points of inhibition by C1INH that could have significance in 
prevention of IRI/DGF, specifically, the role in inhibiting collectin-11 
binding to fucose moieties on renal tubular cells.  
 
 
Figure 3: This figure shows the impact of ischemic injury on RTCs. Ischemia 
induces complement activation through the lectin pathway (MASP-> Collectin-11) 
binding to fucose moieties expressed on injured tubular epithelial cells. 
Complement injury proceeds with damage to RTC epithelium manifest as renal ischemia 
injury with long-term implications.    
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Figure 4 shows the importance of C1INH in this process. Briefly, C1INH inhibits 
early complement activation by blocking C1QRS apposition. More importantly, C1INH 
inactivates collectin-11 and other Mannose binding serine proteases, inhibiting 
their ability to bind to fucose moieties and activate the lectin pathway. These 
findings distinguish the mechanisms of action of anti-C5 v. C1INH and are supported 
by the findings of Heeger et al. who demonstrated that the beneficial effects of 
collectin-11 (-/-) could be recapitulated by using C1INH treatment.  
 
1.4 Evidence for C1INH Prevention of IRI in Animal Models
Although limited, there are recent investigations which show dramatic 
results in prevention of IRI after C1INH treatment. (28) 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-α 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 (29). 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 
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CONFIDENTIAL     C1INH (Berinert®) IRI Study in Kidney Transplant 
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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. Data from animal models of stroke induced by middle 
cerebral artery (MCA) occlusion showed that significant benefits in reducing 
infarct size were obtained with C1INH given at 20U/kg. Here, C1INH was shown 
to bind to microvasculature in the brains of animal who showed protection, 
presumable through prevention of IRI induced complement activation. (30), 
C1-inhibitor protects from brain ischemia-reperfusion injury by combined 
anti-inflammatory and antithrombotic mechanisms. 

Figure 5:  Immunohistochemistry for human C1-INHin an infarcted (left) and healthy 
contralateral (right)rat hemisphere 30 minutes after reperfusion. C1-INH 
immunoreactivity is predominantly located within brain capillaries after stroke. 
This suggest the protective effect is related to C1INH inhibition of complement 
activation on the capillary walls.  
 
1.5 Evidence for Efficacy of C1INH in Preventing IRI/DGF in Human Kidney 
Transplant Recipients 
C1 esterase inhibitor was approved by the United States Food and Drug 
Administration in 2009 for the treatment of hereditary angioedema.  C1 
esterase inhibitor is a serine protease inhibitor targeting C1s and C1r in 
the classical pathway and MASP-1 and MASP-2 in the MBL complement pathway 
and is therefore a relevant intervention to test the impact of complement 
inhibition on short- and long-term kidney function among allografts with 
ischemia-reperfusion injury.  Our group recently reported twelve-month 
outcomes of a double-blind, randomized, placebo-controlled study 
investigating the safety and efficacy of C1 esterase inhibitor among 
deceased donor kidney transplant recipients at high-risk for DGF (25).  
Salient findings from this study were a shorter duration of DGF and higher 
estimated glomerular filtration rate (eGFR) at twelve months among patients 
treated with C1 esterase inhibitor compared to placebo. From our initial 
report we showed that C1INH was associated with a ~50% reduction in need for 
dialysis in the first month post-transplant in high risk patients and a 
clinically significant improvement in eGFR at 1 year. This is shown in 


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figure 6 below. For more details please see the referenced manuscript that 
is attached as an appendix.  
 
 
Figure 6: This figure demonstrates that giving C1INH 50U/kg at time of transplant 
and @24 hrs post-transplant was associated with a near significant reduction in 
need for dialysis during the 1st month post-transplant and a significant improvement 
in eGFR at 1 year compared to placebo. The at risk population was balanced for risk 
factors associated with IRI/DGF being enriched for the risk. This data would 
suggest that prevention of early IRI/DGF has long-term implications for improving 
kidney function.  
 
We have subsequently assessed the long-term (3.5 year) outcomes of patients 
treated with C1INH v. placebo and saw that the results for improvements in 
eGFR have been sustained over the 3.5 year follow up.(31)This is also 
associated with an improved graft survival in the C1INH group and is shown 
in figures 7B and 8 below.  Briefly, in figure7A, we show that in the C1INH 
group, the eGFR is maintained at +0.5 cc/min/1.73m2/year for 3.5 years. 
However, the placebo group showed a decline of - 4.1cc/min/1.73m2/year 
(p=0.03). We also saw that the graft survival was significantly decreased in 
the patients receiving placebo (p=0.007), again suggesting that prevention 
of early IRI/DGF is associated with a beneficial long-term survival and 
function of the kidney allografts. Although not statistically significant, 
there was a numerically important reduction in DSA generation post-
transplant in the C1INH treated patients. This may be related to benefits in 
reducing ischemia-related activation of B-cells with subsequent DSA 
generation.(31) 
Time Since Transplantation (days)
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
Freedom From Dialysis Probability
0.0
0.2
0.4
0.6
0.8
1.0
3415151513131311 7 6 6 5 5 4 3 1
C1INH
3521212117161512 8 8 8 8 7 7 6 6 5 5 5 4 4 3 3 3 3 3 3 3 3 2 2
Placebo
C1INH
Placebo
N at Risk
/RJïrank p=0.136
0
25
50
75
p=0.102
p=0.017
p=0.043
p=0.006
C1INH
Placebo
eGFR (mL/min/1.73m2)
7LPHSRVWïTransplantation (days)
0
100
200
300
365


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Figure 7A: Data from our randomized placebo-controlled trial show that at 3.5 
years C1INH treatment at transplant results in a significant improvement in eGFR 
compared to placebo treatment. The slope of eGFR was -4.1 cc/min/1.73m2/year in 
placebo v. +0.5cc/min/1.73m2/year in C1INH p=0.03.  
 
 
Figure 7B: This figure shows the patient and graft survival at 3.5 years post-
C1INH. Here, we see a significant benefit in prolonging graft survival if C1INH was 
given at time of transplant. There were 3 deaths that occurred in the C1INH group 
at 2-3 years post-transplant that were not related to C1INH administration.  
 
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A summary of the data generated from our 3.5 year follow up study is shown 
below and will be published soon in the Clinical Journal of the American 
Society of Nephrology. 
 
Figure 8: A summary of the data from our 3.5 year follow-up of C1INH treatment of 
high-risk kidney allograft recipients is shown. Briefly the study was a placebo-
controlled, blinded trial of C1INH v. placebo administered to a total of 70 (35 
placebo & 35 C1INH) patients at risk for IRI/DGF. Data at 3.5 years show that C1INH 
treatment was associated with a significant improvement in eGFR and reduction in 
graft loss compared to placebo treated patients.  

2.0 Hypothesis 
Since complement activation is detectable in animal models of IRI and in 
human kidneys after IRI, 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, and since clinical data from humans 
indicate significant benefits in reducing dialysis at 1M post-transplant 
and, more importantly, significant improvements in renal function and graft 
survival 3.5 years after intravenous C1INH infusion,  we hypothesize that 
the use of C1INH perfused into the kidney prior to transplant in patients 
receiving deceased donor (DD) kidney transplants with high risk for DGF 
(KDPI >80)  will also show significant reductions in DGF and improved 
outcomes post-transplant compared with patients receiving KDPI >80 DD 
transplants receiving placebo treatment.  
 
2.1 Study Objectives 
In this study, we propose to investigate the application of pre-operative 
doses of C1INH (Berinert®)administered by infusion into the renal artery vs. 
Methods and Cohort
Outcomes
What are the 3-year outcomes of an RCT assessing the safety 
and efficacy of C1 esterase inhibitor for prevention of DGF?
Edmund Huang, Ashley Vo, Jua Choi, et al. Three-Year Outcomes of a Randomized, Double-
Blind, Placebo-Controlled Study Assessing Safety and Efficacy of C1 Esterase Inhibitor for 
Prevention of Delayed Graft Function in Deceased Donor Kidney Transplant Recipients. 
CJASN doi: 10.2215/CJN.04840419. Visual Abstract by Beatrice Concepcion, MD
Conclusion Treatment of patients at risk for ischemia-
reperfusion injury and delayed graft function with C1 esterase 
inhibitor was associated with lower incidence of graft failure.
Follow-up of 3.5 years
Post-hoc analysis of a
phase I/II RCT
70 recipients of 
deceased donor 
kidney transplants 
at risk for DGF
C1 esterase 
inhibitor 50 U/kg
Placebo
N=35
N=35
eGFR slope
ml/min/1.73m2
eGFR at 3.5y 
ml/min/1.73m2
Cumulative incidence 
of graft failures
Deaths
3
0
21%
3%
0.5 
(-4, 5)
-4 
(-8, -0.1)
56 
(42, 70)
35 
(21, 48)


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placebo, 1-2 hours prior to implantation, in adult subjects receiving a 
deceased donor renal allograft considered at high-risk for IRI and DGF 
(KDPI>80). We 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, we will:  
1. Evaluate and compare the safety of C1INH (500U/kidney) administered 
pre-transplant by surgeons in the operating room  in recipients of 
KDPI >80 kidney allografts from high risk deceased donors.  
The secondary objectives are to:  
1. Determine if Berinert® (C1INH) study dose 500U/kidney results in 
benefits of reducing need for dialysis in the 1st month post-
transplant. 
2. Determine if Berinert® (C1INH) study dose 500U/kidney results in 
benefits in improving long-term patient & graft survival and results 
in improved kidney function at 1 year compared to placebo infusions in 
the kidney. 
 
2.2 Study Synopsis 
TITLE 
A Phase I/II, Double-Blind, Placebo-Controlled Study: 
Assessing Safety and Efficacy of Intraoperative 
Intrarenal Infused  C1 Inhibitor(Human) (C1INH)vs. 
Placebo in Recipients of a Kidney Allograft from Deceased 
High Risk Donor (KDPI >80)and its impact on Risk for  
Delayed Graft Function (DGF) 
INVESTIGATIONAL 
AGENT 
C1INH (Berinert® [human][C1INH]) 
HYPOTHESIS 
Pre-operative, infusion of C1INH into the renal allograft 
artery 1-2 hours prior to implantation will improve early 
graft function and reduce the rate of DGF, requirements 
for dialysis, graft survival and eGFR in patients 
receiving kidney allografts 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.  


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More than 94,653 people are currently waiting for a 
kidney transplant in the United States (UNOS.org 
9/30/2019).  Of the 19,360 kidney transplants performed 
in the US in 2018, 20% were from DCD donors and 9% from 
donors of KDPI>85.    The USRDS reports that more than 
50% of patients on the waiting list are willing to accept 
a kidney from an expanded-criteria donor (KDPI >85). This 
study will seek to expand the use of high KDPI kidneys 
and reduce wastage by showing improved function after 
C1INH treatment.  
 
NUMBER OF PATIENTS 
AND CENTERS 
40 patients will be enrolled into the study (20 C1INH and 
20 Placebo). The study will be performed at Cedars-Sinai 
Medical Center. In 2018, we transplanted 38 kidneys into 
patients with KDPI > 85%. We anticipate the rate of 
offers from OneLegacy will continue at that rate. 
However, we would propose that 18-20 months will be 
required to complete study entry given the vagaries of 
acceptable offers and willingness of individual patients 
to participate in clinical trials.  
INVESTIGATOR / 
CLINICAL 
TRIAL LOCATION 
Stanley C. Jordan, M.D. 
Cedars-Sinai Medical Center 
STUDY OBJECTIVES 
•To evaluate and compare the safety of Berinert® (C1INH) 
500U/kidney in recipients of a kidney allograft from 
high KDPI donors (KDPI >80) receiving kidneys infused 
with Berinert® (C1INH) 500U/kidney or placebo pre-
operatively.   
•To evaluate early kidney function in recipients of a 
kidney allograft from a high KDPI donors following the 
intra-renal administration of Berinert® (C1INH) pre-
operatively compared to placebo. 
 
STUDY DESIGN 
 
Patients who fulfill all I/E criteria will be eligible to 
be enrolled into Study 
I Study Group (40 patients):  
      Treatment Arm I – KDPI >80 kidneys will be infused 
with one intrarenal dose of 500U of Berinert® in OR 
prior to implantation into the recipient. 
    Control Arm – KDPI >80 kidneys will be administered 
one intrarenal dose of normal saline (NS) in the OR in 
a volume identical to the volume of the dose of 
Berinert® before implantation of kidney into the 
patient.  
 
  Drug v. placebo administration will be randomized 1:1. 
Drug preparation and randomization will be carried out 
in a blinded fashion by research pharmacist.   
STUDY POPULATION 
 
Inclusion Criteria: 


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1) Adult men or women (18-77 years of age) who are on 
chronic dialysis therapy and acceptable candidates 
for receipt of a kidney transplant. 
2) Recipients who are ABO compatible with donor 
allograft (A2 to B offers allowable)  
3) Understand and sign a written inform consent prior 
to any study specific procedure 
4). AND one of the below criteria:  
a) Recipients of kidney allograft from KDPI >80 donors 
b) Recipients of kidney allograft from DCD donors 
c) Recipients of kidney allograft with CIT > 24 hours 
d) Recipients of kidney allograft from donor on HD/CRRT 
prior to death/procurement  
e) Recipients of kidney allograft with donor terminal 
creatinine SCr ≥3.0 mg/dL  
f) Patient risk a total risk index score of ≥3 based on 
the following: 
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Exclusion Criteria: 
1) Patients with a known pro-thrombotic disorder. (eg. 
Factor V Leiden) 
2) Patients with a history of thrombosis or 
hypercoagulable state, excluding access clotting. 
3) Patients with a history of administration of C1INH 
containing products or recombinant C1INH within 15 
days prior to study entry. 
4) Patients with a known hypersensitivity to treatment 
with C1INH. 
5) Patients with an abnormal coagulation function. (INR 
>2, PTT> 50, PLT<60,000) who are not on anti-
coagulation. 


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6) Patients with known active presence of malignancies. 
7) Patients who are PCR positive for Hep B, Hep C, or 
HIV. 
8) Recipients of pre-emptive kidney transplantation 
(unless baseline SCr is ≥4 mg/dL, making minimal 
urine output) 
9) All zero mismatch kidneys. 
10)
Recipients of multi-organ transplants. (kidney 
and any other organ) 
11)
Recipients of kidney allograft that was 
arriving on pump preservation  
12)
Recipients of kidney allograft from a living 
donor. 
13)
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 
•
Need for HD in the 1st month post-transplant. 
•
eGFR at 1M, 3M, 6M Patient and graft survival at Day 
180 
•
Rate of acute cellular rejection (ACR) and antibody 
mediated rejection at 6M 
 
EFFICACY ASSESSMENTS:  
Primary Endpoints  
Need for Dialysis in the 1st Month Post-Transplant: 
(Excluding patients who get dialysis for hyperkalemia) 
•
The proportion of patients enrolled who require 
at least one session of dialysis in the first 
30 days post transplant.  
•
Number of dialysis sessions per patient in the 
first 30 days post transplant.  
Renal Function and Graft Survival 6M 
•
eGFR at 6M post-transplant 
•
Patient & Graft survival 6M post-transplant 
 
Secondary Endpoints 
•
Rate of acute cellular and antibody mediated 
rejection episodes by day 180  
•
Calculated creatinine clearance at 1M, days 90, 
180days post transplant. 
•
Development of DSAs at 6M 
•
SOC biopsies will be assessed at time of 
implantation and 6M post implantation.  
IMUNOSUPPRESSION  
REGIMEN  
•
Induction therapy using Thymoglobulin in divided 
doses (total of 6mg/kg) or Campath 1H 30mg SQ x 1. 
•
Calcineurin inhibition (Tacrolimus or Cyclosporine) 
will be initiated as per standard practice   


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•
MMF will be started 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 
Study Timelines 
Phase 1: Patient Entry. Once the study is approved by 
CSMC IRB and contracting, we anticipate a study entry 
period of up to 18-20 months to complete study entry. 
Phase 2: Follow Up to Study Completion. The next phase of 
the study will be having each subject complete the study 
which is 6 months. Depending on our rate of entry, this 
means the study could last an additional 6 months from 
completion of patient entry. 
Phase 3: Data collection, analysis and preparation of 
manuscript. Once every patient has completed the study, 
we anticipate an additional 6M to complete data 
collection, analysis and preparation of abstract 
presentations and manuscript.  
Total Study Time: 36-40M (estimated) 
 
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, 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 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 occur. 
Please see appendix E FDA Guidance for Clinical Trial Sponsors.   
  
4. Investigational Plan  
4.1
Study Design And Plan 
This is a Phase I/II double-blind, randomized, placebo-controlled study 
assessing safety and limited efficacy of intraoperative C1INH (500U/kidney) 
vs. Placebo administered into the graft renal artery 1-2 hours prior to 
implantation in adult subjects receiving a deceased donor kidney allograft 
considered high-risk for development of DGF (KDPI>80). Once eligible 
patients are identified, consented, and have an acceptable kidney transplant 
offer, they will be randomized by the Cedars-Sinai Research Pharmacy to 


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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. The drug will be administered by the transplant surgeon in 
the OR in a blinded manner.  
 
4.1.1Study 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, 1-2 hours 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; however, we will 
administer the C1INH or placebo product at 1-2 hours prior to implantation 
for dosing consistency.  This will constitute the entirety of C1INH vs. 
placebo administration. The study format is shown below in figure 9. 
 
 
Figure 9: 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 


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enter adult patients who are mentally incompetent to give informed consent.  
Exceptions must be approved by the Study Director. 
 
Up to 40 adult men and women (18-77 years of age) who are recipients of a 
kidney transplant and only a kidney allograft from a deceased donor who is 
high risk for DGF will be enrolled in the study (KDPI >80).  
 
4.2.1
Inclusion Criteria 
Recipient Inclusion Criteria 
1). Adult men or women (18-77 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. (A2 to B offers 
allowable) 
4). AND one of the below criteria:  
a) Recipients of kidney allograft from KDPI >80 donors 
b)  Recipients of kidney allograft from DCD donors 
c)  Recipients of kidney allograft with CIT > 24 hours 
d) Recipients of kidney allograft from donor on HD/CRRT prior to 
death/procurement  
e) Recipients of kidney allograft with donor terminal creatinine SCr ≥3.0 
mg/dL  
f) Patient risk a total risk index score of ≥3 based on the following: 
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4.2.2 Exclusion Criteria 
1) Patients with a known pro-thrombotic disorder. (eg. Factor V Leiden) 


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2) Patients with a history of thrombosis or hyper-coagulable state, 
excluding access clotting. 
3) Patients with a history of administration of C1INH containing products or 
recombinant C1INH within 15 days prior to study entry. 
4) Patients with a known hypersensitivity to treatment with C1INH or blood 
products. 
5) Patients with an abnormal coagulation function. (INR >2, PTT> 50, 
PLT<60,000) who are not on anti-coagulation. 
6) Patients with known active presence of malignancies. 
7) Patients who are positive for Hep B, Hep C, or HIV PCR test. 
8) Recipients of pre-emptive kidney transplantation. (unless baseline SCr is 
≥4 mg/dL, making minimal urine output) 
9) All zero mismatch kidneys. 
10)
Recipients of multi-organ transplants. (kidney and any other organ) 
11)
Recipients of kidney allograft that was arriving on pump preservation  
12)
Recipients of kidney allograft from a living donor.  
13)
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. 
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 patient’s 
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. 


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4.4
Premature Termination Of Study/Closure Of Center 
The sponsor has the right to close this study 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) will be retained on site by 
the sponsor/investigator.  
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 20 patients in a treatment arm and 20 
patients in a placebo arm.  
This design is not statistically powered to show significant differences if 
there is a 30-50% reduction in the treatment group but may trend towards 
positive treatment effect since extensive DGF (40-50%)is expected in KDPI 
>80 recipients. The dose of C1INH chosen is (500U/kidney) which should be 
sufficient to bind all endothelial surfaces in the transplanted kidney. 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. Both groups (C1INH or placebo) will 
receive an intrarenal administration of heparinized normal saline before 
study drug administration. 
Patients who fulfill all I/E criteria will be eligible to 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 CSMC Research 
Pharmacy procedures. 
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 as 
a 500U/kidney infusion 1-2 hours prior to implantation of the KDPI >80 
kidney. Participating patients will receive 500U/kidney C1 INH vs placebo 
(0.9% NS) prior to implantation, (see Appendix A). The C1INH or placebo dose 
will be preceded by an intrarenal administration of heparinized normal 
saline. 
 


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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. 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 500U/kidney infused into 
the renal artery pre-operatively 1-2 hours before graft reperfusion. For all 
dose reconstitutions, 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. C1INH will be preceded 
by an intrarenal administration of heparinized normal saline prior to renal 
vein anastomosis. 
 
4.5.4.2 Placebo Dosing 
The placebo used in this study will be 0.9% normal saline administered as a 
single dose into the renal artery, 1-2 hours before graft reperfusion. The 
total volume will be identical to that calculated for Berinert® infusions. 
Placebo will be preceded by an intrarenal administration of heparinized 
normal saline prior to renal vein anastomosis. 
 
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.  
 
4.5.5.1 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-transplant. No induction 
administration of IL-2 receptor inhibitors is permitted in this protocol.  
 


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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 initiated and monitored 
with trough levels using standard institutional treatment guidelines for 
use of these agents in this patient population. If conversion to belatacept 
is deemed necessary per SOC process, this is allowable during study 
participation 
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 used for a 
minimum of 6 months. If PO administration of valgancyclovir is not possible, 
the use of ganciclovir while the patient is inpatient is also permissible.  
 
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.  
 
4.5.7 Selection And Timing Of Dose For Each Subject 
The active treatment arm (Berinert® 500U/kidney) will be compared to a 
placebo control treatment arm, with a total of 20 adult subjects in each 
study group. A total of 40 adult subjects will be enrolled in the study and 
additional subjects will not be enrolled to replace dropouts. This design is 
not statistically powered to show differences in DGF; a 30-50% reduction in 
DGF predicted for the Berinert® study group. Treatment effect will be 
investigated following renal artery infusion with Berinert® or an equivalent 
volume of placebo (0.9% normal saline) pre-operatively prior to graft 
reperfusion.  The C1INH or placebo dose will be preceded by an intrarenal 
administration of heparinized normal saline. 
If a patient is enrolled into the study but the transplant does not occur as 
planned (e.g. transplant is cancelled due to donor organ quality at time of 
transplant), the patient will be considered a “screening without 
transplant”. The patient will be maintained on the study ID # that was 
assigned 
 
 	     	     


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at enrollment but will not be followed past the screening day. IF the 
patient receives another transplant offer (at any time while study 
enrollment is still open), the patient will be allowed to continue with the 
study protocol, with Day of Transplant = Day 0, as if the screening and 
consenting occurred during the current admission.  
 
4.5.8 Blinding 
The investigational drug 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 a non-
siliconized sterile syringe (Berinert® {500U} for all individuals) and 
labeled with: 
•
Protocol Number 
•
Screening number  
•
Randomization number. 
The pharmacist will check the non-siliconized IV syringe for potential 
particulates. If none are found, the blinded syringe of study treatment, 
labeled as stated above, will be transported to the surgical suite and 
matched with the matching patient chart. For the placebo arm, an equivalent 
volume of normal saline will be prepared in an identical dispensing medium 
as the C1INH product, labeled as stated above, and transported to the 
surgical suite and matched with the matching patient chart. Before the study 
treatment (Berinert or placebo), heparinized normal saline will be 
administered to the allograft. This method of drug administration has not 
been FDA approved and may have unforeseen risks  
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 
IRB, 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 IRB 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.  
4.5.9 Treatment Compliance 
There is only one application of the drug, which takes place approximately 
60-120 minutes prior to graft reperfusion administered pre-operatively.  


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4.6
Study Variables 
4.6.1
Efficacy Variables 
4.6.1.1Primary Efficacy Endpoints  
For patients who require dialysis in the first 30 days: (Excluding 
patients who get dialysis for hyperkalemia) 
•
The proportion of patients enrolled who require at least one 
session of dialysis in the first 30 days post transplant.  
•
Number of dialysis sessions per patient in the first 30 days 
post-transplant.  
Renal function and graft survival 6M 
•
eGFR at 6M post-transplant 
•
Patient and graft survival at 6M post-transplant 
 
4.6.1.2Secondary Efficacy Endpoints 
•
Calculated Creatinine Clearance obtained at 1M, 3M, 6M post-transplant.  
•
Rate of acute cellular and antibody mediated rejection episodes by day 
180  
•
Development of DSAs at 6M 
•
Analysis of renal transplant biopsies at time of implantation and at 6M 
as clinically indicated. 
 
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® 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®. Berinert® was well tolerated with minimal 
AE/SAE profile in our kidney transplant studies (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 


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limbs or abdomen, new onset chest pain, shortness of breath, loss of 
sensation or motor power, or altered consciousness, vision, or speech. 
Patients will be assessed for evidence of DVT or other TEs per the usual 
standard process. Routine measurements of coagulation factors to evaluate 
DIC (D-Dimers, fibrinogen, PT, PTT) will be performed per standard process. 
 
 
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. 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 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 and well below therapeutic dosing recommendations (20-50U/kg) 
(500U/kidney once on Day 0), and will be administered intra-renally, 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 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. 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) suggests that thrombotic events do occur with C1INH therapy, 
but most cases are associated with the product (Cinryze®).  
 
 


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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 μg/ml) are produced without 
reported effects (34)(Appendix D). Other investigators have shown that 
ischemia-reperfusion injury is reduced in animals transgenic for C1INH 
expression (Appendix D).   Data provided by CSL Behring (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.   
 
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 the DSMB prior to proceeding. A summary report will be submitted to the 
IRB and FDA. 
4.6.2.6 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. 
4.6.2.7 Secondary Safety Endpoints 
•
Chemistry and coagulation parameters 
•
eGFR at 1M, 3M, 6M 
•
Patient survival at day 180 
•
Graft survival at day 180 
•
Rate of acute cellular and antibody mediated rejection episodes 
at day 180 
•
Rate of de novo Donor Specific Antibody (DSA) development 
4.6.3
Assessment Periods 
4.6.3.1Screening Procedure –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. 
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:  


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•
Informed consent 
•
Medical history 
•
Inclusion/Exclusion criteria review 
•
Vital signs/weight 
•
Complete physical examination  
•
Hematology & chemistry profile 
•
Record PT, PTT, INR collected by SOC 
•
Review historical serologies for HIV, HBV, HCV, CMV and EBV, collected 
by SOC  
•
Concomitant medications 
•
Review of previous Pneumococcal vaccination  
•
Review of Pregnancy test (for WOCP, Age 12-55 years old) 
 
4.6.3.2Day 0 – Day of Transplantation 
•
Vital signs (pre- and post-transplant) 
•
Physical examination (pre- and post-transplant) 
•
Randomization (pre-transplant) 
•
Hematology & chemistry profile (pre- and post-transplant) 
•
Record PT, PTT and INR collected by SOC (pre-transplant) 
•
Concomitant medications (pre- and post-transplant) 
•
ECG (pre-transplant) 
•
Chest x-ray (pre-transplant) 
•
Serum Creatinine (pre-and post-transplant) 
•
Berinert vs. Placebo infusion (on call to OR) with heparinated saline 
•
Campath 1H or Thymoglobulin administration 
•
Assessment of implantation biopsy (if collected) 
•
Urine output measurement if producing urine (post-transplant) 
•
Adverse event assessment 
•
Dialysis assessment 
 
4.6.3.3Day 1-7 Assessments measured on days 1, 3 and 7 (or until discharge) 
•
Concomitant medications 
•
Serum creatinine measurements through Day 7 or until discharge.   
•
Dialysis assessment 
•
Physical examination 
•
Vital Signs/weight 
•
Calculated estimated GFR 
•
Record Urine output measurement if producing urine 
•
Adverse event assessment 
•
Hematology & chemistry profile 
•
Urinalysis if producing urine. Urinary IL-18 to be collected on two 
days, between day 1 to 7, if producing urine and testing is available 
 


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4.6.3.4Day 30 ± 7 days 
•
Concomitant medications 
•
Physical examination (may occur as a video visit) 
•
Vital Signs/weight 
•
Dialysis assessment  
•
Adverse Event Assessment 
•
Calculated estimated GFR 
•
  Hematology & chemistry profile 
•
Urinalysis  
 
4.6.3.5Days 90, 180 ±30 days 
•
Concomitant medications  
•
Physical examination(may occur as a video visit) 
•
Dialysis assessment  
•
Vital Signs/weight 
•
Adverse Event Assessment 
•
Calculated estimated GFR 
•
  Hematology & chemistry profile 
•
Urinalysis  
•
ACR assessment on Day 180  
•
Assessment of SOC biopsies on Day 180 
•
Patient survival assessment on day 180 
•
Graft survival assessment on day 180 
•
Donor Specific Antibody (DSA) assessment at Day 180 
 
4.6.4
Observations And Measurements—see Appendix A. 
 
4.6.4.1Physical Examination 
A complete physical examination will include;  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). Patient visits may occur as video visits with the 
MD as per standard of care procedures.  
 
4.6.4.2Vital 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. 
 
4.6.4.3Serum Creatinine 
Serum creatinine levels will be measured per institutional SOC. 
 
4.6.4.4Calculated GFR 
Estimated GFR will be calculated using the MDRD formula.  
 


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4.6.4.5Urine Output 
Urine output will be collected and recorded for the first 0-7 days post-
transplant, until patient discharge. 
 
4.6.4.6PT, PTT and INR Tests 
PT, PTT and INR tests will be performed per institutional SOC. 
 
4.6.4.7Hematology and Chemistry Profile 
Hematology and Chemistry profile performed per institutional SOC  
 
4.6.4.8ECG Testing 
An ECG will be performed per institutional SOC. 
 
4.6.4.9ACR 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. 
 
4.6.4.10
Rate and Duration of Dialysis 
Duration of dialysis will be measured by the number of sessions of dialysis 
treatment needed in the first 30 days post transplant.  As for rate of 
dialysis, one dialysis session will represent the need for dialysis 
treatment. 
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 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 IRB approval must be 
obtained and retained in site files.  IRB must supply to the sponsor, upon 
request, a list of the IRB Committee members involved in the vote and a 
statement to confirm that the IRB Committee is organized and operates 
according to GCP and applicable laws and regulations. 
 


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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 
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 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 
The Informed Consent Form (ICF) will be provided. Prior to the beginning of 
the study, the investigator must have the 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 IRB 
together with the approved subject information/ICF 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. 
Discussion of the study with the patient will occur in person or via phone. 
While patients may be approached soon after their visit and/or admission 
begins, they can take time to consider and discuss participation with others 
before deciding. All questions will be answered by an investigator prior to 
signing the consent form. In rush/emergency transplant cases, the study will 
not be offered. If the patient wishes to enroll in the study, consenting 
will occur in person with a paper ICF or via phone conversation using 
DocuSign. The process followed will be fully documented with a consent 
progress note. 
 


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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 

Determination of Sample Size
Since this pilot study will be looking at feasibility and safety of a novel 
method of administration of C1INH, sample size determination was not 
performed. 

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 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.  


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• 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. 
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.  


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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, 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 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 subject’s response after drug re-introduction (re-
challenge) should be considered in the view of the usual clinical course 
of the event in question 


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•
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 
•
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 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 IRB and Regulatory Authorities. 
All AEs, SAEs, and SUSARs believed or possibly attributable to the 
investigational product must be reported to the IRB and FDA in accordance 


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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 the IRB 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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8
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27. Weiju Wu, Chengfei Liu, Conrad A. Farrar, Liang Ma, Xia Dong, Steven 
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35. Gandhi P, Gentry W, Bottorff M. Thrombotic events associated with C1 esterase 
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9
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CONFIDENTIAL     C1INH (Berinert®) IRI Study in Kidney Transplant 
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




                 Appendix B 


CONFIDENTIAL     C1INH (Berinert®) IRI Study in Kidney Transplant 
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



	


CONFIDENTIAL     C1INH (Berinert®) IRI Study in Kidney Transplant 
	








CONFIDENTIAL     C1INH (Berinert®) IRI Study in Kidney Transplant 
	





 
Appendix C 


CONFIDENTIAL     C1INH (Berinert®) IRI Study in Kidney Transplant 
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




 
Appendix D 
 
 
Appendix E  
  
 
9.1
Calculation of GFR from age, gender, race, urea, 
creatinine and albumin (MDRD equation) (Levey et al, 
1999; Tattersall, 2003) 
Albumin in g/dL, age in years. GFR in mL/min/1.73 m2.  
 
Multiply by 1.18 if patient is black. Multiply by 0.762 if 
patient is female. 
 
SI units (Creatinine in μmol/L, Urea in mmol/L) 
GFR = 170 x (Creat x 0.0113)-0.999 x age-0.176 x (Urea x 2.8)-
0.17 x Alb0.318 
 
US units (Creatinine in mg/dL, BUN in mg/dL) 
GFR = 170 x Creat-0.999 x age-0.176 x BUN-0.17 x Alb0.318 
 
 
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