Clinical trial NCT02936479
Conditions: Antibody Mediated Rejection of Kidney Transplant
Sponsor: NYU Langone Health
Start date: 2016-10-01; Completion date: 2018-10-30
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label, single arm trial in which patient who have ongoing antibody mediated rejection of a kidney transplant deemed refractory to maximal medical therapy are given the complement inhibitor C1-INH (Berinert) in an effort to protect the graft from ongoing antibody mediated injury. A maximum of 5 patients will be enrolled.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: C1-INH (Berinert)
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
  
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
 
 
 
 
 
 
 
THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY 
MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
 
 
 
 
Regulatory Sponsor: 
Robert Montgomery, M.D., D.Phil., F.A.C.S 
Transplant, Surgery 
NYU Langone Transplant Institute 
530 First Avenue, HCC 7A 
New York, New York 10016 
 
 
Funding Sponsor: 
CSL Behring 
Tel: 216-752-7729  
Study Product: 
C1 esterase inhibitor, Berinert 
Protocol Number: 
s16-01851  
IND Number: 
Exempt from IND requirements 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Initial version: [10/28/16] 
Amended: 
[n/a] 
Amended: 
[n/a] 
 
 
Clinical Research Protocol 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page ii 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Table of Contents 
 
STUDY SUMMARY ................................................................................................................................. 1 
1 
INTRODUCTION ............................................................................................................................... 2 
1.1 
BACKGROUND .............................................................................................................................. 2 
1.2 
INVESTIGATIONAL AGENT............................................................................................................... 2 
1.3 
PRECLINICAL DATA ....................................................................................................................... 2 
1.4 
CLINICAL DATA TO DATE ............................................................................................................... 3 
1.5 
DOSE RATIONALE ......................................................................................................................... 3 
1.6 
RESEARCH RISKS & BENEFITS ....................................................................................................... 3 
1.6.1 
Risk of Study Drug .............................................................................................................. 3 
1.6.2 
Other Risks of Study Participation ....................................................................................... 3 
1.6.3 
Potential benefits ................................................................................................................. 4 
2 
STUDY OBJECTIVES ....................................................................................................................... 4 
3 
STUDY DESIGN ............................................................................................................................... 4 
3.1 
GENERAL DESIGN ......................................................................................................................... 4 
3.2 
PRIMARY STUDY ENDPOINTS ......................................................................................................... 4 
3.3 
SECONDARY STUDY ENDPOINTS .................................................................................................... 5 
3.4 
PRIMARY SAFETY ENDPOINTS ........................................................................................................ 5 
4 
SUBJECT SELECTION AND WITHDRAWAL ................................................................................... 5 
4.1 
INCLUSION CRITERIA ..................................................................................................................... 5 
4.2 
EXCLUSION CRITERIA .................................................................................................................... 5 
4.3 
SUBJECT RECRUITMENT AND SCREENING ....................................................................................... 5 
4.4 
EARLY WITHDRAWAL OF SUBJECTS ................................................................................................ 6 
4.4.1 
When and How to Withdraw Subjects .................................................................................. 6 
4.4.2 
Data Collection and Follow-up for Withdrawn Subjects ........................................................ 6 
5 
STUDY DRUG .................................................................................................................................. 6 
5.1 
DESCRIPTION ............................................................................................................................... 7 
5.2 
TREATMENT REGIMEN ................................................................................................................... 7 
5.3 
METHOD FOR ASSIGNING SUBJECTS TO TREATMENT GROUPS ........................................................... 7 
5.4 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ...................................................................... 7 
5.5 
SUBJECT COMPLIANCE MONITORING .............................................................................................. 8 
5.6 
PRIOR AND CONCOMITANT THERAPY .............................................................................................. 8 
5.7 
PACKAGING ................................................................................................................................. 8 
5.8 
BLINDING OF STUDY DRUG ............................................................................................................ 8 
5.9 
RECEIVING, STORAGE, DISPENSING AND RETURN ............................................................................ 8 
5.9.1 
Receipt of Drug Supplies ..................................................................................................... 8 
5.9.2 
Storage ............................................................................................................................... 8 
5.9.3 
Dispensing of Study Drug .................................................................................................... 8 
5.9.4 
Return or Destruction of Study Drug .................................................................................... 9 
6 
STUDY PROCEDURES .................................................................................................................... 9 
6.1 
VISIT 1 ........................................................................................ ERROR! BOOKMARK NOT DEFINED. 
6.2 
VISIT 2 ........................................................................................ ERROR! BOOKMARK NOT DEFINED. 
6.3 
ETC. ............................................................................................ ERROR! BOOKMARK NOT DEFINED. 
7 
STATISTICAL PLAN ...................................................................................................................... 10 
7.1 
SAMPLE SIZE DETERMINATION ..................................................................................................... 10 
7.2 
STATISTICAL METHODS ............................................................................................................... 10 
7.3 
SUBJECT POPULATION(S) FOR ANALYSIS ...................................................................................... 11 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page iii 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
8 
SAFETY AND ADVERSE EVENTS ................................................................................................. 11 
8.1 
DEFINITIONS .............................................................................................................................. 11 
8.2 
RECORDING OF ADVERSE EVENTS ............................................................................................... 12 
8.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ................................... 13 
8.3.1 
Investigator reporting: notifying the study sponsor ............................................................. 13 
8.3.2 
Investigator reporting: notifying the IRB ............................................................................. 14 
8.3.3 
Sponsor reporting: Notifying the FDA ..................................... Error! Bookmark not defined. 
8.3.4 
Sponsor reporting: Notifying participating investigators .......... Error! Bookmark not defined. 
8.4 
UNBLINDING PROCEDURES .......................................................................................................... 15 
8.5 
STOPPING RULES ....................................................................................................................... 15 
8.6 
MEDICAL MONITORING ................................................................................................................ 15 
8.6.1 
Data Monitoring Committee ................................................... Error! Bookmark not defined. 
9 
DATA HANDLING AND RECORD KEEPING ......................... ERROR! BOOKMARK NOT DEFINED. 
9.1 
CONFIDENTIALITY ......................................................................... ERROR! BOOKMARK NOT DEFINED. 
9.2 
CONFIDENTIALITY AND HIPAA ..................................................................................................... 15 
9.3 
SOURCE DOCUMENTS ................................................................................................................. 16 
9.4 
CASE REPORT FORMS ................................................................................................................ 16 
9.5 
RECORDS RETENTION ................................................................................................................. 16 
10 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................ 16 
10.1 
STUDY MONITORING PLAN ......................................................................................................... 16 
10.2 
AUDITING AND INSPECTING ........................................................................................................ 17 
11 
ETHICAL CONSIDERATIONS ...................................................................................................... 17 
12 
STUDY FINANCES ....................................................................................................................... 18 
12.1 
FUNDING SOURCE .................................................................................................................... 18 
12.2 
CONFLICT OF INTEREST ............................................................................................................. 18 
12.3 
SUBJECT STIPENDS OR PAYMENTS ............................................... ERROR! BOOKMARK NOT DEFINED. 
13 
PUBLICATION PLAN ................................................................................................................... 18 
14 
REFERENCES .............................................................................................................................. 18 
15 
ATTACHMENTS ........................................................................................................................... 18 
 
 
 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page iv 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
List of Abbreviations 
 
 
 
 
 
 
 


[Insert short name of protocol here] 
 
page 1 
Version: 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Study Summary 
Title 
 
The role of C1 Esterase inhibitor in antibody mediated renal allograft rejection-
an open label, Phase ii, single-arm, single center trial  
 
Short Title 
Berinert AMR trial 
Protocol Number 
s16-01851  
Phase 
Phase II 
Methodology 
Open label, single-arm 
Study Duration 
6 months 
Study Center(s) 
Single-center 
Objectives 
The primary objective will be measurement of clinical and histologic resolution 
refractory acute of antibody mediated rejection (AMR) of kidney transplant. 
The secondary objective will be to estimate graft survival and to characterize 
the development of transplant glomerulopathy (TG) in patients who receive 
Berinert for AMR. 
 
Number of Subjects 
Five 
Diagnosis and Main 
Inclusion Criteria 
Diagnosis: Antibody mediated rejection; Inclusion criteria: Patients with AMR 
that is refractory to standard therapy.  
Study Product, Dose, 
Route, Regimen 
C1 esterase inhibitor, Berinert, 25-50 units/kg, intravenous, 7 doses on days 1, 
3, 5, 7, 9, 11, 13 and 50 units/kg twice weekly for a total study period of 6 
months. 
Duration of 
administration 
6 months 
Reference therapy 
10 Historical controls with refractory AMR who received standard of care 
(SOC) therapy with a combination of any or all of the following therapies – 
Plasmapheresis, IVIG, Rituximab, pulse steroids, Thymoglobulin.  
Statistical 
Methodology 
The primary outcome measure will be clinical and histologic resolution of AMR. 
Time to event distributions will be estimated by using the Kaplan-Meier 
method. The significance will be evaluated by the log-rank test. 
 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 2 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
1 Introduction 
This document is a protocol for a human research study. This study is to be conducted in accordance with 
US government research regulations, and applicable international standards of Good Clinical Practice, 
and institutional research policies and procedures. 
1.1 Background 
Antibody mediated rejection (AMR) is a major risk factor for accelerated graft loss in recipients of kidney 
transplants.  This type of rejection is associated with the presence of donor specific antibody (DSA) 
before a transplant or an anamnestic response usually in the first month after transplantation.  If left 
untreated, the acute inflammation in AMR leads to transplant glomerulopathy (TG) characterized by 
interstitial fibrosis, tubular atrophy, and rapid graft failure. If treated promptly, however, renal allografts 
can be salvaged.  The standard of care for treatment of AMR has been clearing donor specific antibodies 
by plasma exchange or immunomodulating with high dose IVIg and anti-CD20, but this process takes 
time and does nothing to minimize inflammation resulting from antibody that has already bound.  The 
inflammation in AMR is known to be regulated by the complement system, and therefore complement 
inhibitors have been explored as a potential means by which to interrupt the antibody-mediated injury at 
the level of the target tissue. Studies from independent groups demonstrate that complement inhibition 
can be effective at salvaging kidneys after severe acute AMR.  Chronic AMR from either preformed DSA 
de novo antibody occurring after the first 3 months post-transplant often does not respond to SOC 
therapy.  These patients have a significantly reduced graft half-life.  This is a significant unmet need.  We 
hypothesized that C4d positive AMR recalcitrant to SOC treatment might benefit from the addition of a 
complement inhibitor as add-on therapy.  
 
1.2 Investigational Agent 
CLINICAL PHARMACOLOGY 
 
Mechanism of Action 
C1 esterase inhibitor is a normal constituent of human plasma and belongs to the group of serine 
protease inhibitors (serpins) that includes antithrombin III, alpha1-protease inhibitor, alpha2-antiplasmin, 
and heparin cofactor II. As with the other inhibitors in this group, C1 esterase inhibitor has an important 
inhibiting potential on several of the major cascade systems of the human body, including the 
complement system, the intrinsic coagulation (contact) system, the fibrinolytic system, and the 
coagulation cascade. Regulation of these systems is achieved through the formation of complexes 
between the proteinase and the inhibitor, resulting in inactivation of both and consumption of 
the C1 esterase inhibitor. C1 esterase inhibitor, which is usually activated during the inflammatory 
process, inactivates its substrate by covalently binding to the reactive site. C1 esterase inhibitor 
is the only known inhibitor for the subcomponent of the complement component 1 (C1r), C1s, coagulation 
factor XIIa, and kallikrein. Additionally, C1 esterase inhibitor is the main inhibitor for coagulation factor XIa 
of the intrinsic coagulation cascade[1]. 
 
Pharmacodynamics and Pharmacokinetics in Hereditary Angioedema (HAE) 
Onset of symptom relief: Median: 15 minutes per attack (for HAE). 
 
Duration of action: Time to complete resolution of HAE symptoms: Median: 8.4 hours.  
 
Half-life elimination: Children and Adolescents: 22 hours (range: 20 to 24 hours). 
 
Adults (following a single dose): 22 hours (range: 17 to 24 hours)[2]. 
 
 
 
 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 3 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
1.3 Preclinical Data 
Xavier Tillou et al previously published a baboon model of preimmunization of prevention 
of acute antibody-mediated rejection by an early inhibition of the classical complement pathway using 
human recombinant C1-inhibitor. Baboons were immunized against peripheral blood mononuclear cells 
from allogeneic donors and, once a specific and stable immunization had been established, they 
received a kidney from the same donor. Rejection occurred at day 2 post-transplant in untreated 
presensitized recipients, with characteristic histological lesions and complement deposition. As 
recombinant human C1-inhibitor blocks in vitro cytotoxicity induced by donor-specific antibodies, other 
alloimmunized baboons received the drug thrice daily intravenously during the first 5 days after 
transplant. Rejection was prevented during this treatment but occurred after discontinuation of treatment. 
They showed that early blockade of complement activation by recombinant human C1-inhibitor can 
prevent acute antibody-mediated rejection in presensitized recipients[3].  
 
1.3 Clinical Data to Date 
Montgomery et al published a phase 2b, multicenter double-blind randomized placebo-controlled pilot 
study to evaluate the use of human plasma-derived C1 esterase inhibitor (C1 INH) as add-on therapy to 
standard of care for AMR. Eighteen patients received 20,000 units of C1 INH or placebo (C1 INH n = 9, 
placebo n = 9) in divided doses every other day for 2 weeks. No discontinuations, graft losses, deaths, or 
study drug-related serious adverse events occurred. While the study’s primary end point, a difference 
between groups in day 20 pathology or graft survival, was not achieved, the C1 INH group demonstrated 
a trend toward sustained improvement in renal function. These finding suggest that C1 INH may be useful 
in the treatment of AMR[4]. 
1.4 Dose Rationale 
The dosing that we propose to use in this study is based on the regimen employed in the study by 
Montgomery that is quoted in the section above. In that study patients received C1 INH every other day 
for 2 weeks (total of seven doses) as adjunct therapy to standard of care (SOC) with plasmapheresis(PP), 
IVIg, and/or anti-CD20 therapy (Rituximab). Based on PK modeling in HAE patients and assuming that 
AMR patients have ongoing C1 INH consumption, the goal was to aim for twice physiological C1 INH 
levels by dosing patients with an intravenous infusion of 5000 U C1 INH (maximum of 100 U/kg) day 1 
after the diagnosis of AMR, followed by 2500 U C1 INH (maximum of 50 U/kg) or placebo on days 3, 5, 7, 
9, 11, and 13. Most patients in this study also received  PP every other day with one volume exchange 
replaced with albumin and crystalloid in most cases or fresh frozen plasma when indicated by coagulation 
studies at the time of an invasive procedure.  We propose a similar dosing regimen for this open-label 
study. 
1.5 Research Risks & Benefits 
1.5.1 Risk of Study Drug 
Risk of Study Drug  
Adverse Reactions  
Frequency >10%: 
Headache, Nausea 
 
Frequency 1% to 10%: 
Dizziness, itching, skin rash, abdominal pain, altered sensation of taste, vomiting, dry mouth, fungal 
infection (vulvovaginal), flu-like symptoms, nasopharyngitis, upper respiratory tract infection, fever, 
infusion-related reaction. 
 
Frequency <1% (Limited to important or life-threatening):  


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 4 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Anaphylaxis (severe allergic reaction), cerebrovascular accident (stroke), chest pain, deep vein 
thrombosis(clot in vein), erythema(redness) at injection site, hypersensitivity reaction (allergic reaction), 
migraine, pain at injection site, pain (not otherwise specified), shock (severe blood pressure instability), 
swelling, transient ischemic attacks (mini stroke).  
 
We hope to prevent these aforementioned allergic reactions by pre medicating patients with 
antihistamines and low dose steroids prior to study drug infusion.  
 
Patients at greater than average risk for thrombotic events will be excluded from the study.  
 
All patients will receive prophylaxis for fungal infections and PCP pneumonia.  
1.5.2 Other Risks of Study Participation 
The primary risk, beyond study drug exposure, will be lack of efficacy of the drug and loss of the kidney 
transplant due to uncontrolled antibody mediated rejection.  We plan to minimize this risk by continuing all 
standard of care therapy in addition to the study drug. This includes any or all of plasmapheresis, IVIG, 
rituximab, splenectomy. 
1.5.3 Potential benefits 
Untreated or inadequately treated antibody mediated rejection can lead to failure of the kidney transplant 
and necessitate initiation or resumption of dialysis. Study subjects who receive Berinert may experience 
an improvement in their antibody mediated rejection of kidney transplant. This could salvage the kidney 
transplant and preclude all the risks associated with dialysis.  
2 Study Objectives 
The primary objective will to assess the efficacy of C1 inhibitor, Berinert in inducing clinical and histologic 
resolution refractory acute of antibody mediated rejection (AMR) of kidney.  
 
The secondary objective will be to estimate the glomerular filtration rate, six month graft survival, to 
characterize incidence of transplant glomerulopathy (TG) and to assess the safety and tolerability of the 
proposed regimen of C1 inhibitor. 
 
A clinical investigation of a marketed drug is exempt from the IND requirements since all of the following 
criteria for an exemption in § 312.2(b) are met:  
• The drug product is lawfully marketed in the United States.  
• The investigation is not intended to be reported to FDA as a well-controlled study in support of a new 
indication and there is no intent to use it to support any other significant change in the labeling of the 
drug.  
• In the case of a prescription drug, the investigation is not intended to support a significant change in the 
advertising for the drug.  
• The investigation does not involve a route of administration, dose, patient population, or other factor that 
significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the 
drug product (21 CFR 312.2(b)(1)(iii)).  
 
 
3 Study Design 
3.1 General Design 
 Phase II, open label, single-arm study.  
 Expected duration of subject participation-6 months.   
 As part of the study, patients will undergo 7 sessions of plasmapheresis. After each session of 
plasmapheresis, the patients will receive IVIg (100mg/kg) and the study drug, Berinert (50 units/kg 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 5 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
after the first and final sessions of plasmapheresis and 25 units/kg after the other sessions). 
Subsequently, subjects will receive Berinert 50 units/kg twice weekly for 5 additional months. The 
patients will also receive IVIg (2gm/kg) monthly for the subsequent 5 months. The patients will 
undergo a biopsy of the kidney transplant 21 days after the initiation of the study. If the biopsy 
shows persistent AMR, the patients will receive IVIg (2gm/kg) and Rituximab (375mg/m2), as per 
standard of care. Blood will be drawn for laboratory testing prior to every session of 
plasmapheresis and at periodic intervals thereafter as part of the study. Patients will be required to 
have a follow up clinic visit every 14 days for the first 2 months of the study period and monthly for 
the remainder of the study period.  
3.2 Primary Study Endpoints 
Clinical and histologic resolution of acute AMR of the transplanted kidney will be the primary endpoint. 
Clinical resolution will be defined as return of serum creatinine to within 150% of baseline serum 
creatinine level. Histologically, AMR will be defined by the Banff 2013 criteria for renal allograft pathology. 
Histologic resolution will be defined by absence of AMR by the same criteria.   
3.3 Secondary Study Endpoints 
Estimated glomerular filtration rate (eGFR by MDRD 6 equation), overall patient and graft survival, death 
censored graft survival, incidence of transplant glomerulopathy and a composite score of chronic 
pathologic lesions severity as defined by Banff 2013 criteria will be assessed as secondary end points.  
3.4 Primary Safety Endpoints 
Incidence of minor and serious adverse events will be recorded as safety measures and will be included 
as primary safety study endpoints.  
4 Subject Selection and Withdrawal 
 
 
Inclusion Criteria 
 
Living-or-deceased-donor kidney transplant recipients at least 18 years of age. 
 
Both male and female patients are eligible for enrollment. 
 
Weight ≥50 kg. 
 
Biopsy-proved AMR as defined by the Banff 2013 classification of renal allograft pathology that 
has not responded to standard of care therapy including any or all of the following – intravenous 
steroids, thymogobulin, plasmapheresis, IVIg, Rituximab. 
 
All episodes of antibody mediated rejection should have occurred more than three months after 
transplantation.  
 
Patients may have blood type incompatibility with their donor, HLA incompatibility or both.  
 
Subjects should be capable of giving informed consent. 
Exclusion Criteria 
 
Pathologic findings on kidney allograft biopsy with Banff classification ≥2 for arteriosclerosis, 
interstitial fibrosis, tubular atrophy.  
 
Confounding surgical or medical condition. 
 
Concurrent infection causing hemodynamic compromise. 
 
A history of abnormal bleeding, clotting, or any coagulopathy (excluding a history of clotted 
hemodialysis access or superficial thrombophlebitis in the absence of medically confirmed 
coagulopathy).  
 
A white blood cell count <0.5 x 109/L or >20 x 109/L or a platelet count <25 x 109/L or >600 x 109/L 
within 48 h before dosing with study drug.  
 
Pregnant or breastfeeding women.  


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 6 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
Patients who received any C1 INH (plasma-derived or recombinant), eculizumab, ecallantide, 
bortezomib within 1 month before the first dose of study drug.  
4.1 Subject Recruitment and Screening 
Subjects will be recruited from investigator or sub-investigator clinical practices. Patients who meet the 
inclusion criteria detailed above will be recruited for the study.  
 
Subjects 18 years of age or older can be included. The study is open to male and female subjects and 
individuals of all races and ethnic groups.  
 
Kidney transplant recipients who are being followed at NYU transplant institute in the practice of the 
primary investigator or one of the sub-investigators will be screened for the study. Those that meet the 
inclusion criteria and do not meet any of the exclusion criteria will be recruited to the study. The consent 
will be obtained from the study subjects by the primary investigator or one of the sub-investigators. 
Informed consent will be obtained either at the transplant ambulatory care clinic or at Tisch Hospital. The 
subjects will be given ample opportunity to peruse the informed consent documents. Any and all 
questions that the subjects may have will be addressed by the investigators. The subjects are free to 
decline their consent to participate in the study. Once the consent document is signed by the subject, it 
will be filed in the clinical charts. It will also be scanned into the subject’s chart in the EPIC electronic 
medical records and be clearly labeled for identification as a research study consent document.  
 
 
The following precautions will be observed to protect the privacy of the subjects: 
 
• The consent will be obtained at the NYU transplant institute ambulatory care clinics or at the inpatient 
service of NYU Langone Medical Center’s Tisch Hospital.  
• The subjects will be asked to provide their name, age and medical history.  
• Patient specific information will be accessible only the primary investigator, sub investigators, study 
coordinator and the study statistical analyst.  
 
4.2 Early Withdrawal of Subjects 
4.2.1 When and How to Withdraw Subjects 
Subject may be withdrawn from the study prior to the expected completion if 
 
The subject withdraws consent. 
 
Violation of study protocol. 
 
Serious adverse events including but not limited to drug related serious systemic infections and 
thrombotic events.  
 
Failure of renal allograft due to progressive rejection or any other cause of renal allograft injury.  
4.2.2 Data Collection and Follow-up for Withdrawn Subjects 
This will be an intention to treat study and even though subjects may be withdrawn prematurely from the 
study. We will collect survival data on such subjects throughout the protocol defined follow-up period for 
that subject and if the subject is not lost to follow up, we will collect all primary efficacy and safety end 
point data as well as secondary end point data.  If a subject withdraws consent to participate in the study, 
attempts will be made to obtain permission to record at least patient and graft survival data up to the 
protocol-described end of subject follow-up period.  Attempts will be made to obtain at least patient and 
graft survival data on all subjects lost to follow-up. In order to consider a subject lost to follow up, the 
subject must not be reachable despite 6 phone calls to the subject over a period of 4 weeks in addition to 
phone 4 phone calls over a period of 2 weeks to any listed next-of-kin.  
 
5 Study Drug  


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 7 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
4.3 Description 
C1 esterase inhibitor is a normal constituent of human plasma and belongs to the group of serine 
protease inhibitors (serpins). As with the other inhibitors in this group, C1 esterase inhibitor has an 
important inhibiting potential on several of the major cascade systems of the human body, including the 
complement system and the fibrinolytic system. Berinert works by blocking the effects of complement 
protein, C1. C1 esterase inhibitors are approved for the treatment and prevention of attacks of hereditary 
angioedema by the FDA. The complement system is a group of proteins that are normally present in 
human blood. These proteins play an important role in immunity against infectious disease. However, 
they also participate in rejection of transplanted organs. During rejection of a kidney transplant, activation 
of the complement system leads to injury and if insufficiently treated, ultimately to failure of the transplant. 
Therefore, inhibiting C1 is expected to prevent ongoing injury in kidney transplant that is being rejected 
and improve kidney function. Although the FDA has approved the use of C1 esterase inhibitors in 
hereditary angioedema, its use in individuals with antibody mediated rejection of the kidney transplant has 
not been approved by the FDA. A few patients with severe antibody mediated rejection have safely 
received this drug as part of research studies. However more evidence is needed before this drug can be 
approved by the FDA for routine use in patients with antibody mediated rejection. Therefore subjects that 
are consented and enrolled to be part of this study will receive C1 esterase inhibitor for an off label 
indication.  
 
Each Berinert vial contains 500 IU of C1 esterase inhibitor as a lyophilized concentrate 
for reconstitution with 10 mL of Sterile Water for Injection, USP provided. 
4.4 Treatment Regimen 
C1 esterase inhibitor, Berinert, 25-50 units/kg, intravenous, 7 doses on days 1, 3, 5, 7, 9, 11, 13 and 50 
units/kg twice weekly for a total study period of 6 months. 
 
 
 
 
4.5 Method for Assigning Subjects to Treatment Groups 
This is an open-label, single arm study. Successive patients at the investigator or the sub-investigator’s 
practice who meet the inclusion criteria and are not ruled out by the exclusion criteria will be recruited for 
the study.  
4.6 Preparation and Administration of Study Drug 
The following are instructions provided by the drug manufacturer[1].  
DOSAGE AND ADMINISTRATION 
For Intravenous Use Only. 
Berinert is provided as a freeze-dried powder for reconstitution with the Sterile Water for Injection, USP 
provided. Store the vial in the original carton in order to protect from light. Do not freeze. 
Preparation and Handling 
• Check the expiration date on the product vial label. Do not use beyond the expiration date. 
• Prepare and administer using aseptic techniques. 
• Use a silicone-free syringe for reconstitution and administration of Berinert. 
• After reconstitution and prior to administration, inspect Berinert visually for particulate matter and 
discoloration. The reconstituted solution should be colorless, clear, and free from visible particles. Do not 
use if the solution is cloudy, discolored, or contains particulates. 
• The Berinert vial is for single use only. Berinert contains no preservative. Any product that has been 
reconstituted should be used promptly. The reconstituted solution must be used within 8 hours. Discard 
partially used vials. 
• Do not freeze the reconstituted solution. 
Reconstitution and Administration 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 8 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Each Berinert vial containing 500 IU of C1 esterase inhibitor as a lyophilized concentrate for reconstitution 
with 10 mL of Sterile Water for Injection, USP provided. 
4.7 Subject Compliance Monitoring 
The study drug will be infused under direct supervision of a health care provider at Tisch Hospital, an 
NYU Langone Medical Center acute care facility or at the an NYU infusion center. This will allow subject 
compliance monitoring.  
4.8 Prior and Concomitant Therapy 
 
The following concomitant medicines/therapies are permitted during the study – intravenous 
methylprednisolone, oral prednisone, thymoglobulin, plasmapheresis, IVIg and Rituximab. Standard 
of care maintenance immunosuppressive therapy will be continued during the course of the study – 
the drugs used may include Tacrolimus, Cyclosporine, Mycophenolate, Azathioprine Prednisone. 
Certain individuals may require surgical intervention in the form of splenectomy.  
 
Patients who received any C1 INH (plasma-derived or recombinant), eculizumab, ecallantide, or 
bortezomib within 1 month before the first dose of study drug are excluded for the study. 
4.9 Packaging 
• Berinert is supplied in a single-use vial. 
• 500 IU vial of Berinert for reconstitution with 10 mL of Sterile Water for Injection, 
USP. 
• The components used in the packaging for Berinert are latex-free. 
 
Each product presentation includes a package insert and the following components: 
• Berinert in a single-use vial  
• 10 mL vial of Sterile Water for Injection 
• Mix2Vial filter transfer set 
• Alcohol swab 
4.10 Blinding of Study Drug 
This is an open label study and does not involve blinding.  
4.11 Receiving, Storage, Dispensing and Return 
4.11.1 Receipt of Drug Supplies 
The drug will be shipped directly from the manufacturer, CSL Behring, and will be received by the 
investigational pharmacy at NYU.  This is located at 160 East 34th Street, Room 610, New York, NY 
10016. 
 
4.11.2 Storage 
• When stored at temperatures of 2-25°C (36-77°F), Berinert is stable for the period 
indicated by the expiration date on the carton and vial label (up to 30 months). 
• Keep Berinert in its original carton until ready to use. 
• Do not freeze. 
• Protect from light. 
4.11.3 Dispensing of Study Drug 
Regular study drug reconciliation will be performed to document drug assigned, drug consumed, and drug 
remaining. This reconciliation will be logged on the drug reconciliation form, and signed and dated by the 
study team. 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 9 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
4.11.4 Return or Destruction of Study Drug 
At the completion of the study, there will be a final reconciliation of drug shipped, drug consumed, and 
drug remaining.  This reconciliation will be logged on the drug reconciliation form, signed and dated.  Any 
discrepancies noted will be investigated, resolved, and documented prior to return or destruction of 
unused study drug.  Drug destroyed on site will be documented in the study files.  
5 Study Procedures 
Visit 1: Day 1, 6 hours 
 
Blood draw: 3-4 teaspoons. Blood will be used to assess kidney function. Donor reactive antibody 
titers will be measured to assess the effectiveness of plasmapheresis to remove the pathogenic 
antibodies. Blood counts will be assessed to determine if they are at safe levels to allow 
performance of plasmapheresis. 
 
Plasmapheresis 
 
IVIg infusion 
 
Berinert infusion, 50 units/kg 
 
Measurement of vital signs 
Visit 2: Day 3, 6 hours 
 
Blood draw: 3-4 teaspoons. Blood will be used to assess kidney function. Donor reactive antibody 
titers will be measured to assess the effectiveness of plasmapheresis to remove the pathogenic 
antibodies. Blood counts will be assessed to determine if they are at safe levels to allow 
performance of plasmapheresis. 
 
Plasmapheresis 
 
IVIg infusion 
 
Berinert infusion, 25 units/kg 
 
Measurement of vital signs 
 
 
Visit 3: Day 5, visit duration 6 hours 
 
Blood draw: 3-4 teaspoons. Blood will be used to assess kidney function. Donor reactive antibody 
titers will be measured to assess the effectiveness of plasmapheresis to remove the pathogenic 
antibodies. Blood counts will be assessed to determine if they are at safe levels to allow 
performance of plasmapheresis. 
 
Plasmapheresis 
 
IVIg infusion 
 
Berinert infusion, 25 units/kg 
 
Measurement of vital signs 
 
Visit 4: Day 7, visit duration 6 hours 
 
Blood draw: 3-4 teaspoons. Blood will be used to assess kidney function. Donor reactive antibody 
titers will be measured to assess the effectiveness of plasmapheresis to remove the pathogenic 
antibodies. Blood counts will be assessed to determine if they are at safe levels to allow 
performance of plasmapheresis. 
 
Plasmapheresis 
 
IVIg infusion 
 
Berinert infusion, 25 units/kg 
 
Measurement of vital signs 
 
Visit 5: Day 9, visit duration 6 hours 
 
Blood draw: 3-4 teaspoons. Blood will be used to assess kidney function. Donor reactive antibody 
titers will be measured to assess the effectiveness of plasmapheresis to remove the pathogenic 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 10 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
antibodies. Blood counts will be assessed to determine if they are at safe levels to allow 
performance of plasmapheresis. 
 
Plasmapheresis 
 
IVIg infusion 
 
Berinert infusion, 25 units/kg 
 
Measurement of vital signs 
 
 
Visit 6: Day 11, visit duration 6 hours 
 
Blood draw: 3-4 teaspoons. Blood will be used to assess kidney function. Donor reactive antibody 
titers will be measured to assess the effectiveness of plasmapheresis to remove the pathogenic 
antibodies. Blood counts will be assessed to determine if they are at safe levels to allow 
performance of plasmapheresis. 
 
Plasmapheresis 
 
IVIg infusion 
 
Berinert infusion, 25 units/kg 
 
Measurement of vital signs 
 
Visit 7: Day 13, visit duration 6 hours 
 
Blood draw: 3-4 teaspoons. Blood will be used to assess kidney function. Donor reactive antibody 
titers will be measured to assess the effectiveness of plasmapheresis to remove the pathogenic 
antibodies. Blood counts will be assessed to determine if they are at safe levels to allow 
performance of plasmapheresis. 
 
Plasmapheresis 
 
IVIg infusion 
 
Berinert infusion, 50 units/kg 
 
Measurement of vital signs 
 
Visit 8: Day 21, visit duration 12 hours 
 
Ambulatory procedure – ultrasound guided kidney transplant biopsy 
 
Blood draw: 3-4 teaspoons. Blood will be used to assess kidney function. Donor reactive antibody 
titers will be measured to assess the effectiveness of plasmapheresis to remove the pathogenic 
antibodies. Blood counts and coagulation panel will be assessed to determine if they are at safe 
levels to allow performance of kidney transplant biopsy. 
 
 
Berinert 50 units/kg infusion at NYULMC infusion center twice weekly x 5 months. 
 
IVIg (2g/kg) infusion at NYULMC infusion center – once a month x 5 months.  
 
High dose IVIg(2gm/kg) and Rituximab 375 mg/m2 if biopsy on day 21 shows persistent rejection.  
 
Weekly blood draw (3-4 teaspoons) x 1 month 
 
Blood draw (3-4 teaspoons)every month x 6 months 
 
6 Statistical Plan 
6.1 Sample Size Determination 
We expect to enroll 5 patients in this study.  
6.2 Statistical Methods 
Clinical, serological and histological data will be compared between the two groups of AMR treatment 
(study arm and historical controls) using for categorical data, Fisher’s exact test or Pearson’s chi-square 
test. For continuous data, comparisons will be made using standard t -tests. Kaplan–Meier survival 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 11 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
estimates will be calculated for graft loss (dialysis or GFR ≤ 15 mL/min/1.73 m2). Graft survival curves 
were compared between the two groups using the log-rank test.  Univariate analysis will be performed to 
evaluate the association of clinical and morphologic parameters with Outcome by standard 
techniques. 
6.3 Subject Population(s) for Analysis 
Data pertaining to any subject enrolled into the study that received at least one dose of study drug will be 
analyzed.  
7 Safety and Adverse Events 
7.1 Definitions 
Unanticipated Problems Involving Risk to Subjects or Others 
Any incident, experience, or outcome that meets all of the following criteria:  
 Unexpected in nature, severity, or frequency  (i.e. not described in study-related documents such 
as the IRB-approved protocol or consent form, the investigators brochure, etc) 
 Related or possibly related to participation in the research (i.e. possibly related means there is a 
reasonable possibility that the incident experience, or outcome may have been caused by the 
procedures involved in the research) 
 Suggests that the research places subjects or others at greater risk of harm (including physical, 
psychological, economic, or social harm). 
 
 
 
 
Adverse Event 
An adverse event (AE) is any symptom, sign, illness or experience that develops or worsens in severity 
during the course of the study.  Intercurrent illnesses or injuries should be regarded as adverse events.  
Abnormal results of diagnostic procedures are considered to be adverse events if the abnormality: 
 results in study withdrawal 
 is associated with a serious adverse event 
 is associated with clinical signs or symptoms 
 leads to additional treatment or to further diagnostic tests 
 is considered by the investigator to be of clinical significance 
 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  A serious adverse event is any AE that is:  
 fatal 
 life-threatening 
 requires or prolongs hospital stay 
 results in persistent or significant disability or incapacity 
 a congenital anomaly or birth defect 
 an important medical event 
 
Important medical events are those that may not be immediately life threatening, but are clearly of major 
clinical significance.   They may jeopardize the subject, and may require intervention to prevent one of the 
other serious outcomes noted above.  For example, drug overdose or abuse, a seizure that did not result 
in in-patient hospitalization, or intensive treatment of bronchospasm in an emergency department would 
typically be considered serious.  
 
All adverse events that do not meet any of the criteria for serious should be regarded as non-serious 
adverse events.  


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 12 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 
Adverse Event Reporting Period 
The study period during which adverse events must be reported is normally defined as the period from 
the initiation of any study procedures to the end of the study treatment follow-up.  For this study, the study 
treatment follow-up is defined as six months following the last administration of study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during 
the study period. 
 
General Physical Examination Findings 
At screening, any clinically significant abnormality should be recorded as a preexisting condition.  At the 
end of the study, any new clinically significant findings/abnormalities that meet the definition of an 
adverse event must also be recorded and documented as an adverse event.  
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
investigator should instruct each subject to report any subsequent event(s) that the subject, or the 
subject’s personal physician, believes might reasonably be related to participation in this study.  The 
investigator should notify the study sponsor of any death or adverse event occurring at any time after a 
subject has discontinued or terminated study participation that may reasonably be related to this study.  
The sponsor should also be notified if the investigator should become aware of the development of 
cancer or of a congenital anomaly in a subsequently conceived offspring of a subject that has participated 
in this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if any one of the following 
conditions is met:  
 The laboratory abnormality is not otherwise refuted by a repeat test to confirm the abnormality 
 The abnormality suggests a disease and/or organ toxicity 
 The abnormality is of a degree that requires active management; e.g. change of dose, 
discontinuation of the drug, more frequent follow-up assessments, further diagnostic investigation, 
etc. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any 
condition responsible for surgery should be documented as an adverse event if the condition meets the 
criteria for and adverse event.  
 
Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse 
event in the following circumstances: 
 Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the 
purpose of the surgery was elective or diagnostic and the outcome was uneventful. 
 Hospitalization or prolonged hospitalization required to allow efficacy measurement for the study. 
 Hospitalization or prolonged hospitalization for therapy of the target disease of the study, unless it 
is a worsening or increase in frequency of hospital admissions as judged by the clinical 
investigator. 
7.2 Recording of Adverse Events 
At each contact with the subject, the investigator must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 13 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
immediately in the source document, and also in the appropriate adverse event module of the case report 
form (CRF).  All clearly related signs, symptoms, and abnormal diagnostic procedures results should 
recorded in the source document, though should be grouped under one diagnosis. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been determined that the study treatment or 
participation is not the cause.  Serious adverse events that are still ongoing at the end of the study period 
must be followed up to determine the final outcome.  Any serious adverse event that occurs after the 
study period and is considered to be possibly related to the study treatment or study participation should 
be recorded and reported immediately. 
7.3 Reporting of Serious Adverse Events and Unanticipated Problems 
Investigators and the protocol sponsor must conform to the adverse event reporting timelines, formats 
and requirements of the various entities to which they are responsible, but at a minimum those events 
that must be reported are those that are: 
 related to study participation, 
 unexpected, and  
 serious or involve risks to subjects or others  
(see definitions, section 8.1).   
 
For Narrative Reports of Safety Events 
If the report is supplied as a narrative, the minimum necessary information to be provided at the time of 
the initial report includes: 
 
Study identifier 
 
Study Center 
 
Subject number 
 
A description of the event 
 
Date of onset 
 
Current status 
 
Whether study treatment was discontinued 
 
The reason why the event is classified as serious 
 
Investigator assessment of the association 
between the event and study treatment 
7.3.1 Investigator reporting: notifying the study sponsor 
 
The following describes events that must be reported to the study sponsor in an expedited fashion. 
 
Initial Report: within 24 hours: 
The following events must be reported to the study sponsor by telephone within 24 hours of awareness of 
the event:  
 
Unanticipated problems related to study participation,  
 
Serious adverse events, regardless of whether they are unexpected.  
Additionally, an FDA Form 3500A (MEDWATCH Form; see Attachment 2) must be completed by the 
investigator and faxed to the study sponsor within 24 hours.  The investigator shall maintain a copy of the 
MEDWATCH Form on file at the study site.  
   
Sponsor: 
Robert A. Montgomery, MD DPhil 
530 First Avenue, HCC Suite 7A 
New York, NY 10016 
Office phone:  646-501-2418 
Office fax:  646-501-2419 
 
Follow-up report: within 48 hours: 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 14 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
As a follow-up to the initial report, within the following 48 hours of awareness of the event, the investigator 
shall provide further information, as applicable, on the unanticipated device event or the unanticipated 
problem in the form of a written narrative.  This should include a copy of the completed Unanticipated 
Problem form, and any other diagnostic information that will assist the understanding of the event.  
Significant new information on ongoing unanticipated adverse device effects shall be provided promptly to 
the study sponsor. 
 
Other Reportable events: 
 
Deviations from the study protocol 
Deviations from the protocol must receive both Sponsor and the investigator’s IRB approval 
before they are initiated. Any protocol deviations initiated without Sponsor and the investigator’s 
IRB approval that may affect the scientific soundness of the study, or affect the rights, safety, or 
welfare of study subjects, must be reported to the Sponsor and to the investigator’s IRB as soon 
as a possible, but no later than 5 working days of the protocol deviation. 
 
 
 
 
Withdrawal of IRB approval 
An investigator shall report to the sponsor a withdrawal of approval by the investigator’s reviewing 
IRB as soon as a possible, but no later than 5 working days of the IRB notification of withdrawal 
of approval. 
7.3.2 Investigator reporting: notifying the IRB 
 
Federal regulations require timely reporting by investigators to their local IRB of unanticipated problems 
posing risks to subjects or others.  The following describes the NYULMC IRB reporting requirements, 
though Investigators at participating sites are responsible for meeting the specific requirements of their 
IRB of record.  
 
Report Promptly, but no later than 5 working days: 
Researchers are required to submit reports of the following problems promptly but no later than 5 working 
days from the time the investigator becomes aware of the event: 
 
Unanticipated problems including adverse events that are unexpected and related 
– Unexpected: An event is “unexpected” when its specificity and severity are not accurately 
reflected in the protocol-related documents, such as the IRB-approved research protocol, any 
applicable investigator brochure, and the current IRB-approved informed consent document 
and other relevant sources of information, such as product labeling and package inserts.  
– Related to the research procedures: An event is related to the research procedures if in the 
opinion of the principal investigator or sponsor, the event was more likely than not to be 
caused by the research procedures.  
– Harmful: either caused harm to subjects or others, or placed them at increased risk 
 
Other Reportable events: 
The following events also require prompt reporting to the IRB, though no later than 5 working days: 
 Complaint of a research subject when the complaint indicates unexpected risks or the complaint 
cannot be resolved by the research team. 
 Protocol deviations or violations (includes intentional and accidental/unintentional deviations 
from the IRB approved protocol) for any of the following situations:  
– one or more participants were placed at increased risk of harm  
– the event has the potential to occur again 
– the deviation was necessary to protect a subject from immediate harm 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 15 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
 Breach of confidentiality 
 Incarceration of a participant when the research was not previously approved under Subpart C 
and the investigator believes it is in the best interest of the subject to remain on the study. 
 New Information indicating a change to the risks or potential benefits of the research, in 
terms of severity or frequency. (e.g. analysis indicates lower-than-expected response rate or a 
more severe or frequent side effect; Other research finds arm of study has no therapeutic value; 
FDA labeling change or withdrawal from market) 
 
 
 
Reporting Process 
The reportable events noted above will be reported to the IRB using the Reportable New Information 
submission” or as a written report of the event (including a description of the event with information 
regarding its fulfillment of the above criteria, follow-up/resolution and need for revision to consent form 
and/or other study documentation). 
 
Copies of each report and documentation of IRB notification and receipt will be kept in the Clinical 
Investigator’s study file. 
7.4 Unblinding Procedures 
This study will be an open label study and will not require unblinding since all enrolled patients and 
investigators are aware of the drug assignment.  
7.5 Stopping Rules  
The study will be stopped in the event of a patient death related to infusion of the study drug.  The study 
will be stopped if serious adverse events occur in multiple patients without evidence of any benefit. 
7.6 Medical Monitoring 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This 
safety monitoring will include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a site data and safety-monitoring plan (see 
section 9 Auditing, Monitoring and Inspecting).  Medical monitoring will include a regular assessment of 
the number and type of serious adverse events. 
 
7.7 Confidentiality and HIPAA 
Information about study subjects will be kept confidential and managed according to the requirements of 
the Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a 
signed subject authorization informing the subject of the following:  
 What protected health information (PHI) will be collected from subjects in this study 
 Who will have access to that information and why 
 Who will use or disclose that information  
 The rights of a research subject to revoke their authorization for use of their PHI.  
 All study subject related medical information will be extracted by review of NYU electronic medical 
records by the primary investigator and the sub-investigators. Pertinent data will entered and 
saved in excel spreadsheet format as password protected files. Only the primary investigator and 
the sub-investigators will have access to the data files. No other personnel will be granted access 
to the data files. De-identified data will be supplied to a study statistician who will analyze the data.  
 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, 
retains the ability to use all information collected prior to the revocation of subject authorization.  For 
subjects that have revoked authorization to collect or use PHI, attempts should be made to obtain 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 16 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
permission to collect at least vital status (i.e. that the subject is alive) at the end of their scheduled study 
period. 
7.8 Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a 
clinical trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in 
source documents.  Examples of these original documents, and data records include: hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, microfilm 
or magnetic media, x-rays, subject files, and records kept at the pharmacy, at the laboratories, and at 
medico-technical departments involved in the clinical trial. 
7.9 Case Report Forms 
The study case report form (CRF) is the primary data collection instrument for the study.  All data 
requested on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is 
left blank because the procedure was not done or the question was not asked, write “N/D”.  If the item is 
not applicable to the individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any 
entry error has been made, to correct such an error, draw a single straight line through the incorrect entry 
and enter the correct data above it.  All such changes must be initialed and dated.  DO NOT ERASE OR 
WHITE OUT ERRORS.  For clarification of illegible or uncertain entries, print the clarification above the 
item, then initial and date it. 
7.10 Records Retention 
It is the investigator’s responsibility to retain study essential documents for at least 2 years after the last 
approval of a marketing application in their country and until there are no pending or contemplated 
marketing applications in their country or at least 2 years have elapsed since the formal discontinuation of 
clinical development of the investigational product.  These documents should be retained for a longer 
period if required by an agreement with the sponsor.  In such an instance, it is the responsibility of the 
sponsor to inform the investigator/institution as to when these documents no longer need to be retained.  
 
8 Study Monitoring, Auditing, and Inspecting 
8.1 Study Monitoring Plan 
This study will be monitored according to the monitoring plan.  The investigator will allocate adequate 
time for such monitoring activities.  The Investigator will also ensure that the monitor or other compliance 
or quality assurance reviewer is given access to all the above noted study-related documents and study 
related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to conduct the 
monitoring visit. 
 
The study will be conducted in accordance with a data safety monitoring plan that entails a systematic, 
periodic review of data pertaining to study subjects to ensure safe and proper conduct of the study.  The 
data safety monitors will determine whether the study should continue with or without modifications or be 
stopped based on the outcome of the reviews and whether stopping criteria have been met. 
 
The data safety monitoring plan is outlined below: 
The following individuals will have the responsibility of monitoring the data 
1. Study sub-investigator - Vasishta Tatapudi, MD,  
Clinical Instructor of Medicine, Division of Nephrology, Department of Medicine, New York 
University School of Medicine. 
2. Study sub-investigator - Bonnie Lonze, MD PhD  
Assistant Professor, Department of Surgery, NYU Langone Transplant Institute. 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 17 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
Data safety monitoring reviews will be conducted every six months throughout the duration of the study 
and ad hoc reviews will be conducted in the event of occurrence of major unexpected events in the study 
population.  The study period is defined as the period from the initiation of study drug in the first subject to 
the end of the study treatment follow-up in the last enrolled subject.  For this study, the study treatment 
follow-up is defined as six months following the last administration of study treatment.  
Following every semi-annual data safety monitoring review, the study-monitors with compile a report and 
submit it to the NYU IRB.  
The following parameters will be scrutinized by the study monitors 
1. Kidney allograft (transplant) loss or failure.   
2. Patient/study subject death.  
3. Incidence of serious adverse events including but not limited to major study drug related infusion 
reactions, infections, malignancies or hospitalizations.  
4. Drop-out/withdrawal rate from the study.  
Unanticipated problems and serious adverse events related to study participation will be reported to the 
study sponsor in an expedited fashion as outlined in the study protocol. 
As required by federal regulations, unanticipated problems posing risks to subjects or others will be 
reported by investigators to their NYU IRB in a timely fashion as outlined in the study protocol.   
In addition to abiding by the aforementioned processes, the study investigators with apply stopping rules 
as outlined in the study protocol. The study will be stopped in the event of a patient death related to 
infusion of the study drug.  The study will be stopped if serious adverse events occur in multiple patients 
without evidence of any benefit. 
 
8.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/EC, the sponsor, 
government regulatory bodies, and University compliance and quality assurance groups of all study 
related documents (e.g. source documents, regulatory documents, data collection instruments, study data 
etc.).  The investigator will ensure the capability for inspections of applicable study-related facilities (e.g. 
pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable University compliance and quality assurance offices. 
9 Ethical Considerations 
 
This study is to be conducted accordance with applicable US government regulations and international 
standards of Good Clinical Practice, and applicable institutional research policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted Institutional Review Board 
(IRB) or independent Ethics Committee (EC) in agreement with local legal prescriptions, for formal 
approval of the study conduct.  The decision of the IRB/EC concerning the conduct of the study will be 
made in writing to the investigator and a copy of this decision will be provided to the sponsor before 
commencement of this study.  The investigator should provide a list of IRB/EC members and their affiliate 
to the sponsor. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  See 
Attachment 1 for a copy of the Subject Informed Consent Form.  This consent form will be submitted with 
the protocol for review and approval by the IRB/EC for the study.  The formal consent of a subject, using 
the IRB/EC-approved consent form, must be obtained before that subject undergoes any study 
procedure.  The consent form must be signed by the subject or legally acceptable surrogate, and the 
investigator-designated research professional obtaining the consent.  
 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN 
LABEL, PHASE II, SINGLE-ARM, SINGLE CENTER TRIAL  
 
Page 18 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as 
authorized in writing by the study sponsor 
In addition, describe who will obtain consent and how the process of informed consent will be structured 
to be conducive to rational and thoughtful decision making by the subject/subject’s legally authorized 
representative. If children and/ or cognitively impaired adults will be subjects, include a specific plan to 
assess comprehension during assent or the subject’s agreement Individuals who are authorized to obtain 
consent must be listed on the protocol (or FDA form 1572) and consent form document. If necessary to 
use ‘Auditor/Witness’ and/or translator, these roles would be described in this section. 
Include a plan for assessing subject capacity in cognitively impaired subjects. Describe the anticipated 
degree of impairment relative to their ability to consent and the anticipated direct benefits to the subjects. 
 
10 Study Finances 
10.1 Funding Source 
There will be no monetary funding provided for this trial.  CSL Behring will supply all drug for the study at 
no cost to the participants or the Institution.  Subjects will not be paid for participating in the study nor will 
they be charged for participation. 
10.2 Conflict of Interest 
Any investigator who has a conflict of interest with this study (patent ownership, royalties, or financial gain 
greater than the minimum allowable by their institution, etc.) must have the conflict reviewed by a properly 
constituted Conflict of Interest Committee with a Committee-sanctioned conflict management plan that 
has been reviewed and approved by the study sponsor prior to participation in this study.  All NYULMC 
investigators will follow the applicable University conflict of interest policies. 
11 Publication Plan 
 
Neither the complete nor any part of the results of the study carried out under this protocol, nor any of the 
information provided by the sponsor for the purposes of performing the study, will be published or passed 
on to any third party without the consent of the study sponsor.  Any investigator involved with this study is 
obligated to provide the sponsor with complete test results and all data derived from the study. 
12 References 
1. http://www.fda.gov/downloads/%E2%80%A6/UCM186268.pdfAuthor, Title of work, periodical and 
associated information. 
2. UpToDate®.  
3. Tillou X, Poirier N, Le Bas-Bernardet S, et al. Recombinant human C1-inhibitor prevents acute 
antibody-mediated rejection in alloimmunized baboons. Kidney Int. 2010 Jul;78(2):152-9.  
4. Montgomery RA, Orandi BJ, Racusen L et al.  Plasma-Derived C1 Esterase Inhibitor for Acute 
Antibody-Mediated Rejection Following Kidney Transplantation: Results of a Randomized 
Double-Blind Placebo-Controlled Pilot Study. Am J Transplant. 2016 May 16. 
 
13 Attachments 
1. Consent From 
2. FDA Form 3500A 
3. Study Procedures Flowchart/Table 


THE ROLE OF C1 ESTERASE INHIBITOR IN ANTIBODY MEDIATED RENAL ALLOGRAFT REJECTION-AN OPEN LABEL, PHASE II, SINGLE-ARM, SINGLE 
CENTER TRIAL  
 
Page 1 
Version: 10/28/16 
CONFIDENTIAL 
This material is the property of the NYU School of Medicine and Langone Medical Center.  Do not disclose or use except as authorized in writing by the study sponsor 
Attachment: [3] 
 
Activity 
Screening 
 
AMR 
treatment 
regimen 
[Day 1, 3, 5, 
7, 9, 11, 13] 
DSA 
screen 
 
[Day 1] 
DSA 
screen 
 
[Day 13] 
Kidney 
transplant 
biopsy 
[Day 21] 
Ritux, IVIG 
for 
persistent 
rejection 
[Window – 1 
week post 
biopsy] 
C1 INH 
periodic 
infusion 
visit 
[Twice 
weekly, 
ending at 6 
months] 
Periodic 
blood draw 
 
[Monthly 
ending at 6 
months] 
Study team procedures 
  
  
 
 
  
  
  
 
Consent 
X 
 
 
 
Medical History 
X 
 
 
 
Physical Exam 
X 
 
 
 
Height 
X 
 
 
 
Weight 
X 
 
 
 
Vitals signs 
X 
X 
X 
X 
X 
X 
 
Study drug dispensation 
 
X 
 
 
 
 
X 
 
Procedures/Infusions 
 
 
 
C1 INH  
 
X 
 
 
X 
 
Plasmapheresis 
 
X 
 
 
 
IVIG 2g/kg 
 
 
 
 
 
X 
 
 
IVIG 100 mg/kg 
 
X 
 
 
 
 
 
 
Rituximab 
 
 
 
 
 
X 
 
 
Kidney transplant biopsy 
 
 
 
 
X 
 
 
 
Laboratory Assessments 
 
 
 
 Chemistry panel 
X 
X 
 
 
X 
X 
 CBC with differential 
X 
X 
 
 
X 
X 
Tacrolimus level 
 
X 
X 
X 
X 
X 
 
X 
Urine protein/creatinine 
 
 
X 
X 
X 
 
 
X 
 Donor specific antibody (DSA) 
screening 
X 
 
X 
X 
X 
X 
 
 
Imaging Assessments 
 
 
 
Ultrasound guidance for biopsy 
 
 
X 
 
 
Formatted: Not Different first page header