Berinert (C1INH) vs Placebo for DGF/IRI

Study Overview
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Brief Summary
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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
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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.

Official Title
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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)

Conditions
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End Stage Renal Disease, Chronic Kidney Diseases

Intervention / Treatment
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* Drug: Berinert
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult men or women (18-70 years of age) who are on chronic dialysis therapy and acceptable candidates for receipt of a kidney transplant. Recipients who are ABO compatible with donor allograft Understand and sign a written inform consent prior to any study specific procedure Women of childbearing potential must have a negative pregnancy test prior to randomization, and must be on an acceptable form of birth control. . 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 Exclusion Criteria: Patients with a known pro-thrombotic disorder. (eg. Factor V Leiden) Patients with a history of thrombosis or hypercoagulable state, excluding access clotting. Patients with a history of administration of C1INH containing products or recombinant C1INH within 15 days prior to study entry. Patients with a known hypersensitivity to treatment with C1INH. Patients with an abnormal coagulation function. (INR>2, PTT> 50, PLT<60,000)who are not on anti-coagulation. Patients with known active presence of malignancies. Patients who arePCR positive for Hep B, Hep C, or HIV. Recipients of pre-emptive kidney transplantation. All zero mismatch kidneys. Recipients of multi-organ transplants. (kidney and any other organ) Recipients of kidney allograft that was on pump preservation for any period prior to transplantation. Recipients of kidney allograft from a living donor.13)Female subjects who are pregnant or lactating.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 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). Patients will be randomized in a 1:1 manner
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Berinert<br>Berinert 500 units | Drug: Berinert<br>* Intrarenal dose of 500 U of Berinert<br>* Other names: C1 Esterase Inhibitor (C1INH);|
| Placebo Comparator: Placebo<br>Normal Saline in identical volume to Berinert | Drug: Placebo<br>* Normal Saline placebo<br>* Other names: Normal Saline;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for Dialysis in the First 30 Days Post-transplant | The percentage of patients enrolled who require at least one session of dialysis in the first 30 days post transplant. | 30 days | 
| Renal Function 6 Months | eGFR at 6M post-transplant | 6 months | 
| Graft Survival 6 Months | Number of participants with graft survival at 6 Months | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rejection Episodes at 6 Months | Number of participants with a rejection episodes by day 180 | Month 6 | 
| Development of Donor Specific Antibodies (DSA) at 6 Months | Number of participants with Donor Specific Antibodies (DSA) at 6 Months | Month 6 |