C1INH Inhibitor Preoperative and Post Kidney Transplant to Prevent DGF & IRI
Keywords
Abstract
Description
Early graft function has a long-term effect on graft survival. Poor early graft function and delayed graft function (DGF) contributes to decreased short- and long-term patient and graft survival, increased incidence of acute rejection, prolonged hospitalization, and higher costs of transplantation. Although multiple factors contribute to the impaired graft function, ischemia-reperfusion injury (IRI) is the underlying pathophysiology leading to poor early graft function and DGF. A >35% incidence of DGF has remained constant over time despite significant improvements in immunosuppressive strategies and patient management. This may be due to increased use of kidneys from "extended-criteria" and/or non-heart-beating donors, where even greater rates (>60%) of DGF have been reported.
More than 96,680 people are currently waiting for a kidney transplant in the United States (United Network for Organ Sharing (UNOS); UNOS.org 3/22/13). Of the 15,092 kidney transplants performed in the US in 2011, ~11,000 (62%) were from deceased donors. Of these, approximately 17% were from expanded-criteria donors. The USRDS reports that more than 50% of patients on the waiting list are willing to accept a kidney from an expanded-criteria donor (ECD) or donors after cardiac death (DCD).
From the investigators previous studies with C1INH (Berinert®) for prevention of antibody mediated rejection (ABMR), the investigators noted that no patients developed ABMR during treatment with C1INH, the investigators also noted a near significant reduction in DGF due to IRI (ClinicalTrials.gov(NCT01134510), FDA Investigational New Drug (IND#): 14363). These findings suggest an important role for complement in the mediation of IRI and that inhibition of early complement activation using C1INH in patients receiving at risk kidneys for IRI should reduce this costly and often devastating complication of kidney transplantation. In addition, numerous other studies in animal models have shown dramatic improvements in IRI models with the use of C1INH. Complement activation is detectable in animal and in human kidneys models after IRI and experimental data suggests that use of C1INH prior to induction of IRI significantly reduces IRI as well as inflammatory cell infiltrates. Based on this, the investigators hypothesize that the use of C1INH in patients receiving deceased donor (DD) kidney transplants with high risk for DGF will show significant reductions in DGF and improved outcomes post-transplant compared with patients receiving DD transplants who do not receive C1INH treatment. Here, the investigators propose to investigate the application of pre-operative and post-transplant doses of C1INH (Berinert®) vs. placebo in adult subjects receiving a DD renal allograft considered at high-risk for IRI and DGF. The investigators hypothesize that C1INH treated patients will demonstrate improved function of the kidney allograft compared to placebo, with equivalence in safety. The primary objectives of this study are: Using a double blinded, placebo controlled format, the investigators will:
1. Evaluate and compare the safety of C1INH (50 units/kilogram, round to the nearest 500 unit) administered pre-transplant and 24 hrs post-transplant in recipients of kidney allografts from high risk for IRI deceased donors.
The secondary objectives are to:
1. On the basis of safety and efficacy, determine appropriate Berinert® study dose for Phase III investigation, and
2. Determine appropriate endpoint choice for Phase III investigation.
Dates
| Last Verified: | 05/31/2018 |
| First Submitted: | 02/18/2014 |
| Estimated Enrollment Submitted: | 05/07/2014 |
| First Posted: | 05/08/2014 |
| Last Update Submitted: | 06/19/2018 |
| Last Update Posted: | 06/24/2018 |
| Date of first submitted results: | 03/12/2018 |
| Date of first submitted QC results: | 06/19/2018 |
| Date of first posted results: | 06/24/2018 |
| Actual Study Start Date: | 08/31/2014 |
| Estimated Primary Completion Date: | 03/12/2017 |
| Estimated Study Completion Date: | 03/12/2017 |
Condition or disease
Intervention/treatment
Drug: C1-Inhibitor (Berinert) (Human) (C1INH)
Drug: Normal Saline
Phase
Arm Groups
| Arm | Intervention/treatment |
|---|---|
| Experimental: C1-Inhibitor (Berinert) (Human) (C1INH) 35 patients will receive C1 esterase inhibitor in addition to standard of care immunosuppressive therapy. | Drug: C1-Inhibitor (Berinert) (Human) (C1INH) C1 Esterase Inhibitor 50 units per kilogram intravenous infusion administered on day of transplant, and another dose at 24 hours post-operatively. Total: 2 doses |
| Placebo Comparator: Normal Saline 35 patients will receive placebo in addition to standard of care immunosuppressive therapy. | Drug: Normal Saline Placebo medication identical to study drug (C1 esterase inhibitor) volume will be administered on day of transplant, and another dose at 24 hours post-operatively. Total: 2 doses |
Eligibility Criteria
| Ages Eligible for Study | 18 Years To 18 Years |
| Sexes Eligible for Study | All |
| Accepts Healthy Volunteers | Yes |
| Criteria | Inclusion Criteria: - 18-70 yrs of age; recipient of ECD/DCD/ECD&DCD with risk index 3-8 for DGF based on specific criteria - recipient who are ABO compatible with donor allograft - pretransplant with meningococcal vaccination - understand and sign a written consent prior to any study specific procedure. Risk index (minimum 3- maximum 8): DGF scale: Donor Age (<40yr = 0, 41-49yr = 1, 50-54yr = 2, 55-59yr = 3, >60yr=6), Cold Ischemia Time (0-12= 0, 13-18=1, 19-24=2, 24-30=3, 31-36=4, >37=6; Recipient Race (nonblack = 0, black =1); Donor death due to Cerebrovascular Accident (CVA) (donor age <50yrs = 0, donor age >50yrs = 3). Exclusion Criteria: - patients with known prothrombotic disorder (e.g. factor V leiden) - history of thrombosis or hypercoagulable state excluding access clotting - history of administration of C1INH containing products or recombinant C1INH within 15 days prior to study entry - patients with known contraindication to treatment with C1INH - patients with abnormal coagulation function (INR >2, partial thromboplastin time (PTT) > 50, platelets <80,000) - who are not on anti-coagulation - patients with known active presence of malignancies - Polymerase chain reaction (PCR) positive for hep B/hep C/or HIV - preemptive kidney transplantation recipient - recipients of multi-organ transplants (kidney and any other organ) - recipients of kidney allograft from DD who: cold ischemia time (CIT) <18h, terminal serum creatinine |
Outcome
Primary Outcome Measures
1. Number of Patients Enrolled With Serum Creatinine >3mg/dL on Postoperative Day 5. [First 7 days post-transplant]
2. Number of Patients Enrolled Who Require at Least One Session of Dialysis in the First 7 Days Post Transplant. [First 7 days post-transplant]
3. Number of Patients With Serum Creatinine Reduction Ratio of < 30% From 24 to 48 Hours Post-transplant. [First 7 days post-transplant]
4. Number of Dialysis Sessions Per Patient in the First 7 Days Post Transplant. [First 7 days post-transplant]
Secondary Outcome Measures
1. Serum Creatinine [Up to 90 days post-transplant]
2. Creatinine Clearance [Up to 90 days post-transplant]
3. 24h Urine Output [24 hours post-transplant]
4. Mean Number of Patients on Dialysis [15 to 30 days post-transplantation]
5. Number of Patients With Delayed Graft Function (DGF) (Categorized by DGF Scale) [First 7 days post-transplant]
Other Outcome Measures
1. Overall Incidence of Serious Adverse Events [Up to 9 months post-transplant]
2. Patient Survival [Up to 90 days post-transplant]
3. Rate of Acute Cellular Rejection (ACR) [Up to 90 days post-transplant]
4. Graft Survival [Day 90 Post-transplant]
