C1INH Inhibitor Preoperative and Post Kidney Transplant to Prevent DGF & IRI (C1INHDGF)
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|ClinicalTrials.gov Identifier: NCT02134314|
Recruitment Status : Completed
First Posted : May 9, 2014
Results First Posted : June 25, 2018
Last Update Posted : June 25, 2018
|Condition or disease||Intervention/treatment||Phase|
|End Stage Renal Disease Kidney Failure Delayed Graft Function Ischemic Reperfusion Injury||Drug: C1 Esterase Inhibitor Drug: Placebo||Phase 1 Phase 2|
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:
- On the basis of safety and efficacy, determine appropriate Berinert® study dose for Phase III investigation, and
- Determine appropriate endpoint choice for Phase III investigation.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||70 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Assessing Safety and Efficacy of Preoperative and Post-Transplant C1 Inhibitor (Berinert®) vs. Placebo in Recipients of a Renal Allograft From Deceased High Risk Donors and Its Impact on DGF and IRI|
|Study Start Date :||September 2014|
|Actual Primary Completion Date :||March 13, 2017|
|Actual Study Completion Date :||March 13, 2017|
Experimental: C1-Inhibitor (Berinert) (Human) (C1INH)
35 patients will receive C1 esterase inhibitor in addition to standard of care immunosuppressive therapy.
Drug: C1 Esterase Inhibitor
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
Other Name: Berinert (C1INH)
Placebo Comparator: Normal Saline
35 patients will receive placebo in addition to standard of care immunosuppressive therapy.
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
Other Name: Normal Saline (0.9%NaCl)
- Number of Patients Enrolled With Serum Creatinine >3mg/dL on Postoperative Day 5. [ Time Frame: First 7 days post-transplant ]Number of participants in the C1INH and placebo groups with serum creatinine >3mg/dL on postoperative day 5
- Number of Patients Enrolled Who Require at Least One Session of Dialysis in the First 7 Days Post Transplant. [ Time Frame: First 7 days post-transplant ]The proportion of patients enrolled who require at least one session of dialysis in the first 7 days post transplant (excluding those who are dialyzed for hyperkalemia).
- Number of Patients With Serum Creatinine Reduction Ratio of < 30% From 24 to 48 Hours Post-transplant. [ Time Frame: First 7 days post-transplant ]Number of patients in the C1INH and placebo groups with serum creatinine reduction of < 30% from 24 to 48 hours post-transplant.
- Number of Dialysis Sessions Per Patient in the First 7 Days Post Transplant. [ Time Frame: First 7 days post-transplant ]Mean quantity of dialysis sessions per patient in the first 7 days post transplant.
- Serum Creatinine [ Time Frame: Up to 90 days post-transplant ]Mean serum creatinine on day 90 in mg/dL
- Creatinine Clearance [ Time Frame: Up to 90 days post-transplant ]Creatinine clearance calculated based on serum creatinine, milliliters per minute.
- 24h Urine Output [ Time Frame: 24 hours post-transplant ]24 hour urine output post-transplantation measured in milliliters
- Mean Number of Patients on Dialysis [ Time Frame: 15 to 30 days post-transplantation ]Mean number of patients on dialysis at 15 to 30 days post-transplant
- Number of Patients With Delayed Graft Function (DGF) (Categorized by DGF Scale) [ Time Frame: First 7 days post-transplant ]
Grade 1 - immediate urine production and no need for dialysis with creatinine reduction ratio (CRR) between time 0 of transplantation and day 7 post-transplantation >70%
Grade 2 - creatinine reduction ratio (CRR) between time 0 of transplantation and day 7 post-transplantation of >70% with need for dialysis
Grade 3 - creatinine reduction ratio (CRR) between time 0 of transplantation and day 7 post-transplantation <70% with no need for dialysis
Grade 4 - creatinine reduction ratio (CRR) between time 0 of transplantation and day 7 post-transplantation of <70% with need for dialysis.
- Overall Incidence of Serious Adverse Events [ Time Frame: Up to 9 months post-transplant ]Overall incidence of serious adverse events in the C1INH and placebo groups, number of events.
- Patient Survival [ Time Frame: Up to 90 days post-transplant ]Patient survival at 90 days post-transplantation
- Rate of Acute Cellular Rejection (ACR) [ Time Frame: Up to 90 days post-transplant ]Number of acute cellular and antibody mediated rejection episodes by day 90.
- Graft Survival [ Time Frame: Day 90 Post-transplant ]Number of Participants with Graft Survival at 90 Days Post-Transplant
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02134314
|United States, California|
|Cedars-Sinai Medical Center|
|Los Angeles, California, United States, 90048|
|Principal Investigator:||Stanley C Jordan, MD||Cedars-Sinai Medical Center, Los Angeles, CA|
|Study Director:||Ashley Vo, PharmD||Cedars-Sinai Medical Center, Los Angeles, CA|