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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
Sponsor:
Information provided by (Responsible Party):
Stanley Jordan, MD, Cedars-Sinai Medical Center

Tracking Information
First Submitted Date  ICMJE February 19, 2014
First Posted Date  ICMJE May 9, 2014
Results First Submitted Date  ICMJE March 13, 2018
Results First Posted Date  ICMJE June 25, 2018
Last Update Posted Date June 25, 2018
Study Start Date  ICMJE September 2014
Actual Primary Completion Date March 13, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 20, 2018)
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 8, 2014)
  • Number of Patients Enrolled With Serum Creatinine >3mg/dL on Postoperative Day 5. [ Time Frame: First 7 days ]
  • Number of Patients Enrolled Who Require at Least One Session of Dialysis in the First 7 Days Post Transplant. [ Time Frame: First 7 days ]
  • Number of Patients With Serum Creatinine Reduction Ratio of < 30% From 24 to 48 Hours Post-transplant. [ Time Frame: First 2 days ]
  • Number of Dialysis Sessions Per Patient in the First 7 Days Post Transplant. [ Time Frame: First 7 days ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 20, 2018)
  • 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 ]
    DGF Scale: 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 8, 2014)
  • Serum Creatinine [ Time Frame: Up to 90 days ]
  • Creatinine Clearance [ Time Frame: Up to 90 days ]
  • 24h Urine Output [ Time Frame: Up to 90 days ]
  • Number of Dialysis use and duration per patient [ Time Frame: Up to 90 days ]
  • Number of Patients With Delayed Graft Function (DGF) (Categorized by DGF Scale) [ Time Frame: First 7 days ]
    DGF Scale: 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.
Current Other Pre-specified Outcome Measures
 (submitted: June 20, 2018)
  • 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
Original Other Pre-specified Outcome Measures
 (submitted: May 8, 2014)
  • Overall incidence of adverse events and serious adverse events and relationship of AE and SAEs to the study treatment [ Time Frame: Up to 90 days ]
  • Evaluation of blood chemistry, hematology, and coagulation parameters [ Time Frame: Up to 90 days ]
  • Patient and graft survival [ Time Frame: Up to 90 days ]
  • Rate of Acute Cellular Rejection (ACR) [ Time Frame: Up to 90 days ]
 
Descriptive Information
Brief Title  ICMJE C1INH Inhibitor Preoperative and Post Kidney Transplant to Prevent DGF & IRI
Official Title  ICMJE 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
Brief Summary The use of C1INH (Berinert) in patients receiving deceased donor kidney transplants with high risk for delayed graft function (DGF) may show significant improvement in outcomes post transplant compared with patients that do not receive C1INH treatment. Complement activation has been detected in animal models and human kidneys with ischemic reperfusion injury (IRI) and inflammatory cell infiltrates. By blocking complement activation the investigators hope to improve kidney graft function post transplant in these recipients.
Detailed 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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Prevention
Condition  ICMJE
  • End Stage Renal Disease
  • Kidney Failure
  • Delayed Graft Function
  • Ischemic Reperfusion Injury
Intervention  ICMJE
  • 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)
  • Drug: Placebo
    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)
Study Arms  ICMJE
  • Experimental: C1-Inhibitor (Berinert) (Human) (C1INH)
    35 patients will receive C1 esterase inhibitor in addition to standard of care immunosuppressive therapy.
    Intervention: Drug: C1 Esterase Inhibitor
  • Placebo Comparator: Normal Saline
    35 patients will receive placebo in addition to standard of care immunosuppressive therapy.
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: May 8, 2014)
70
Original Estimated Enrollment  ICMJE Same as current
Actual Study Completion Date  ICMJE March 13, 2017
Actual Primary Completion Date March 13, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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 </= 1mg/dl, recipient of kidney allograft that was on pump preservation for any period prior to transplantation, recipient of kidney allograft from a living donor, female subject who are pregnant or lactating.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02134314
Other Study ID Numbers  ICMJE C1INH (Berinert) for DGF
IND15806 ( Other Identifier: FDA )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Stanley Jordan, MD, Cedars-Sinai Medical Center
Study Sponsor  ICMJE Cedars-Sinai Medical Center
Collaborators  ICMJE Not Provided
Investigators  ICMJE
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
PRS Account Cedars-Sinai Medical Center
Verification Date June 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP