Delayed Graft Function, End Stage Renal Disease, Ischemic Reperfusion Injury, Kidney Failure
Conditions
Keywords
ESRD (End Stage Renal Disease), CKD (Chronic Kidney Disease), Kidney Transplant, ECD, delayed graft function, chronic kidney disease, expanded-criteria donor, end stage renal disease
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.
Interventions
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
DRUGPlacebo
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
Sponsors
Cedars-Sinai Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Serum Creatinine Reduction Ratio of < 30% From 24 to 48 Hours Post-transplant. | 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 Patients Enrolled With Serum Creatinine >3mg/dL on Postoperative Day 5. | 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. | 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 Dialysis Sessions Per Patient in the First 7 Days Post Transplant. | First 7 days post-transplant | Mean quantity of dialysis sessions per patient in the first 7 days post transplant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Delayed Graft Function (DGF) (Categorized by DGF Scale) | 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. |
| 24h Urine Output | 24 hours post-transplant | 24 hour urine output post-transplantation measured in milliliters |
| Serum Creatinine | Up to 90 days post-transplant | Mean serum creatinine on day 90 in mg/dL |
| Creatinine Clearance | Up to 90 days post-transplant | Creatinine clearance calculated based on serum creatinine, milliliters per minute. |
| Mean Number of Patients on Dialysis | 15 to 30 days post-transplantation | Mean number of patients on dialysis at 15 to 30 days post-transplant |
Other
| Measure | Time frame | Description |
|---|---|---|
| Overall Incidence of Serious Adverse Events | Up to 9 months post-transplant | Overall incidence of serious adverse events in the C1INH and placebo groups, number of events. |
| Graft Survival | Day 90 Post-transplant | Number of Participants with Graft Survival at 90 Days Post-Transplant |
| Rate of Acute Cellular Rejection (ACR) | Up to 90 days post-transplant | Number of acute cellular and antibody mediated rejection episodes by day 90. |
| Patient Survival | Up to 90 days post-transplant | Patient survival at 90 days post-transplantation |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) 35 patients will receive C1 esterase inhibitor in addition to standard of care immunosuppressive therapy.
C1 Esterase Inhibitor: C1 Esterase Inhibitor 50 units/kg intravenous infusion administered on day of transplant, and another dose 24 hours post op. Total: 2 doses | 35 |
| Normal Saline 35 patients will receive placebo in addition to standard of care immunosuppressive therapy.
Placebo: Placebo medication identical to study drug (C1 esterase inhibitor) volume will be administered on day of transplant, and another dose 24 hours post op. Total: 2 doses | 35 |
| Total | 70 |
Baseline characteristics
| Characteristic | Total | Normal Saline | C1-Inhibitor (Berinert) (Human) (C1INH) |
|---|---|---|---|
| Age, Continuous | 57.9 years STANDARD_DEVIATION 9.54 | 58.14 years STANDARD_DEVIATION 11.18 | 57.66 years STANDARD_DEVIATION 7.74 |
| Anti-HLA DSA | 5 Participants | 2 Participants | 3 Participants |
| Diabetes | 41 Participants | 20 Participants | 21 Participants |
| Donor Age | 47.37 years STANDARD_DEVIATION 14.13 | 45.57 years STANDARD_DEVIATION 15.69 | 49.17 years STANDARD_DEVIATION 12.35 |
| Donor Creatinine | 1.77 mg/dL STANDARD_DEVIATION 1.69 | 1.75 mg/dL STANDARD_DEVIATION 1.92 | 1.78 mg/dL STANDARD_DEVIATION 1.44 |
| Donor DCD Cause of Death | 23 Participants | 12 Participants | 11 Participants |
| Donor KDPI | 66.17 % STANDARD_DEVIATION 23.56 | 64.63 % STANDARD_DEVIATION 25.39 | 67.71 % STANDARD_DEVIATION 21.83 |
| Donor KDPI equal to or greater than 85% | 21 Participants | 11 Participants | 10 Participants |
| HLA Class I Antibodies Present | 3 Participants | 1 Participants | 2 Participants |
| HLA Class II Antibodies Present | 2 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized African-American | 8 Participants | 4 Participants | 4 Participants |
| Race/Ethnicity, Customized Not African-American | 62 Participants | 31 Participants | 31 Participants |
| Sex: Female, Male Female | 28 Participants | 13 Participants | 15 Participants |
| Sex: Female, Male Male | 42 Participants | 22 Participants | 20 Participants |
| Transplant Cold Ischemia Time | 19.06 hours STANDARD_DEVIATION 5.54 | 19.84 hours STANDARD_DEVIATION 6.1 | 18.27 hours STANDARD_DEVIATION 4.89 |
| Treatment with Alemtuzumab at transplantation | 17 Participants | 7 Participants | 10 Participants |
| Treatment with Thymoglobulin at transplantation | 53 Participants | 28 Participants | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 35 | 0 / 35 |
| other Total, other adverse events | 28 / 35 | 26 / 35 |
| serious Total, serious adverse events | 10 / 35 | 10 / 35 |
Outcome results
Primary
Number of Dialysis Sessions Per Patient in the First 7 Days Post Transplant.
Mean quantity of dialysis sessions per patient in the first 7 days post transplant.
Time frame: First 7 days post-transplant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Number of Dialysis Sessions Per Patient in the First 7 Days Post Transplant. | 0.97 dialysis sessions | Standard Deviation 1.22 |
| Normal Saline | Number of Dialysis Sessions Per Patient in the First 7 Days Post Transplant. | 1.54 dialysis sessions | Standard Deviation 1.54 |
Primary
Number of Patients Enrolled Who Require at Least One Session of Dialysis in the 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).
Time frame: First 7 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Number of Patients Enrolled Who Require at Least One Session of Dialysis in the First 7 Days Post Transplant. | 15 Participants |
| Normal Saline | Number of Patients Enrolled Who Require at Least One Session of Dialysis in the First 7 Days Post Transplant. | 21 Participants |
Primary
Number of Patients Enrolled With Serum Creatinine >3mg/dL on Postoperative Day 5.
Number of participants in the C1INH and placebo groups with serum creatinine \>3mg/dL on postoperative day 5
Time frame: First 7 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Number of Patients Enrolled With Serum Creatinine >3mg/dL on Postoperative Day 5. | 29 Participants |
| Normal Saline | Number of Patients Enrolled With Serum Creatinine >3mg/dL on Postoperative Day 5. | 32 Participants |
Primary
Number of Patients With Serum Creatinine Reduction Ratio of < 30% From 24 to 48 Hours Post-transplant.
Number of patients in the C1INH and placebo groups with serum creatinine reduction of \< 30% from 24 to 48 hours post-transplant.
Time frame: First 7 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Number of Patients With Serum Creatinine Reduction Ratio of < 30% From 24 to 48 Hours Post-transplant. | 30 Participants |
| Normal Saline | Number of Patients With Serum Creatinine Reduction Ratio of < 30% From 24 to 48 Hours Post-transplant. | 28 Participants |
Secondary
24h Urine Output
24 hour urine output post-transplantation measured in milliliters
Time frame: 24 hours post-transplant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | 24h Urine Output | 873.5 milliliters | Standard Deviation 1257 |
| Normal Saline | 24h Urine Output | 607.8 milliliters | Standard Deviation 782.4 |
Secondary
Creatinine Clearance
Creatinine clearance calculated based on serum creatinine, milliliters per minute.
Time frame: Up to 90 days post-transplant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Creatinine Clearance | 56.4 ml/minute | Standard Deviation 15.558 |
| Normal Saline | Creatinine Clearance | 51.2 ml/minute | Standard Deviation 17.335 |
Secondary
Mean Number of Patients on Dialysis
Mean number of patients on dialysis at 15 to 30 days post-transplant
Time frame: 15 to 30 days post-transplantation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Mean Number of Patients on Dialysis | 0 Participants |
| Normal Saline | Mean Number of Patients on Dialysis | 5 Participants |
Secondary
Number of Patients With Delayed Graft Function (DGF) (Categorized by DGF Scale)
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.
Time frame: First 7 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Number of Patients With Delayed Graft Function (DGF) (Categorized by DGF Scale) | 15 Participants |
| Normal Saline | Number of Patients With Delayed Graft Function (DGF) (Categorized by DGF Scale) | 21 Participants |
Secondary
Serum Creatinine
Mean serum creatinine on day 90 in mg/dL
Time frame: Up to 90 days post-transplant
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Serum Creatinine | 1.3 mg/dL | Standard Deviation 0.317 |
| Normal Saline | Serum Creatinine | 1.7 mg/dL | Standard Deviation 1.41 |
Other Pre-specified
Graft Survival
Number of Participants with Graft Survival at 90 Days Post-Transplant
Time frame: Day 90 Post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Graft Survival | 34 Participants |
| Normal Saline | Graft Survival | 34 Participants |
Other Pre-specified
Overall Incidence of Serious Adverse Events
Overall incidence of serious adverse events in the C1INH and placebo groups, number of events.
Time frame: Up to 9 months post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Overall Incidence of Serious Adverse Events | 11 events |
| Normal Saline | Overall Incidence of Serious Adverse Events | 16 events |
Other Pre-specified
Patient Survival
Patient survival at 90 days post-transplantation
Time frame: Up to 90 days post-transplant
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Patient Survival | 35 Participants |
| Normal Saline | Patient Survival | 35 Participants |
Other Pre-specified
Rate of Acute Cellular Rejection (ACR)
Number of acute cellular and antibody mediated rejection episodes by day 90.
Time frame: Up to 90 days post-transplant
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| C1-Inhibitor (Berinert) (Human) (C1INH) | Rate of Acute Cellular Rejection (ACR) | 0 episodes |
| Normal Saline | Rate of Acute Cellular Rejection (ACR) | 0 episodes |