End-Stage Renal Disease, Kidney Failure
Conditions
Keywords
Renal transplantation, Kidney transplantation
Brief summary
In a non-blinded pilot study conducted at the University of Nebraska Medical Center, evidence was found that a single large dose of Thymoglobulin on the day of kidney transplantation produced better kidney function than the standard dosing plan, when the same amount is divided into smaller doses on 4 days. This new study repeats that dose comparison, but with double-blinding and at multiple transplantation centers.
Detailed description
This study is designed to confirm the one-year safety of single-dose rabbit anti-thymocyte globulin induction at kidney transplantation, compared to the conventional administration of the same overall dose divided into four smaller doses across four days. Two randomized groups of kidney transplant recipients will be each administered the drug Thymoglobulin according to a different dosing regimen. The control group will receive the usual and traditional regimen of a total of 6 mg/Kg divided into 4 doses, 1 on the day of transplantation and 1 each day on the next 3 days. The experimental group will receive the same total Thymoglobulin dose, 6 mg/Kg, but entirely on the day of transplantation. The study will be double-blinded, with placebo doses of Thymoglobulin administered as needed to enrollees in the experimental group. Enrollment is targeted at 165, with 150 subjects needed to complete the study for adequate evaluation.
Interventions
BIOLOGICALSingle-dose rabbit Anti-thymocyte Globulin induction
6 mg of rATG administered in a single dose on the day of kidney transplantation
BIOLOGICALDivided-dose rabbit Anti-thymocyte Globulin induction
6 mg/kg total rabbit Anti-thymocyte Globulin dose administered as 1.5 mg/kg doses on 4 sequential days, beginning on the day of kidney transplantation.
Sponsors
Sanofi
University of Arizona
Wake Forest University
University of Nebraska
The Methodist Hospital Research Institute
Wright State University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Subject capable of giving written informed consent, with end-stage kidney disease, who is a suitable candidate for primary kidney transplantation * Male or female subject who has reached legal age in the state where they reside and is at least 18 years of age * Deceased or living donors * Compatible ABO blood type * Expanded-criteria donor (ECD) kidneys with a donor grade score of ≤ 25 (as developed by Nyberg, et al.) * If Kidneys are pumped, they must meet the following pumping parameters: resistance \<0.35 with a flow rate of \>60 ml/min.
Exclusion criteria
* Recipient age \>65 years * PRA \>50%, or donor-specific antibody * CIT \>30 hours * Re-transplant patients * Multi-organ transplant recipients (example: kidney/pancreas or kidney/liver) * Renal transplant recipients planned for future pancreas transplantation * Current unstable cardiovascular disease or history of myocardial infarction within the previous 6 months * Current malignancy or history or malignancy (within the previous 5 years) with the exception of non-metastatic basal or squamous cell carcinoma of the skin or carcinoma in-situ of the cervix that has been treated successfully. * Hepatitis B and C recipients or active liver disease * HIV positive recipients * Primary disease requiring treatment with steroids after transplantation * Expanded-criteria donor kidneys (current UNOS criteria) with a donor grade score of \> 25 * Donation after cardiac death (DCD) donors * Dual adult kidneys * Recipients of pediatric (age \<12 years) unilateral or en-bloc kidneys * Previous treatment with rATG * Known hypersensitivity, extensive exposure, or allergy to rabbits * Pregnant * Any condition that in the investigator's opinion may compromise study participation (e.g., history or likelihood of non-compliance with immunosuppression regimen, protocol visits, tests, and studies) Relative
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite Endpoint of 5 Components: Fever, Hypoxia, Hypotension, Cardiac Events, and Delayed Graft Function | During first 7 days after kidney transplantation | The composite endpoint components and definitions are: * Fever: Body temperature ≥ 38.5˚C. * Hypotension: After rATG initiation, systolic blood pressure ≤ 90 mmHg requiring de novo treatment with vasopressors. * Hypoxia: During transplantation surgery, increase in FiO2 to ≥ 60% following rATG initiation. Following transplantation, starting in recovery room, FiO2 ≥ 50% or nasal cannula delivering ≥ 3 liters, either singly or combined, for \> 12 hours out of a 24 hour period. * Cardiac events: Myocardial Infarction, clinically significant dysrhythmia (atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia) * Delayed graft function (DGF): Requirement for dialysis within 7 days of transplantation |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Patient Survival | 12 months post-transplantation | Kaplan-Meier estimate of the number of patients who survived for the 12 months after kidney transplantation. |
| Graft Survival | 12 months post-transplantation | Kaplan-Meier estimates of graft survival probability for 12 months after transplantation |
| Acute Kidney Rejection | 12 months post-transplantation | Kaplan-Meier probability estimates of rejection rates |
| Incomplete Thymoglobulin Infusion | First 7 days post-transplantation | — |
| Kidney Function | 12 months post-transplantation | Estimated Glomerular Filtration Rate using the abbreviated MDRD formula (Modification of Diet in Renal Disease study) |
Countries
United States
Participant flow
Recruitment details
Trial enrollment occurred between 3/30/2010 and 3/25/2014. Patients scheduled to undergo kidney transplantation were evaluated for trial suitability/enrollment in the transplant hospital or clinic just before transplantation, typically from a few hours to \ 24 hours before transplantation.
Pre-assignment details
Occasionally patients were evaluated and thought to be suitable trial candidates until transplantation was imminent, when they were ruled out by last-minute observation of medical problems or donor shortcomings.
Participants by arm
| Arm | Count |
|---|---|
| Single-dose Thymoglobulin Biological/Vaccine Single-dose rabbit Anti-thymocyte Globulin induction, 6 mg/kg IV infusion
Single-dose rabbit Anti-thymocyte Globulin induction: 6 mg of rATG administered in a single dose on the day of kidney transplantation | 44 |
| Divided-dose Thymoglobulin Biological/Vaccine Divided-dose rabbit Anti-thymocyte Globulin induction, 1.5 mg/kg IV infusion QD x 4
Divided-dose rabbit Anti-thymocyte Globulin induction: 6 mg/kg total rabbit Anti-thymocyte Globulin dose administered as 1.5 mg/kg doses on 4 sequential days, beginning on the day of kidney transplantation. | 51 |
| Total | 95 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Primary Endpoint (Early Safety) | Physician Decision | 1 | 0 |
| Primary Endpoint (Early Safety) | Untransplantable donor kidney | 0 | 1 |
| Primary Endpoint (Early Safety) | Withdrawal by Subject | 1 | 0 |
| Secondary Endpoints (Long-term Safety) | Adverse Event | 2 | 2 |
| Secondary Endpoints (Long-term Safety) | Death | 0 | 1 |
Baseline characteristics
| Characteristic | Divided-dose Thymoglobulin | Total | Single-dose Thymoglobulin |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 5 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 48 Participants | 90 Participants | 42 Participants |
| Age, Continuous | 49.0 years STANDARD_DEVIATION 12.4 | 48.5 years STANDARD_DEVIATION 12.1 | 48.0 years STANDARD_DEVIATION 11.8 |
| Region of Enrollment United States | 51 participants | 95 participants | 44 participants |
| Sex: Female, Male Female | 13 Participants | 28 Participants | 15 Participants |
| Sex: Female, Male Male | 38 Participants | 67 Participants | 29 Participants |
| Type of kidney donor Deceased donor | 22 participants | 40 participants | 18 participants |
| Type of kidney donor Living donor | 29 participants | 55 participants | 26 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 44 / 44 | 49 / 51 |
| serious Total, serious adverse events | 23 / 44 | 21 / 51 |
Outcome results
Primary
Composite Endpoint of 5 Components: Fever, Hypoxia, Hypotension, Cardiac Events, and Delayed Graft Function
The composite endpoint components and definitions are: * Fever: Body temperature ≥ 38.5˚C. * Hypotension: After rATG initiation, systolic blood pressure ≤ 90 mmHg requiring de novo treatment with vasopressors. * Hypoxia: During transplantation surgery, increase in FiO2 to ≥ 60% following rATG initiation. Following transplantation, starting in recovery room, FiO2 ≥ 50% or nasal cannula delivering ≥ 3 liters, either singly or combined, for \> 12 hours out of a 24 hour period. * Cardiac events: Myocardial Infarction, clinically significant dysrhythmia (atrial fibrillation, atrial flutter, ventricular fibrillation and ventricular tachycardia) * Delayed graft function (DGF): Requirement for dialysis within 7 days of transplantation
Time frame: During first 7 days after kidney transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single-dose Thymoglobulin | Composite Endpoint of 5 Components: Fever, Hypoxia, Hypotension, Cardiac Events, and Delayed Graft Function | 13 participants |
| Divided-dose Thymoglobulin | Composite Endpoint of 5 Components: Fever, Hypoxia, Hypotension, Cardiac Events, and Delayed Graft Function | 12 participants |
Comparison: The analysis compares the rates at which patients in each of the two groups cumulatively exceed the five composite endpoint thresholds. There are five safety outcomes monitored during the first seven post-transplantation days. The rates of observed vs. possible safety outcomes are compared.p-value: 0.64Fisher Exact
Secondary
Acute Kidney Rejection
Kaplan-Meier probability estimates of rejection rates
Time frame: 12 months post-transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single-dose Thymoglobulin | Acute Kidney Rejection | 5 participants |
| Divided-dose Thymoglobulin | Acute Kidney Rejection | 5 participants |
p-value: 0.78Log Rank
Secondary
Graft Survival
Kaplan-Meier estimates of graft survival probability for 12 months after transplantation
Time frame: 12 months post-transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single-dose Thymoglobulin | Graft Survival | 42 participants |
| Divided-dose Thymoglobulin | Graft Survival | 50 participants |
p-value: 0.47Log Rank
Secondary
Incomplete Thymoglobulin Infusion
Time frame: First 7 days post-transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single-dose Thymoglobulin | Incomplete Thymoglobulin Infusion | 3 participants |
| Divided-dose Thymoglobulin | Incomplete Thymoglobulin Infusion | 5 participants |
p-value: 0.72Fisher Exact
Secondary
Kidney Function
Estimated Glomerular Filtration Rate using the abbreviated MDRD formula (Modification of Diet in Renal Disease study)
Time frame: 12 months post-transplantation
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Single-dose Thymoglobulin | Kidney Function | 59.3 mL/min/1.73m^2 | Standard Deviation 15.6 |
| Divided-dose Thymoglobulin | Kidney Function | 61.3 mL/min/1.73m^2 | Standard Deviation 23.3 |
p-value: 0.85t-test, 2 sided
Secondary
Patient Survival
Kaplan-Meier estimate of the number of patients who survived for the 12 months after kidney transplantation.
Time frame: 12 months post-transplantation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Single-dose Thymoglobulin | Patient Survival | 44 participants |
| Divided-dose Thymoglobulin | Patient Survival | 50 participants |
p-value: 0.35Log Rank