Safety Trial of Single Versus Multiple Dose Thymoglobulin Induction in Kidney Transplantation

Study Overview
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Brief Summary
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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
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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.

Official Title
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Prospective, Randomized, Double-Blind, Double-Dummy, Multicenter Trial to Assess Safety of Single Dose vs. Traditional Administration of Thymoglobulin Induction for Renal Transplantation

Conditions
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End-Stage Renal Disease, Kidney Failure

Intervention / Treatment
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* Biological: Single-dose rabbit Anti-thymocyte Globulin induction
* Biological: Divided-dose rabbit Anti-thymocyte Globulin induction


Participation Criteria
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Eligibility Criteria
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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 Exclusion Criteria: Patients with a BMI > 37 should be considered on an individual basis based on overall health and body habitus.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single-dose Thymoglobulin<br>Biological/Vaccine Single-dose rabbit Anti-thymocyte Globulin induction, 6 mg/kg IV infusion | Biological: Single-dose rabbit Anti-thymocyte Globulin induction<br>* 6 mg of rATG administered in a single dose on the day of kidney transplantation<br>* Other names: rATG;|
| Active Comparator: Divided-dose Thymoglobulin<br>Biological/Vaccine Divided-dose rabbit Anti-thymocyte Globulin induction, 1.5 mg/kg IV infusion QD x 4 | Biological: Divided-dose rabbit Anti-thymocyte Globulin induction<br>* 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.<br>* Other names: rATG;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | During first 7 days after kidney transplantation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Patient Survival | Kaplan-Meier estimate of the number of patients who survived for the 12 months after kidney transplantation. | 12 months post-transplantation | 
| Graft Survival | Kaplan-Meier estimates of graft survival probability for 12 months after transplantation | 12 months post-transplantation | 
| Acute Kidney Rejection | Kaplan-Meier probability estimates of rejection rates | 12 months post-transplantation | 
| Incomplete Thymoglobulin Infusion |  | First 7 days post-transplantation | 
| Kidney Function | Estimated Glomerular Filtration Rate using the abbreviated MDRD formula (Modification of Diet in Renal Disease study) | 12 months post-transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Renal transplantation, Kidney transplantation