Improved Induction and Maintenance Immunosuppression in Kidney Transplantation

Study Overview
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Brief Summary
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This 2 x 2 sequential factorial study evaluates two potential improvements to the standard immunosuppression regimen used at the investigators' institution to prevent rejection of transplanted kidneys. These two potential improvements are each applied in sequence to half of the study patients, creating 4 study arms; the other half receive the standard treatment. The two potential improvements are: Administering the immunosuppression induction agent rATG (rabbit anti-thymocyte globulin) in a single dose at the time of transplantation, instead of in the usual series of 4 smaller doses over 6 days. After 6 months, modifying the maintenance immunosuppression used to prevent rejection by replacing the drug tacrolimus with mycophenolate mofetil (MMF). The two interventions, spaced sequentially six months apart, enable independent analysis of the two treatments so long as it can be shown that there is no synergistic interaction between them.

Detailed Description
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The two treatment innovations in this study of immunosuppression in kidney transplantation are aimed at making the transplanted kidney function sooner and last longer than is usual with standard immunosuppression regimens, but without increasing the likelihood of rejection. The first innovation, delivering the induction agent rATG in a single large dose rather than as a series of smaller doses over 6-8 days, is expected to produce better graft function right away, possibly by reducing some of the injury to the kidney that accompanies the restoration of blood flow during transplantation (reperfusion injury). Some evidence has been developed by investigators elsewhere to suggest this will happen. The second innovation, replacing tacrolimus with MMF after 6 months, is intended to eliminate a well-established major cause of ongoing toxic damage to the kidney. While tacrolimus does a good job of preventing rejection, the cost in continuing toxic injury to the kidney is high, leading inevitably to eventual graft failure, the inability of the transplanted kidney to continue filtering the blood and making adequate volumes of high-quality urine.

Official Title
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Prospective, Randomized 2 x 2 Factorial Trial of Rabbit Anti-thymocyte Globulin Induction (Single vs. Alternate Day Administration) at Renal Transplantation, With Delayed Calcineurin-inhibitor Withdrawal vs. Minimization

Conditions
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End-stage Renal Disease

Intervention / Treatment
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* Drug: rabbit anti-thymocyte globulin - single dose
* Drug: mycophenolate mofetil
* Drug: rabbit anti-thymocyte globulin - 4 doses
* Drug: sirolimus
* Drug: tacrolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Primary renal transplant recipient for end-stage renal disease Exclusion Criteria: Recipient age < 18 years or > 65 years Previous history of CMV disease Hepatitis B and C recipients Primary disease states that require steroids for immunosuppression Re-transplant with immunological cause of renal or pancreas loss Non heart beating donors Recipient of pediatric en bloc kidneys Recipient with a Panel Reactive Antibody (PRA) score >75% Patients who have received 3 or more prior transplants, excluding pancreas Patients who are past recipients of other solid organ transplants Previous history of BK virus Previous treatment with Thymoglobulin Allergy to rabbits Simultaneous Kidney/Pancreas transplantation

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: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1<br>Kidney transplant recipients given a single large dose of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression. | Drug: rabbit anti-thymocyte globulin - single dose<br>* A single 6 mg/kg dose of rATG administered intravenously over 24 hours, beginning before kidney transplantation. Administration of the drug is begun as early as practical, usually after general anesthesia has been established but before surgery has started. The rATG is therefore administered for about two hours before blood flow is restored to the kidney undergoing transplantation.<br>* Other names: rATG;Drug: sirolimus<br>* Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection<br>* Other names: Rapamune, rapamycin;Drug: tacrolimus<br>* Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.<br>* Other names: ProGraf;|
| Experimental: Group 2<br>Kidney transplant recipients given 4 small doses of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression. | Drug: rabbit anti-thymocyte globulin - 4 doses<br>* 6 mg/kg rabbit anti-thymocyte globulin delivered in 4 doses of 1.5 mg/kg each, the first administered at the time of kidney transplantation. Subsequent doses are administered on days 2, 4, and 6.<br>* Other names: Thymoglobulin;Drug: sirolimus<br>* Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection<br>* Other names: Rapamune, rapamycin;Drug: tacrolimus<br>* Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.<br>* Other names: ProGraf;|
| Experimental: Group 3<br>Kidney transplant recipients given a single large dose of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression until tacrolimus is replaced with mycophenolate mofetil after about 6 months. | Drug: rabbit anti-thymocyte globulin - single dose<br>* A single 6 mg/kg dose of rATG administered intravenously over 24 hours, beginning before kidney transplantation. Administration of the drug is begun as early as practical, usually after general anesthesia has been established but before surgery has started. The rATG is therefore administered for about two hours before blood flow is restored to the kidney undergoing transplantation.<br>* Other names: rATG;Drug: mycophenolate mofetil<br>* Patients are switched approximately 6 months after kidney transplantation from maintenance immunosuppression with tacrolimus and sirolimus to maintenance with mycophenolate mofetil and sirolimus. The drug is administered orally, taken daily, with dose adjusted in proportion to measured blood levels, and is required indefinitely to prevent rejection of the transplanted kidney.<br>* Other names: Myfortic;Drug: sirolimus<br>* Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection<br>* Other names: Rapamune, rapamycin;Drug: tacrolimus<br>* Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.<br>* Other names: ProGraf;|
| Experimental: Group 4<br>Kidney transplant recipients given 4 small doses of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression until tacrolimus is replaced with mycophenolate mofetil after about 6 months. | Drug: mycophenolate mofetil<br>* Patients are switched approximately 6 months after kidney transplantation from maintenance immunosuppression with tacrolimus and sirolimus to maintenance with mycophenolate mofetil and sirolimus. The drug is administered orally, taken daily, with dose adjusted in proportion to measured blood levels, and is required indefinitely to prevent rejection of the transplanted kidney.<br>* Other names: Myfortic;Drug: rabbit anti-thymocyte globulin - 4 doses<br>* 6 mg/kg rabbit anti-thymocyte globulin delivered in 4 doses of 1.5 mg/kg each, the first administered at the time of kidney transplantation. Subsequent doses are administered on days 2, 4, and 6.<br>* Other names: Thymoglobulin;Drug: sirolimus<br>* Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection<br>* Other names: Rapamune, rapamycin;Drug: tacrolimus<br>* Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.<br>* Other names: ProGraf;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chronic Allograft Nephropathy (Cumulative Calcineurin-inhibitor Nephrotoxicity/Transplant Nephropathy) Per Protocol Surveillance Kidney Biopsies (Banff Grading Criteria). | Protocol kidney biopsies collected at approximately 12 and 24 months were scored by a transplant renal pathologist blinded to treatment group assignment for evidence of rejection, BK virus nephropathy, antibody-mediated rejection, recurrent disease, inflammation, and Banff 2005 categories of chronic renal injury. Chronic injury categories were arteriolar hyaline thickening (ah), allograft glomerulopathy (cg), interstitial fibrosis (ci), tubular atrophy (ct), and vascular fibrous intimal thickening (cv). Severity scores within each category could be 0 (<5%; none or minimal), 1 (>5% - <25%; mild), 2 (>25% - <50%, moderate), or 3 (>50%, severe). The proportions of patients in each severity grade (0, 1, 2, and 3) for both the individual categories and a composite were compared using Fisher's exact test. | Two years | 
| Average of Renal Function | Calculated Glomerular Filtration Rate (GFR) by using the abbreviated MDRD (aMDRD) formula and patient serum creatinine and demographic data; averaged values from months four through 24. | Two years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Profile | Number of events: cytomegalovirus (CMV) disease, opportunistic infections (bacteremia, abscess, pneumonia, fungal), Post-transplantation Lymphoproliferative Disorder (PTLD), wound healing problems within 30 days, and lymphoceles. | Two years | 
| Requirement for Additional Immunosuppression (Such as Corticosteroids, Antimetabolites or Other Immunosuppressive Agents) |  | Two years | 
| Acute Rejection Per Kidney Biopsy (Banff Grading Criteria) |  | Two years | 
| Acute Tubular Necrosis (ATN) Rate, Defined as the Requirement for Dialysis Within 7 Days Post-transplantation. |  | Seven days | 
| Graft Survival | Graft failure = permanent return of patient to dialysis. | Two years | 
| Patient Survival |  | Two years | 
| Lymphoid Cell Sub-type CD3 Absolute Numbers |  | One year | 
| New-onset Polyomavirus (BK Virus) Disease Per Kidney Biopsy |  | Two years | 
| New-onset Diabetes and Hyperglycemia After Transplantation (NODAT) |  | Six months | 
| Ratio of CD4/CD8 Lymphoid Cells |  | One year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Induction, rATG, Calcineurin-inhibitor withdrawal