Clinical trial NCT00556933
Conditions: End-stage Renal Disease
Keywords: Induction rATG Calcineurin-inhibitor withdrawal
Sponsor: University of Nebraska
Start date: 2004-04-01; Completion date: 2011-06-01
Enrollment: 180 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
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:

1. 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.
2. 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:
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.

Arms: arm 1: Kidney transplant recipients given a single large dose of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression. arm 2: Kidney transplant recipients given 4 small doses of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression. arm 3: 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. arm 4: 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.
Interventions: intervention 1: rabbit anti-thymocyte globulin - single dose intervention 2: mycophenolate mofetil intervention 3: rabbit anti-thymocyte globulin - 4 doses intervention 4: sirolimus intervention 5: tacrolimus
Intervention descriptions: intervention 1: 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. intervention 2: 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. intervention 3: 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. intervention 4: Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection intervention 5: Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.

Protocol documents: