Improved Induction and Maintenance Immunosuppression in Kidney Transplantation

University of Nebraska

Status and phase: Completed; Phase 4

Conditions: End-stage Renal Disease

Treatments: Drug: rabbit anti-thymocyte globulin - 4 doses; Drug: rabbit anti-thymocyte globulin - single dose; Drug: tacrolimus; Drug: mycophenolate mofetil; Drug: sirolimus

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00556933

0286-03-FB

Details and patient eligibility

About

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.

Full 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.

Enrollment: 180 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: None (Open label)

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180 participants in 4 patient groups

Group 1

Experimental group

Description:

Kidney transplant recipients given a single large dose of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression.

Treatment:

Drug: sirolimus

Drug: tacrolimus

Drug: rabbit anti-thymocyte globulin - single dose

Group 2

Experimental group

Description:

Kidney transplant recipients given 4 small doses of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression.

Treatment:

Drug: sirolimus

Drug: tacrolimus

Drug: rabbit anti-thymocyte globulin - 4 doses

Group 3

Experimental group

Description:

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.

Treatment:

Drug: sirolimus

Drug: tacrolimus

Drug: mycophenolate mofetil

Drug: rabbit anti-thymocyte globulin - single dose

Group 4

Experimental group

Description:

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.

Treatment:

Drug: sirolimus

Drug: tacrolimus

Drug: mycophenolate mofetil

Drug: rabbit anti-thymocyte globulin - 4 doses