Improved Induction and Maintenance Immunosuppression in Kidney Transplantation

The recruitment status of this study is unknown because the information has not been verified recently.
Verified January 2010 by University of Nebraska.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Genzyme, a Sanofi Company
Information provided by:
University of Nebraska
ClinicalTrials.gov Identifier:
NCT00556933
First received: November 9, 2007
Last updated: January 25, 2010
Last verified: January 2010
  Purpose

This 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).

Condition Intervention
End-Stage Renal Disease
Renal Transplantation
Drug: rabbit anti-thymocyte globulin (rATG)
Drug: mycophenolate mofetil
Drug: rabbit anti-thymocyte globulin
Procedure: kidney transplantation
Drug: sirolimus
Drug: tacrolimus

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Prospective, Randomized Trial of Thymoglobulin Induction Therapy for Renal Transplantation: Single Versus Alternate Day Administration

Resource links provided by NLM:


Further study details as provided by University of Nebraska:

Primary Outcome Measures:
  • Chronic Allograft Nephropathy (cumulative calcineurin-inhibitor nephrotoxicity/transplant nephropathy) per clinically-indicated and protocol surveillance biopsies (Banff grading criteria). [ Time Frame: Two years ] [ Designated as safety issue: No ]
  • Renal function by either measured 24-hour urine creatinine clearance at 1, 3, 6, 12 and 24 months or calculated GFR (Glomerular Filtration Rate) by using the abbreviated MDRD (aMDRD) formula and patient serum creatinine and demographic data. [ Time Frame: Two years ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Safety profile to consist of CMV disease, opportunistic infections, PTLD, hyperlipidemia, wound healing problems, and lymphoceles [ Time Frame: Two years ] [ Designated as safety issue: Yes ]
  • Requirement for additional immunosuppression (such as corticosteroids, antimetabolites or other immunosuppressive agents) [ Time Frame: Two years ] [ Designated as safety issue: No ]
  • Acute rejection per kidney biopsy (Banff grading criteria) [ Time Frame: Two years ] [ Designated as safety issue: No ]
  • Acute Tubular Necrosis (ATN) rate, defined as the requirement for dialysis within 7 days post-transplantation. [ Time Frame: Two years ] [ Designated as safety issue: No ]
  • Graft survival [ Time Frame: Two years ] [ Designated as safety issue: No ]
  • Patient survival [ Time Frame: Two years ] [ Designated as safety issue: Yes ]
  • Immunological parameters, i.e., lymphoid cell sub-type absolute numbers and ratios [ Time Frame: Two years ] [ Designated as safety issue: No ]
  • New-onset BK virus infection per kidney biopsy [ Time Frame: Two years ] [ Designated as safety issue: Yes ]
  • New-onset diabetes and hyperglycemia after transplantation [ Time Frame: Two years ] [ Designated as safety issue: No ]

Enrollment: 180
Study Start Date: April 2004
Estimated Study Completion Date: June 2013
Estimated Primary Completion Date: April 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group 1
Kidney transplant recipients given a single large dose of rATG and maintained on tacrolimus and sirolimus for chronic immunosuppression.
Drug: rabbit anti-thymocyte globulin (rATG)
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.
Other Name: Thymoglobulin
Procedure: kidney transplantation
Transplantation of an organ-donor kidney into a dialysis-dependent patient with renal failure.
Drug: sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Other Name: Rapamune, rapamycin
Drug: tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Other Names:
  • FK506
  • ProGraf
Active Comparator: Group 2
Kidney transplant recipients given 4 small doses of rATG and maintained on tacrolimus and sirolimus for chronic immunosuppression.
Drug: rabbit anti-thymocyte globulin
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.
Other Name: Thymoglobulin
Procedure: kidney transplantation
Transplantation of an organ-donor kidney into a dialysis-dependent patient with renal failure.
Drug: sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Other Name: Rapamune, rapamycin
Drug: tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Other Names:
  • FK506
  • ProGraf
Experimental: Group 3
Kidney transplant recipients given a single large dose of 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 (rATG)
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.
Other Name: Thymoglobulin
Drug: mycophenolate mofetil
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.
Other Names:
  • CellCept
  • MMF
  • mycophenolic acid
  • Myfortic
Procedure: kidney transplantation
Transplantation of an organ-donor kidney into a dialysis-dependent patient with renal failure.
Drug: sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Other Name: Rapamune, rapamycin
Drug: tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Other Names:
  • FK506
  • ProGraf
Experimental: Group 4
Kidney transplant recipients given 4 small doses of rATG and maintained on tacrolimus and sirolimus for chronic immunosuppression until tacrolimus is replaced with mycophenolate mofetil after about 6 months.
Drug: mycophenolate mofetil
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.
Other Names:
  • CellCept
  • MMF
  • mycophenolic acid
  • Myfortic
Drug: rabbit anti-thymocyte globulin
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.
Other Name: Thymoglobulin
Procedure: kidney transplantation
Transplantation of an organ-donor kidney into a dialysis-dependent patient with renal failure.
Drug: sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
Other Name: Rapamune, rapamycin
Drug: tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Other Names:
  • FK506
  • ProGraf

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.

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 PRA > 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00556933

Locations
United States, Nebraska
The Nebraska Medical Center
Omaha, Nebraska, United States, 68198
Sponsors and Collaborators
University of Nebraska
Genzyme, a Sanofi Company
Investigators
Study Director: R. Brian Stevens, MD, PhD University of Nebraska
  More Information

No publications provided by University of Nebraska

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: R Brian Stevens, MD, PhD, University of Nebraska Medical Center
ClinicalTrials.gov Identifier: NCT00556933     History of Changes
Other Study ID Numbers: 286-03
Study First Received: November 9, 2007
Last Updated: January 25, 2010
Health Authority: United States: Institutional Review Board

Keywords provided by University of Nebraska:
Induction
rATG
Calcineurin-inhibitor withdrawal

Additional relevant MeSH terms:
Kidney Diseases
Kidney Failure, Chronic
Urologic Diseases
Renal Insufficiency, Chronic
Renal Insufficiency
Antilymphocyte Serum
Mycophenolate mofetil
Sirolimus
Everolimus
Tacrolimus
Mycophenolic Acid
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 20, 2014