Improved Induction and Maintenance Immunosuppression in Kidney Transplantation
NCT ID: NCT00556933
Last Updated: 2023-09-18
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE4
180 participants
INTERVENTIONAL
2004-04-01
2011-06-01
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
FACTORIAL
TREATMENT
NONE
Study Groups
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Group 1
Kidney transplant recipients given a single large dose of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression.
rabbit anti-thymocyte globulin - single dose
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.
sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Group 2
Kidney transplant recipients given 4 small doses of rabbit anti-thymocyte globulin (rATG) and maintained on tacrolimus and sirolimus for chronic immunosuppression.
rabbit anti-thymocyte globulin - 4 doses
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.
sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Group 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.
rabbit anti-thymocyte globulin - single dose
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.
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.
sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Group 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.
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.
rabbit anti-thymocyte globulin - 4 doses
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.
sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Interventions
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rabbit anti-thymocyte globulin - single dose
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.
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.
rabbit anti-thymocyte globulin - 4 doses
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.
sirolimus
Oral maintenance immunosuppressant administered daily, dose adjusted according to measured serum trough levels, continued indefinitely to prevent kidney rejection
tacrolimus
Oral maintenance immunosuppressant, taken daily, dose adjusted to maintain target blood trough levels, required indefinitely to prevent kidney rejection.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
Exclusion Criteria
* 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
18 Years
65 Years
ALL
No
Sponsors
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Genzyme, a Sanofi Company
INDUSTRY
University of Nebraska
OTHER
Responsible Party
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Principal Investigators
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R. Brian Stevens, MD, PhD
Role: STUDY_DIRECTOR
Wright State University Boonshoft School of Medicine, Dayton, OH
Locations
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Unversity of Nebraska Medical Center
Omaha, Nebraska, United States
Countries
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References
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Miles CD, Skorupa JY, Sandoz JP, Rigley TH, Nielsen KJ, Stevens RB. Albuminuria after renal transplantation: maintenance with sirolimus/low-dose tacrolimus vs. mycophenolate mofetil/high-dose tacrolimus. Clin Transplant. 2011 Nov-Dec;25(6):898-904. doi: 10.1111/j.1399-0012.2010.01353.x. Epub 2010 Nov 16.
Stevens RB. Modern approaches to combining sirolimus with calcineurin inhibitors. Transplant Proc. 2008 Dec;40(10 Suppl):S21-4. doi: 10.1016/j.transproceed.2008.10.012.
Sulanc E, Lane JT, Puumala SE, Groggel GC, Wrenshall LE, Stevens RB. New-onset diabetes after kidney transplantation: an application of 2003 International Guidelines. Transplantation. 2005 Oct 15;80(7):945-52. doi: 10.1097/01.tp.0000176482.63122.03.
Stevens RB, Foster KW, Miles CD, Lane JT, Kalil AC, Florescu DF, Sandoz JP, Rigley TH, Nielsen KJ, Skorupa JY, Kellogg AM, Malik T, Wrenshall LE. A randomized 2x2 factorial trial, part 1: single-dose rabbit antithymocyte globulin induction may improve renal transplantation outcomes. Transplantation. 2015 Jan;99(1):197-209. doi: 10.1097/TP.0000000000000250.
Stevens RB, Lane JT, Boerner BP, Miles CD, Rigley TH, Sandoz JP, Nielsen KJ, Skorupa JY, Skorupa AJ, Kaplan B, Wrenshall LE. Single-dose rATG induction at renal transplantation: superior renal function and glucoregulation with less hypomagnesemia. Clin Transplant. 2012 Jan-Feb;26(1):123-32. doi: 10.1111/j.1399-0012.2011.01425.x. Epub 2011 Mar 14.
Snow MH, Cannella AC, Stevens RB, Mikuls TR. Presumptive serum sickness as a complication of rabbit-derived antithymocyte globulin immunosuppression. Arthritis Rheum. 2009 Sep 15;61(9):1271-4. doi: 10.1002/art.24788. No abstract available.
Stevens RB, Mercer DF, Grant WJ, Freifeld AG, Lane JT, Groggel GC, Rigley TH, Nielsen KJ, Henning ME, Skorupa JY, Skorupa AJ, Christensen KA, Sandoz JP, Kellogg AM, Langnas AN, Wrenshall LE. Randomized trial of single-dose versus divided-dose rabbit anti-thymocyte globulin induction in renal transplantation: an interim report. Transplantation. 2008 May 27;85(10):1391-9. doi: 10.1097/TP.0b013e3181722fad.
Stevens RB, Foster KW, Miles CD, Kalil AC, Florescu DF, Sandoz JP, Rigley TH, Malik T, Wrenshall LE. A Randomized 2x2 Factorial Clinical Trial of Renal Transplantation: Steroid-Free Maintenance Immunosuppression with Calcineurin Inhibitor Withdrawal after Six Months Associates with Improved Renal Function and Reduced Chronic Histopathology. PLoS One. 2015 Oct 14;10(10):e0139247. doi: 10.1371/journal.pone.0139247. eCollection 2015.
Other Identifiers
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0286-03-FB
Identifier Type: -
Identifier Source: org_study_id
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