Improved Induction and Maintenance Immunosuppression in Kidney Transplantation

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.

Timeline

Start

2004-04-01

Primary completion

2011-04-01

Completion

2011-06-01

Outcome

Mixed primary results

registry analysis (unspecified test); Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus vs Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus vs Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil vs Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil; p = 0.0004; Chi-squared NCT00556933 ↗

registry NUMBER Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus: Banff histopathology cumulative grade = 0: 43 percentage of participants NCT00556933 ↗

registry NUMBER Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil: Banff histopathology cumulative grade = 0: 53 percentage of participants NCT00556933 ↗

registry analysis (unspecified test); Single Dose rATG (6 mg/kg x 1) and Tacrolimus/Sirolimus vs Divided-dose rATG (1.5mg/kg x 4) and Tacrolimus/Sirolimus vs Single-dose rATG (6mg/kg ) and Sirolimus/Mycophenolate Mofetil vs Divided-dose rATG(6mg/kg ) and Sirolimus/Mycophenolate Mofetil; p = 0.45; General Linear Model NCT00556933 ↗

Publications

• Background 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.
• Background 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.
• Background 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.
• Results 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.
• Results 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.
• Results 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.
• Results 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.

Drugs

Evaluation	Drug	Modality	Dose	Route
Subject	Mycophenolate Mofetil	Small molecule	2 g	Oral
Subject	Tacrolimus	Small molecule	—	Oral
Subject	rabbit anti-thymocyte globulin	Protein / enzyme biologic	1.5 mg/kg	—
Subject	rabbit anti-thymocyte globulin	Protein / enzyme biologic	6 mg/kg	—
Background	Sirolimus	Small molecule	—	Oral

Indications