A Trial of Two Steroid-Free Approaches Toward Mycophenolate Mofetil-Based Monotherapy Immunosuppression

Summary

This is an open label, single-center, randomized phase IV pilot study of steroid and calcineurin inhibitor avoidance in renal transplant recipients. All patients will receive two doses of alemtuzumab to achieve peripheral T-cell depletion. Intravenous glucocorticoids will be administered prior to alemtuzumab administration to limit cytokine release syndrome in association with this monoclonal antibody, and continued for the first two days post-transplant. Thereafter, steroids will not be used for immunosuppression. All transplant recipients will be started on oral immunosuppressive therapy with mycophenolate mofetil (MMF) prior to transplant. Pretransplant, these patients will be randomized to receive, in addition, either tacrolimus (Tac) or sirolimus. After six months, patients in the tacrolimus arm who do not experience rejection will be randomized to continue on tacrolimus or to be converted to the combination of sirolimus and MMF. Individuals in this arm of the study who do not experience acute rejection, and demonstrate evidence of donor specific hyporesponsiveness at 9 months post-transplant (those staying on Tac + MMF) or 3 months post-conversion (those converted from Tac + MMF to sirolimus + MMF) will be weaned to MMF monotherapy. Individuals in the sirolimus + MMF arm who do not experience acute rejection and demonstrate evidence of donor specific hyporesponsiveness at 6 months post-transplant will be weaned to MMF monotherapy.

Timeline

Start

2005-04

Primary completion

2010-04

Completion

2010-04

Publications

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• Background Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000 Mar 2;342(9):605-12. doi: 10.1056/NEJM200003023420901.
• Background Barry JM. Immunosuppressive drugs in renal transplantation. A review of the regimens. Drugs. 1992 Oct;44(4):554-66. doi: 10.2165/00003495-199244040-00003.
• Background Suthanthiran M, Strom TB. Renal transplantation. N Engl J Med. 1994 Aug 11;331(6):365-76. doi: 10.1056/NEJM199408113310606. No abstract available.
• Background Helderman JH, Van Buren DH, Amend WJ Jr, Pirsch JD. Chronic immunosuppression of the renal transplant patient. J Am Soc Nephrol. 1994 Feb;4(8 Suppl):S2-9. doi: 10.1681/ASN.V48s2.
• Background Gaston RS. Maintenance immunosuppression in the renal transplant recipient: an overview. Am J Kidney Dis. 2001 Dec;38(6 Suppl 6):S25-35. doi: 10.1053/ajkd.2001.28923.
• Background Pirsch JD, D'Alessandro AM, Sollinger HW, Knechtle SJ, Reed A, Kalayoglu M, Belzer FO. Hyperlipidemia and transplantation: etiologic factors and therapy. J Am Soc Nephrol. 1992 Jun;2(12 Suppl):S238-42. doi: 10.1681/ASN.V212s238.
• Background Shaw LM, Kaplan B, Kaufman D. Toxic effects of immunosuppressive drugs: mechanisms and strategies for controlling them. Clin Chem. 1996 Aug;42(8 Pt 2):1316-21.
• Background Boubenider S, Hiesse C, Goupy C, Kriaa F, Marchand S, Charpentier B. Incidence and consequences of post-transplantation lymphoproliferative disorders. J Nephrol. 1997 May-Jun;10(3):136-45.
• Background Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 1998 Jun 11;338(24):1741-51. doi: 10.1056/NEJM199806113382407. No abstract available.
• Background DeMario MD, Liebowitz DN. Lymphomas in the immunocompromised patient. Semin Oncol. 1998 Aug;25(4):492-502.
• Background Sia IG, Paya CV. Infectious complications following renal transplantation. Surg Clin North Am. 1998 Feb;78(1):95-112. doi: 10.1016/s0039-6109(05)70637-x.
• Background Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group. Transplantation. 1997 Apr 15;63(7):977-83. doi: 10.1097/00007890-199704150-00013.
• Background Ahsan N, Hricik D, Matas A, Rose S, Tomlanovich S, Wilkinson A, Ewell M, McIntosh M, Stablein D, Hodge E. Prednisone withdrawal in kidney transplant recipients on cyclosporine and mycophenolate mofetil--a prospective randomized study. Steroid Withdrawal Study Group. Transplantation. 1999 Dec 27;68(12):1865-74. doi: 10.1097/00007890-199912270-00009.
• Background Vincenti F, Ramos E, Brattstrom C, Cho S, Ekberg H, Grinyo J, Johnson R, Kuypers D, Stuart F, Khanna A, Navarro M, Nashan B. Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation. 2001 May 15;71(9):1282-7. doi: 10.1097/00007890-200105150-00017.
• Background Randhawa PS, Shapiro R, Jordan ML, Starzl TE, Demetris AJ. The histopathological changes associated with allograft rejection and drug toxicity in renal transplant recipients maintained on FK506. Clinical significance and comparison with cyclosporine. Am J Surg Pathol. 1993 Jan;17(1):60-8. doi: 10.1097/00000478-199301000-00007.
• Background Birkeland SA. Steroid-free immunosuppression after kidney transplantation with antithymocyte globulin induction and cyclosporine and mycophenolate mofetil maintenance therapy. Transplantation. 1998 Nov 15;66(9):1207-10. doi: 10.1097/00007890-199811150-00016.
• Background Calne R, Friend P, Moffatt S, Bradley A, Hale G, Firth J, Bradley J, Smith K, Waldmann H. Prope tolerance, perioperative campath 1H, and low-dose cyclosporin monotherapy in renal allograft recipients. Lancet. 1998 Jun 6;351(9117):1701-2. doi: 10.1016/S0140-6736(05)77739-4. No abstract available.
• Background Calne RY. Initial Experience with Campath-1H in Renal Transplantation. Transplantation Reviews 2003, in press.
• Background Knechtle SJ, Pirsch JD, H Fechner J Jr, Becker BN, Friedl A, Colvin RB, Lebeck LK, Chin LT, Becker YT, Odorico JS, D'Alessandro AM, Kalayoglu M, Hamawy MM, Hu H, Bloom DD, Sollinger HW. Campath-1H induction plus rapamycin monotherapy for renal transplantation: results of a pilot study. Am J Transplant. 2003 Jun;3(6):722-30. doi: 10.1034/j.1600-6143.2003.00120.x.
• Background Kirk AD, Hale DA, Mannon RB, Kleiner DE, Hoffmann SC, Kampen RL, Cendales LK, Tadaki DK, Harlan DM, Swanson SJ. Results from a human renal allograft tolerance trial evaluating the humanized CD52-specific monoclonal antibody alemtuzumab (CAMPATH-1H). Transplantation. 2003 Jul 15;76(1):120-9. doi: 10.1097/01.TP.0000071362.99021.D9.
• Background Hricik DE, Rodriguez V, Riley J, Bryan K, Tary-Lehmann M, Greenspan N, Dejelo C, Schulak JA, Heeger PS. Enzyme linked immunosorbent spot (ELISPOT) assay for interferon-gamma independently predicts renal function in kidney transplant recipients. Am J Transplant. 2003 Jul;3(7):878-84. doi: 10.1034/j.1600-6143.2003.00132.x.
• Background Gebauer BS, Hricik DE, Atallah A, Bryan K, Riley J, Tary-Lehmann M, Greenspan NS, Dejelo C, Boehm BO, Hering BJ, Heeger PS. Evolution of the enzyme-linked immunosorbent spot assay for post-transplant alloreactivity as a potentially useful immune monitoring tool. Am J Transplant. 2002 Oct;2(9):857-66. doi: 10.1034/j.1600-6143.2002.20908.x.
• Background Reinsmoen NL. Cellular methods used to evaluate the immune response in transplantation. Tissue Antigens. 2002 Apr;59(4):241-50. doi: 10.1034/j.1399-0039.2002.590401.x.

Drugs

Indications