A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation

Paul Keown, Pekka Häyry, Peter Morris, Calvin Stiller, Chris Barker, Lisa Carr, David Landsberg, Ian Hardie, Russell Rigby, Helena Isoniemi, Derek Gray, Philip Belitsky, Allan McDonald, Tim Mathew, A. Clarkson, L. Barratt, B. Buchholz, Rowan Walker, Günther Kirste, Norman MuirheadDavid Tiller, Geoff Duggin, Philip Halloran, Pierre Daloze, Gilles St. Louis, David Russell, David Ludwin, P. Vialtel, U. Binswanger, J. A C Buckels, Jean Louis Touraine, David Hickey, Giuseppe Remuzzi, Giuseppe Locatelli, F. T. Lam, Ed Tapper

Research output: Contribution to journalArticle

Abstract

Mycophenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multicenter trial to compare the efficacy and safety of MMF and azathioprine within a standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.0% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3 g group (P = 0.0045) and 38.2% in the MMF 2 g group (P = 0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF 2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1%, 10.4%, and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were treated for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.

Original languageEnglish
Pages (from-to)1029-1037
Number of pages9
JournalTransplantation
Volume61
Issue number7
DOIs
Publication statusPublished - Apr 15 1996

Fingerprint

Mycophenolic Acid
Kidney Transplantation
Randomized Controlled Trials
Azathioprine
Graft Rejection
Treatment Failure
Transplantation
Cytomegalovirus Infections
Immunosuppressive Agents

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. / Keown, Paul; Häyry, Pekka; Morris, Peter; Stiller, Calvin; Barker, Chris; Carr, Lisa; Landsberg, David; Hardie, Ian; Rigby, Russell; Isoniemi, Helena; Gray, Derek; Belitsky, Philip; McDonald, Allan; Mathew, Tim; Clarkson, A.; Barratt, L.; Buchholz, B.; Walker, Rowan; Kirste, Günther; Muirhead, Norman; Tiller, David; Duggin, Geoff; Halloran, Philip; Daloze, Pierre; St. Louis, Gilles; Russell, David; Ludwin, David; Vialtel, P.; Binswanger, U.; Buckels, J. A C; Touraine, Jean Louis; Hickey, David; Remuzzi, Giuseppe; Locatelli, Giuseppe; Lam, F. T.; Tapper, Ed.

In: Transplantation, Vol. 61, No. 7, 15.04.1996, p. 1029-1037.

Research output: Contribution to journalArticle

Keown, P, Häyry, P, Morris, P, Stiller, C, Barker, C, Carr, L, Landsberg, D, Hardie, I, Rigby, R, Isoniemi, H, Gray, D, Belitsky, P, McDonald, A, Mathew, T, Clarkson, A, Barratt, L, Buchholz, B, Walker, R, Kirste, G, Muirhead, N, Tiller, D, Duggin, G, Halloran, P, Daloze, P, St. Louis, G, Russell, D, Ludwin, D, Vialtel, P, Binswanger, U, Buckels, JAC, Touraine, JL, Hickey, D, Remuzzi, G, Locatelli, G, Lam, FT & Tapper, E 1996, 'A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation', Transplantation, vol. 61, no. 7, pp. 1029-1037. https://doi.org/10.1097/00007890-199604150-00008
Keown, Paul ; Häyry, Pekka ; Morris, Peter ; Stiller, Calvin ; Barker, Chris ; Carr, Lisa ; Landsberg, David ; Hardie, Ian ; Rigby, Russell ; Isoniemi, Helena ; Gray, Derek ; Belitsky, Philip ; McDonald, Allan ; Mathew, Tim ; Clarkson, A. ; Barratt, L. ; Buchholz, B. ; Walker, Rowan ; Kirste, Günther ; Muirhead, Norman ; Tiller, David ; Duggin, Geoff ; Halloran, Philip ; Daloze, Pierre ; St. Louis, Gilles ; Russell, David ; Ludwin, David ; Vialtel, P. ; Binswanger, U. ; Buckels, J. A C ; Touraine, Jean Louis ; Hickey, David ; Remuzzi, Giuseppe ; Locatelli, Giuseppe ; Lam, F. T. ; Tapper, Ed. / A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. In: Transplantation. 1996 ; Vol. 61, No. 7. pp. 1029-1037.
@article{ce21e41cadb14e31ac3bc4fb15ec1f7d,
title = "A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation",
abstract = "Mycophenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multicenter trial to compare the efficacy and safety of MMF and azathioprine within a standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.0{\%} of patients in the AZA group by 6 months after transplantation, compared with 34.8{\%} in the MMF 3 g group (P = 0.0045) and 38.2{\%} in the MMF 2 g group (P = 0.0287). Biopsy-proven rejection occurred in 15.9{\%} of patients in the MMF 3 g group and 19.7{\%} in the MMF 2 g group, compared with 35.5{\%} in the AZA group. Rejection of histologic severity grade II or more developed in 6.1{\%}, 10.4{\%}, and 19.9{\%} of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4{\%} of patients on MMF 3 g and 31.0{\%} on MMF 2 g were treated for acute rejection, compared with 47.5{\%} on AZA. Only 4.9{\%} on MMF 3 g and 8.8{\%} on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4{\%} of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.",
author = "Paul Keown and Pekka H{\"a}yry and Peter Morris and Calvin Stiller and Chris Barker and Lisa Carr and David Landsberg and Ian Hardie and Russell Rigby and Helena Isoniemi and Derek Gray and Philip Belitsky and Allan McDonald and Tim Mathew and A. Clarkson and L. Barratt and B. Buchholz and Rowan Walker and G{\"u}nther Kirste and Norman Muirhead and David Tiller and Geoff Duggin and Philip Halloran and Pierre Daloze and {St. Louis}, Gilles and David Russell and David Ludwin and P. Vialtel and U. Binswanger and Buckels, {J. A C} and Touraine, {Jean Louis} and David Hickey and Giuseppe Remuzzi and Giuseppe Locatelli and Lam, {F. T.} and Ed Tapper",
year = "1996",
month = "4",
day = "15",
doi = "10.1097/00007890-199604150-00008",
language = "English",
volume = "61",
pages = "1029--1037",
journal = "Transplantation",
issn = "0041-1337",
publisher = "Lippincott Williams and Wilkins",
number = "7",

}

TY - JOUR

T1 - A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation

AU - Keown, Paul

AU - Häyry, Pekka

AU - Morris, Peter

AU - Stiller, Calvin

AU - Barker, Chris

AU - Carr, Lisa

AU - Landsberg, David

AU - Hardie, Ian

AU - Rigby, Russell

AU - Isoniemi, Helena

AU - Gray, Derek

AU - Belitsky, Philip

AU - McDonald, Allan

AU - Mathew, Tim

AU - Clarkson, A.

AU - Barratt, L.

AU - Buchholz, B.

AU - Walker, Rowan

AU - Kirste, Günther

AU - Muirhead, Norman

AU - Tiller, David

AU - Duggin, Geoff

AU - Halloran, Philip

AU - Daloze, Pierre

AU - St. Louis, Gilles

AU - Russell, David

AU - Ludwin, David

AU - Vialtel, P.

AU - Binswanger, U.

AU - Buckels, J. A C

AU - Touraine, Jean Louis

AU - Hickey, David

AU - Remuzzi, Giuseppe

AU - Locatelli, Giuseppe

AU - Lam, F. T.

AU - Tapper, Ed

PY - 1996/4/15

Y1 - 1996/4/15

N2 - Mycophenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multicenter trial to compare the efficacy and safety of MMF and azathioprine within a standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.0% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3 g group (P = 0.0045) and 38.2% in the MMF 2 g group (P = 0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF 2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1%, 10.4%, and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were treated for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.

AB - Mycophenolate mofetil (MMF) is a powerful immunosuppressant that inhibits the proliferation of T and B lymphocytes by blocking the enzyme inosine monophosphate dehydrogenase. MMF has been shown to prevent acute graft rejection in animal experiments and may have an important role in clinical renal transplantation. We conducted a prospective, double-blind, multicenter trial to compare the efficacy and safety of MMF and azathioprine within a standard immunosuppressive regimen for patients receiving a first or second cadaveric renal graft. A total of 503 patients were randomized to groups receiving MMF 3 g (n=164), MMF 2 g (n=173), or azathioprine (AZA) 100-150 mg (n=166) daily. All were treated simultaneously with equivalent doses of cyclosporine and oral corticosteroids and followed for 12 months. The primary endpoint was treatment failure, defined as the occurrence of biopsy-proven graft rejection, graft loss, patient death, or discontinuation of the study drug during the first 6 months after transplantation. Treatment failure occurred in 50.0% of patients in the AZA group by 6 months after transplantation, compared with 34.8% in the MMF 3 g group (P = 0.0045) and 38.2% in the MMF 2 g group (P = 0.0287). Biopsy-proven rejection occurred in 15.9% of patients in the MMF 3 g group and 19.7% in the MMF 2 g group, compared with 35.5% in the AZA group. Rejection of histologic severity grade II or more developed in 6.1%, 10.4%, and 19.9% of patients in the MMF 3 g, MMF 2 g, and AZA groups, respectively. Patients receiving MMF required less frequent and less intensive treatment for acute rejection: 24.4% of patients on MMF 3 g and 31.0% on MMF 2 g were treated for acute rejection, compared with 47.5% on AZA. Only 4.9% on MMF 3 g and 8.8% on MMF 2 g required antilymphocyte antibodies for treatment of severe or steroid-resistant rejection, compared with 15.4% of the patients on AZA. At 1 year after transplantation, graft survival in the MMF groups was marginally superior to that in the AZA group, although this difference was not statistically significant. Gastrointestinal toxicity and tissue-invasive cytomegalovirus infection were more common in the MMF 3 g group. Noncutaneous malignancies occurred in six patients on MMF 3 g, three patients on MMF 2 g, and four patients on AZA. Lymphoproliferative disorders occurred in two patients per MMF group, compared with one patient receiving AZA. MMF appears to be an important advance in prophylaxis following renal transplantation. It is associated with a significantly lower rate of treatment failure compared with AZA during the first 6 months after renal transplantation and produces a clinically important reduction in the incidence, severity, and treatment of acute graft rejection. These differences persist throughout the first year of follow-up. Clinical benefit was greatest with a dose of MMF 3 g/day, but gastrointestinal effects, invasive cytomegalovirus infection, and malignancies were slightly more common at that dose. The appropriate dose may lie between 2 g and 3 g per day and may require individualization depending on clinical course or other factors.

UR - http://www.scopus.com/inward/record.url?scp=0006986048&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0006986048&partnerID=8YFLogxK

U2 - 10.1097/00007890-199604150-00008

DO - 10.1097/00007890-199604150-00008

M3 - Article

C2 - 8623181

AN - SCOPUS:0006986048

VL - 61

SP - 1029

EP - 1037

JO - Transplantation

JF - Transplantation

SN - 0041-1337

IS - 7

ER -