MMF vs. AZA for Kidney Transplantation (ATHENA)
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|ClinicalTrials.gov Identifier: NCT00494741|
Recruitment Status : Completed
First Posted : July 2, 2007
Last Update Posted : December 13, 2017
|First Submitted Date ICMJE||June 29, 2007|
|First Posted Date ICMJE||July 2, 2007|
|Last Update Posted Date||December 13, 2017|
|Study Start Date ICMJE||May 2007|
|Actual Primary Completion Date||July 2016 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Cumulative incidence of biopsy-proven CAN at 3 years follow-up in patients completing CsA withdrawal in the two treatment groups (end phase B). [ Time Frame: At 3 years follow-up. ]|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT00494741 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||- To assess the overall incidence of acute rejections at 1 and 2 years. - To assess the overall incidence of CAN at 3 years. - To assess graft and patient survival at 4 years. [ Time Frame: At 1,2,3 and 4 years ]|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||MMF vs. AZA for Kidney Transplantation|
|Official Title ICMJE||A Randomized, Prospective, Multicenter Trial to Compare the Effect on Chronic Allograft Nephropathy Prevention of Mycophenolate Mofetil Versus Azathioprine as the Sole Immunosuppressive Therapy for Kidney Transplant Recipients|
The Mycophenolate Steroid Sparing (MYSS) study demonstrated that, in the setting of a maintenance immunosuppressive regimen without steroids, mycophenolate mofetil (MMF) and azathioprine (AZA) provided the same efficacy in preventing acute rejection episodes and allograft dysfunction in kidney transplant recipients. Induction therapy with basiliximab combined with low-dose thymoglobulin (RATG), through a transient depletion/inhibition of T lymphocytes, allows further reducing the need for maintenance immunosuppression.
Aim of the present study is to assess whether under this induction strategy MMF and AZA are equally effective in preventing acute rejection and chronic allograft nephropathy (CAN), even after cyclosporine (CsA) withdrawal.
Two-hundred-twenty-four kidney transplant recipients from deceased donors given induction therapy with two 20 mg basiliximab injections 4 days apart and a seven-day course of RATG (0.5 mg/kg/day), will be randomly allocated on a 1:1 basis to 3-year treatment with low-dose MMF or AZA, added-on CsA maintenance therapy. At 1 year, rejection-free patients with no evidence of tubulitis at kidney biopsy will withdraw CsA and will have a kidney biopsy 3 year post-transplant for evaluating the presence and severity of CAN. Should the cumulative incidence of acute rejection exceed 15% during CsA withdrawal the study will be stopped. Should the incidence differ by >30% between the two treatment arms, all patients will be given the most effective treatment and the follow up will be continued. A final biopsy will be repeated 4 years post-transplant.
Most patients are expected to be effectively maintained on single drug immunosuppression, which implies less steroid- and CsA- related complications and treatment costs. MMF is expected to prevent CAN more effectively than AZA. However, should AZA be more or as effective compared to MMF, at study end all patients could be shifted to AZA, that is 15-fold less expensive than MMF. Extended to clinical practice, these findings should translate in improved patient care and major cost-savings for the Health Care System.
INTRODUCTION The introduction of triple-therapy regimens that include a calcineurin inhibitor, steroids, and azathioprine (AZA) or mycophenolate mofetil (MMF) greatly reduced the risk of acute rejection in renal transplantation. However, the long-term use of both calcineurin inhibitors and steroids is associated with serious toxicities that ultimately impact patient and graft survival. Minimisation of chronic immunosuppression is therefore of paramount importance to improve patient and graft survival. Thus, the quest for strategies inducing specific immune hyporesponsiveness or even tolerance - ideally via short-term interventions that would target only the pathogenic immune response and leave the protective host immune response unimpaired - has provided a "holy grail" for transplant immunologists.
We recently found that induction therapy with basiliximab and lower (about one fourth) than conventional doses of Rabbit Anti-human Thymocyte Globulin (RATG), combined to low-dose CsA and MMF maintenance therapy, allowed ineffective prevention of acute rejection without steroids. Of note, unlike induction protocols with "standard" RATG doses, the above regimen was extremely well tolerated, avoided the risk of acute cytolysis reactions, reduced the incidence of immuno-hemolytic anemia and the need for red blood cell transfusions. Moreover, this approach did not increase the risk of CMV reactivations or lymphoproliferative disorders, even as compared to standard triple immunosuppressive regimens without induction therapy.
The doses of CsA employed in the above protocol were about half the doses currently used in clinical practice. However, even these very low doses have been reported to have a significant toxicity that, in the long-term, may adversely affect the graft function and survival. Thus, implementing innovative immunosuppressive strategies allowing to early and safely withdraw calcineurin inhibitor therapy might have major clinical implications in term of improved kidney function and long term survival. This would also avoid the adverse effects of chronic CsA therapy on arterial blood pressure, lipid profile and blood glucose that, altogether, remarkably increase the overall cardiovascular risk in these patients.
To this purpose, induction therapy with basiliximab plus low-dose RATG might help inducing a condition of reduced immuno-responsiveness that might allow to sequentially withdraw steroids and CsA without adversely affect the outcome of the graft.
Evidence that MMF suppresses the production of anti-HLA antibodies, inhibits the recruitment of mononuclear cells into the allograft, as well as the proliferation of arterial smooth muscle cells, has been taken to suggest that MMF might play an important protective effect against the development and progression of CAN. Thus, an immunosuppressive regimen based on low-dose MMF as sole antirejection drug not only would avoid chronic toxicity of steroids, and calcineurin inhibitors, but would also limit the risk of CAN, the main cause of allograft loss in the long-term. On the other hand, however, the Mycophenolate Steroid Sparing (MYSS) trial found that AZA was as effective as MMF in preventing acute allograft rejection in CsA-treated kidney transplant recipients, even after steroid withdrawal. Since acute allograft rejection is one of the strongest predictor of CAN, these findings can be taken to suggest that, in the long-term, AZA might share with MMF also a similar protective effect against the development of CAN. Moreover, it must be emphasized that chronic CsA nephrotoxicity is a major component of CAN. Thus, the prevalence and severity of CAN may be reduced in patients on CsA-free immunosuppressive regimens. In this clinical setting, the benefits of MMF against the development of CAN might not appreciably exceed those of AZA. Should this be the case, AZA might confer the same benefits of MMF, but at remarkably lower costs since, at equivalent doses, AZA is about 15 times less expensive than MMF.
Regardless of the above, MMF or AZA monotherapy would avoid or limit most of the complications of chronic immunosuppressive regimens including steroids and calcineurin inhibitors, such as metabolic, osteomuscular and cardiovascular diseases, cancer and opportunistic infections.
AIMS Primary To compare the incidence of CAN 3 years post-transplantation in patients receiving induction therapy with basiliximab and low-dose RATG and randomized to maintenance immunosuppression with low-dose MMF or AZA monotherapy.
DESIGN Two-hundred-twenty-four kidney transplant recipients from deceased donors given induction therapy with two 20 mg basiliximab injections 4 days apart, a seven-day course of RATG (0.5 mg/kg/day) and intravenous methylprednisolone for six days, will be randomly allocated on a 1:1 basis to 3-year treatment with low-dose MMF or AZA, added-on CsA maintenance therapy. At 1 year, rejection-free patients with no evidence of tubulitis at kidney biopsy will progressively taper/withdraw CsA and will have a kidney biopsy 3 year post-transplant for evaluating the presence and severity of CAN. Should the cumulative incidence of acute rejection exceed 15% during CsA withdrawal the study will be stopped. Should the incidence differ by >30% between the two treatment arms, all patients will be given the most effective treatment and the follow up will be continued. A final biopsy will be repeated 4 years post-transplant.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 4|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Kidney Transplant|
|Publications *||Cravedi P, Mannon RB, Remuzzi G. Lymphocyte depletion for kidney transplantation: back to the past? Nat Clin Pract Nephrol. 2008 Oct;4(10):534-5. doi: 10.1038/ncpneph0914. Epub 2008 Aug 26.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date||November 29, 2017|
|Actual Primary Completion Date||July 2016 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 75 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Italy|
|Removed Location Countries|
|NCT Number ICMJE||NCT00494741|
|Other Study ID Numbers ICMJE||ATHENA
2006-005604-14 ( EudraCT Number )
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Mario Negri Institute for Pharmacological Research|
|Study Sponsor ICMJE||Mario Negri Institute for Pharmacological Research|
|Collaborators ICMJE||Agenzia Italiana del Farmaco|
|PRS Account||Mario Negri Institute for Pharmacological Research|
|Verification Date||December 2017|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP