Study of Sirolimus Versus Mycophenolate Liver Transplant Recipients With Recurrent Hepatitis C Virus (HCV)
NCT ID: NCT01134952
Last Updated: 2015-02-26
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE4
11 participants
INTERVENTIONAL
2010-06-30
2014-12-31
Brief Summary
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Detailed Description
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A large industry sponsored phase III clinical trial has been underway for several years where patients have substituted sirolimus (SRL) for calcineurin inhibitors after liver transplantation. The object of that study is to determine impact of conversion on renal function. No detrimental effect (thrombosis, rejection or recurrent viral infection) was apparent to the safety board after two reviews. No study has compared SRL to MMF after liver transplantation.
SRL, an immunosuppressive drug that inhibits the activation and proliferation of T-lymphocytes, is associated with reduction of Epstein Barr Virus (EBV) post-transplantation viral load in children. Experimentally it inhibits the growth of EBV B-cell lymphoma. A pilot study of tacrolimus with SRL showed a powerful anti-rejection effect but a subsequent trial was halted early because of an increase in hepatic artery thrombosis even though the rates of thrombosis in either arm of the study was below that expected. A recent large series in patients with hepatocellular carcinoma (most of whom had HCV) who received large doses of SRL showed a beneficial anti-cancer effect without thrombosis. The randomised trials and the reported series all had large numbers of patients with HCV. The absence of obvious recurrent HCV hepatitis and the low rates of cytomegalovirus (CMV) disease coupled with the known inhibition of EBV replication gives hope that SRL has anti-viral properties at immunosuppressive doses. Early reports confirm that hope: 1) successful liver transplantation in patients with HIV and HCV. "Significantly better control of HIV and HCV replication was found among patients taking RAPA monotherapy (P=0.0001 and 0.03, respectively)"; 2) switching to sirolimus in renal transplant recipients with hepatitis C virus: HCV replication reduced by switch to sirolimus; 3) sustained, spontaneous disappearance of serum HCV-RNA under immunosuppression after liver transplantation for HCV cirrhosis: two liver recipients who spontaneously cleared HCV after switch to sirolimus.
SRL (2 mg/day) and MMF (2g/day) are licensed as adjuvant immunosuppressive agents to be used in kidney transplantation with cyclosporine so that immunosuppressive equivalent doses are 1mg SRL = 1g MMF.
Conditions
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Study Design
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NA
SINGLE_GROUP
PREVENTION
NONE
Study Groups
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Mycophenolate to sirolimus switch
Liver transplant recipients with Hepatitis C virus switched from mycophenolate mofetil (MMF) to sirolimus (SRL) for 3 months and then switched back to MMF
Mycophenolate to sirolimus switch
Sirolimus given for 3 months instead of mycophenolate at a starting dose equivalent of 1 mg sirolimus equal to 1000 mg of mycophenolate.
Interventions
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Mycophenolate to sirolimus switch
Sirolimus given for 3 months instead of mycophenolate at a starting dose equivalent of 1 mg sirolimus equal to 1000 mg of mycophenolate.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Taking mycophenolate mofetil
* Stable liver function
Exclusion Criteria
* Intolerance or allergy to sirolimus
* Patients taking anti-HCV therapy
* Patients taking medications known to alter the levels of sirolimus
* History of thromboembolic disease
18 Years
ALL
No
Sponsors
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London Health Sciences Centre
OTHER
Responsible Party
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Vivian McAlister
Principal investigator
Principal Investigators
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Vivian McAlister, MB, FRCSC
Role: STUDY_DIRECTOR
London Health Sciences Centre
Natasha Chandok, MD, FRCPC
Role: PRINCIPAL_INVESTIGATOR
London Health Sciences Centre
Locations
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London Health Sciences Centre
London, Ontario, Canada
Countries
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References
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Zekry A, Gleeson M, Guney S, McCaughan GW. A prospective cross-over study comparing the effect of mycophenolate versus azathioprine on allograft function and viral load in liver transplant recipients with recurrent chronic HCV infection. Liver Transpl. 2004 Jan;10(1):52-7. doi: 10.1002/lt.20000.
McAlister VC, Gao Z, Peltekian K, Domingues J, Mahalati K, MacDonald AS. Sirolimus-tacrolimus combination immunosuppression. Lancet. 2000 Jan 29;355(9201):376-7. doi: 10.1016/S0140-6736(99)03882-9.
Di Benedetto F, Di Sandro S, De Ruvo N, Montalti R, Ballarin R, Guerrini GP, Spaggiari M, Guaraldi G, Gerunda G. First report on a series of HIV patients undergoing rapamycin monotherapy after liver transplantation. Transplantation. 2010 Mar 27;89(6):733-8. doi: 10.1097/TP.0b013e3181c7dcc0.
Gallego R, Henriquez F, Oliva E, Camacho R, Hernandez R, Hortal L, Sablon N, Quintana B, Santana R, Gonzalez F, Palop L, Vega N. Switching to sirolimus in renal transplant recipients with hepatitis C virus: a safe option. Transplant Proc. 2009 Jul-Aug;41(6):2334-6. doi: 10.1016/j.transproceed.2009.06.064.
Samonakis DN, Cholongitas E, Triantos CK, Griffiths P, Dhillon AP, Thalheimer U, Patch DW, Burroughs AK. Sustained, spontaneous disappearance of serum HCV-RNA under immunosuppression after liver transplantation for HCV cirrhosis. J Hepatol. 2005 Dec;43(6):1091-3. doi: 10.1016/j.jhep.2005.08.005. Epub 2005 Sep 15.
Ballardini G, De Raffele E, Groff P, Bioulac-Sage P, Grassi A, Ghetti S, Susca M, Strazzabosco M, Bellusci R, Iemmolo RM, Grazi G, Zauli D, Cavallari A, Bianchi FB. Timing of reinfection and mechanisms of hepatocellular damage in transplanted hepatitis C virus-reinfected liver. Liver Transpl. 2002 Jan;8(1):10-20. doi: 10.1053/jlts.2002.30141.
Charlton M. Liver biopsy, viral kinetics, and the impact of viremia on severity of hepatitis C virus recurrence. Liver Transpl. 2003 Nov;9(11):S58-62. doi: 10.1053/jlts.2003.50245.
Sindhi R, Webber S, Venkataramanan R, McGhee W, Phillips S, Smith A, Baird C, Iurlano K, Mazariegos G, Cooperstone B, Holt DW, Zeevi A, Fung JJ, Reyes J. Sirolimus for rescue and primary immunosuppression in transplanted children receiving tacrolimus. Transplantation. 2001 Sep 15;72(5):851-5. doi: 10.1097/00007890-200109150-00019.
Nepomuceno RR, Balatoni CE, Natkunam Y, Snow AL, Krams SM, Martinez OM. Rapamycin inhibits the interleukin 10 signal transduction pathway and the growth of Epstein Barr virus B-cell lymphomas. Cancer Res. 2003 Aug 1;63(15):4472-80.
Kneteman NM, Oberholzer J, Al Saghier M, Meeberg GA, Blitz M, Ma MM, Wong WW, Gutfreund K, Mason AL, Jewell LD, Shapiro AM, Bain VG, Bigam DL. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl. 2004 Oct;10(10):1301-11. doi: 10.1002/lt.20237.
Iacob S, Cicinnati VR, Hilgard P, Iacob RA, Gheorghe LS, Popescu I, Frilling A, Malago M, Gerken G, Broelsch CE, Beckebaum S. Predictors of graft and patient survival in hepatitis C virus (HCV) recipients: model to predict HCV cirrhosis after liver transplantation. Transplantation. 2007 Jul 15;84(1):56-63. doi: 10.1097/01.tp.0000267916.36343.ca.
Kornberg A, Kupper B, Tannapfel A, Hommann M, Scheele J. Impact of mycophenolate mofetil versus azathioprine on early recurrence of hepatitis C after liver transplantation. Int Immunopharmacol. 2005 Jan;5(1):107-15. doi: 10.1016/j.intimp.2004.09.010.
Haddad EM, McAlister VC, Renouf E, Malthaner R, Kjaer MS, Gluud LL. Cyclosporin versus tacrolimus for liver transplanted patients. Cochrane Database Syst Rev. 2006 Oct 18;2006(4):CD005161. doi: 10.1002/14651858.CD005161.pub2.
Rostaing L, Izopet J, Sandres K, Cisterne JM, Puel J, Durand D. Changes in hepatitis C virus RNA viremia concentrations in long-term renal transplant patients after introduction of mycophenolate mofetil. Transplantation. 2000 Mar 15;69(5):991-4. doi: 10.1097/00007890-200003150-00055.
Related Links
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Transplant Program website
Other Identifiers
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UWO12961
Identifier Type: -
Identifier Source: org_study_id
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