Study of Sirolimus Versus Mycophenolate Liver Transplant Recipients With Recurrent Hepatitis C Virus (HCV)
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|ClinicalTrials.gov Identifier: NCT01134952|
Recruitment Status : Completed
First Posted : June 2, 2010
Results First Posted : January 21, 2015
Last Update Posted : February 26, 2015
|Condition or disease||Intervention/treatment||Phase|
|Hepatitis C||Drug: Mycophenolate to sirolimus switch||Phase 4|
Hepatitis C virus (HCV) persistence after liver transplantation for HCV end-stage liver disease is universal and in this clinical setting, HCV mediated liver injury has been reported to follow a more progressive course compared to the non-immunosuppressed patient. Additionally, patients with recurrent chronic hepatitis C develop higher viral load compared to pre-transplant levels. Such persistently high viral burden post transplant may contribute to allograft damage. The choice of calcineurin inhibitor (CNI) does not effect recurrence rates of HCV hepatitis. HCV is also associated with renal dysfunction so that reduction in exposure to calcineurin inhibitors (CNI) is desirable. Unfortunately steroids are associated with a marked increase in HCV replication and cannot be used to reduce CNI doses. Mycophenolate mofetil (MMF) increases HCV viral load. A recent increase in the severity of recurrent hepatitis in patients with HCV receiving liver transplants has been attributed to MMF and interleukin-2 receptor blockers. Increased fibrosis of the liver occurs during antiviral anti HCV treatment in patients taking mycophenolate but patients on azathioprine develop cirrhosis faster, possibly because of rejection.
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.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||11 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Prospective Cross-over Study Comparing the Effect of Sirolimus Versus Mycophenolate on Viral Load in Liver Transplant Recipients With Recurrent Chronic HCV Infection|
|Study Start Date :||June 2010|
|Primary Completion Date :||December 2014|
|Study Completion Date :||December 2014|
Experimental: 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
Drug: 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.
- Delta Hepatitis C Viral Load [ Time Frame: 3 month ]Percent change in HCV load determined 3 months after switch from MMF to SRL.
- Final Hepatitis C Viral Load [ Time Frame: 3 month ]Percent change in HCV load determined 3 months after switch from SRL to MMF
- Sirolimus Trough Level [ Time Frame: 3 month ]
- Delta Tacrolimus Trough Level [ Time Frame: 3 month ]Percent change determined 3 months after switch from MMF to SRL
- Delta Bilirubin [ Time Frame: 3 month ]Percent change determined 3 months after switch from MMF to SRL
- Delta Alkaline Phosphatase [ Time Frame: 3 month ]Percent change determined 3 months after switch from MMF to SRL
- Delta Alanine Aminotransferase [ Time Frame: 3 month ]Percent change determined 3 months after switch from MMF to SRL
- Delta Hemoglobin [ Time Frame: 3 month ]Percent change determined 3 months after switch from MMF to SRL
- Delta Platelet Count [ Time Frame: 3 month ]Percent change determined 3 months after switch from MMF to SRL
- Delta Cholesterol Fasting Level [ Time Frame: 3 month ]Percent change determined 3 months after switch from MMF to SRL
- Delta Triglyceride Fasting Level [ Time Frame: 3 month ]Percent change determined 3 months after switch from MMF to SRL
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01134952
|London Health Sciences Centre|
|London, Ontario, Canada, N6A5A5|
|Study Director:||Vivian McAlister, MB, FRCSC||London Health Sciences Centre|
|Principal Investigator:||Natasha Chandok, MD, FRCPC||London Health Sciences Centre|