Study of Sirolimus Versus Mycophenolate Liver Transplant Recipients With Recurrent Hepatitis C Virus (HCV)

The recruitment status of this study is unknown because the information has not been verified recently.
Verified June 2011 by London Health Sciences Centre.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
London Health Sciences Centre
ClinicalTrials.gov Identifier:
NCT01134952
First received: May 27, 2010
Last updated: June 24, 2011
Last verified: June 2011
  Purpose

Different immunosuppressive drugs used in transplantation may reduce the body's defences against infection differently. It is known that patients with Hepatitis C virus, known as HCV, who switched from azathioprine to mycophenolate mofetil experienced an increase in viral load. Despite this, mycophenolate mofetil is used because it prevents rejection more reliably than azathioprine. Sirolimus is an another immunosuppressive agent that reliably prevents rejection and may have antiviral activity. This study is designed to see if the viral load of HCV and other viruses is reduced by switching from mycophenolate to sirolimus.


Condition Intervention Phase
Recurrent Hepatitis C After Liver Transplantation
Drug: mycophenolate to sirolimus switch
Phase 4

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Prevention
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

Resource links provided by NLM:


Further study details as provided by London Health Sciences Centre:

Primary Outcome Measures:
  • Hepatitis C viral load [ Time Frame: 3 months after switching drug ] [ Designated as safety issue: Yes ]
    HCV particles / ml determined before switch from MMF to SRL and 3 months after return to MMF for comparison to 3 month level


Secondary Outcome Measures:
  • Epstein Barr virus (EBV) levels [ Time Frame: 3 months after switch ] [ Designated as safety issue: Yes ]
    EBV particles / ml determined before switch from MMF to SRL and 3 months after return to MMF for comparison with 3 month level

  • Cytomegalovirus (CMV) levels [ Time Frame: 3 months after switch ] [ Designated as safety issue: Yes ]
    CMV viral copies per ml to be compared to time 0 and to 3 months after return to MMF


Estimated Enrollment: 30
Study Start Date: June 2010
Estimated Study Completion Date: June 2012
Estimated Primary Completion Date: March 2012 (Final data collection date for primary outcome measure)
Intervention Details:
    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.
    Other Names:
    • rapamune
    • rapamycin
    • mycophenolic mofetil
    • mycophenolic acid
    • cellcept
Detailed Description:

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Recurrent HCV after liver transplantation
  • Taking mycophenolate mofetil
  • Stable liver function

Exclusion Criteria:

  • Pregnant females or couples unwilling to use contraception
  • Intolerance or allergy to sirolimus
  • Patients taking anti-HCV therapy
  • Patients taking medications known to alter the levels of sirolimus
  • History of thromboembolic disease
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01134952

Contacts
Contact: Vivian C McAlister, MB, FRCSC 5196632920 vmcalist@uwo.ca
Contact: Kimberly Boughner 5196632920 kimberly.boughner@lhsc.on.ca

Locations
Canada, Ontario
London Health Sciences Centre Recruiting
London, Ontario, Canada, N6A5A5
Contact: Vivian C McAlister, MB, FRCSC    5196632920    vmcalist@uwo.ca   
Contact: Natasha Chandok, MD, FRCPC    5196858500    Natasha.Chandok@lhsc.on.ca   
Sub-Investigator: Mark Levstik, MD         
Principal Investigator: Natasha Chandok, MD, FRCPC         
Sponsors and Collaborators
London Health Sciences Centre
Investigators
Study Director: Vivian McAlister, MB, FRCSC London Health Sciences Centre
Principal Investigator: Natasha Chandok, MD, FRCPC London Health Sciences Centre
  More Information

Additional Information:
Publications:

Responsible Party: Vivian McAlister, London Health Sciences Centre
ClinicalTrials.gov Identifier: NCT01134952     History of Changes
Other Study ID Numbers: UWO12961
Study First Received: May 27, 2010
Last Updated: June 24, 2011
Health Authority: Canada: Health Canada

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis C
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Mycophenolic Acid
Sirolimus
Mycophenolate mofetil
Everolimus
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents

ClinicalTrials.gov processed this record on July 24, 2014