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Hepatitis CPhase 4NCT01134952

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

A Phase 4 study testing Mycophenolate to sirolimus switch in people with Hepatitis C, run by London Health Sciences Centre at 1 site in Canada.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Hepatitis C
What is being tested?
Mycophenolate to sirolimus switch
Could I receive a placebo?
No, everyone receives an active treatment
How many people
11 participants
Where
1 siteCanada
Study dates
Jun 2010to Dec 2014
Phase
Phase 4
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

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

Who cannot join

  • 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

Trial locations and contacts

1 site in 1 country.

Canada1 site
  • London Health Sciences Centre

    London, Ontario, N6A5A5

Other trials in Canada

About this study

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

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.

Read the 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.

Conditions
Hepatitis C
Being tested
Mycophenolate to sirolimus switch
Keywords
sirolimus, everolimus, mycophenolic acid, hepatitis C virus, tacrolimus, viral load
Medical subject headings
Hepatitis C

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Mycophenolate to sirolimus switchDrug

    Also called rapamune, rapamycin, mycophenolic mofetil, mycophenolic acid

    Sirolimus given for 3 months instead of mycophenolate at a starting dose equivalent of 1 mg sirolimus equal to 1000 mg of mycophenolate.

Study groups in NCT01134952
Study groupRoleWhat they receive
Mycophenolate to sirolimus switchExperimentalLiver transplant recipients with Hepatitis C virus switched from mycophenolate mofetil (MMF) to sirolimus (SRL) for 3 months and then switched back to MMF
Receives: Drug: Mycophenolate to sirolimus switch

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Delta Hepatitis C Viral Load

    Percent change in HCV load determined 3 months after switch from MMF to SRL.

    Measured: 3 month

Secondary outcomes (10)
  1. Final Hepatitis C Viral Load

    Percent change in HCV load determined 3 months after switch from SRL to MMF

    Measured: 3 month

  2. Sirolimus Trough Level

    Measured: 3 month

  3. Delta Tacrolimus Trough Level

    Percent change determined 3 months after switch from MMF to SRL

    Measured: 3 month

  4. Delta Bilirubin

    Percent change determined 3 months after switch from MMF to SRL

    Measured: 3 month

  5. Delta Alkaline Phosphatase

    Percent change determined 3 months after switch from MMF to SRL

    Measured: 3 month

  6. Delta Alanine Aminotransferase

    Percent change determined 3 months after switch from MMF to SRL

    Measured: 3 month

  7. Delta Hemoglobin

    Percent change determined 3 months after switch from MMF to SRL

    Measured: 3 month

  8. Delta Platelet Count

    Percent change determined 3 months after switch from MMF to SRL

    Measured: 3 month

  9. Delta Cholesterol Fasting Level

    Percent change determined 3 months after switch from MMF to SRL

    Measured: 3 month

  10. Delta Triglyceride Fasting Level

    Percent change determined 3 months after switch from MMF to SRL

    Measured: 3 month

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted2 Jun 2010 (estimated)
  2. Study startJun 2010
  3. Primary completionDec 2014
  4. Study completionDec 2014

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Prevention
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
11 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01134952
Sponsor's protocol ID
UWO12961
Status last verified
Feb 2015
First submitted
27 May 2010
Last updated
26 Feb 2015
Data monitoring committee
No

Publications

  • 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.

    PubMed 14755778
  • 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.

    PubMed 10665560
  • 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.

    PubMed 20048692
  • 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.

    PubMed 19715912
  • 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.

    PubMed 16239045
  • 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.

    PubMed 11799480
  • 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.

    PubMed 14586897
  • 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.

    PubMed 11571449
  • 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.

    PubMed 12907620
  • 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.

    PubMed 15376305
  • 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.

    PubMed 17627238
  • 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.

    PubMed 15589468
  • 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.

    PubMed 17054241
  • 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.

    PubMed 10755563

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Mycophenolate to sirolimus switch in people with Hepatitis C, run by London Health Sciences Centre at 1 site in Canada.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 3 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 Feb 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 21 Jan 2015). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Delta Hepatitis C Viral Load (time frame: 3 month). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01134952, which also lists 14 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 Feb 2015.

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