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

• Sponsor: London Health Sciences Centre (Other)
• Overall Status: Completed
• CT.gov ID: NCT01134952
• Collaborator: (none)
• Enrollment: 11
• Location: 1
• Arm: 1
• Duration (Months): 54
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief 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. 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 or Disease	Intervention/Treatment	Phase
Hepatitis C	Drug: Mycophenolate to sirolimus switch	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 11 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (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
• Study Start Date: Jun 1, 2010
• Actual Primary Completion Date: Dec 1, 2014
• Actual Study Completion Date: Dec 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
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.; Other Names: rapamune rapamycin mycophenolic mofetil mycophenolic acid cellcept

Outcome Measures

Primary Outcome Measures

1. Delta Hepatitis C Viral Load [3 month]

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

Secondary Outcome Measures

1. Final Hepatitis C Viral Load [3 month]

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

2. Sirolimus Trough Level [3 month]

3. Delta Tacrolimus Trough Level [3 month]

   Percent change determined 3 months after switch from MMF to SRL

4. Delta Bilirubin [3 month]

   Percent change determined 3 months after switch from MMF to SRL

5. Delta Alkaline Phosphatase [3 month]

   Percent change determined 3 months after switch from MMF to SRL

6. Delta Alanine Aminotransferase [3 month]

   Percent change determined 3 months after switch from MMF to SRL

7. Delta Hemoglobin [3 month]

   Percent change determined 3 months after switch from MMF to SRL

8. Delta Platelet Count [3 month]

   Percent change determined 3 months after switch from MMF to SRL

9. Delta Cholesterol Fasting Level [3 month]

   Percent change determined 3 months after switch from MMF to SRL

10. Delta Triglyceride Fasting Level [3 month]

    Percent change determined 3 months after switch from MMF to SRL

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1	London Health Sciences Centre	London	Ontario	Canada	N6A5A5

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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• PI research website
• Transplant Program website

Publications

• 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.
• 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. Review.
• 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, Hernández R, Hortal L, Sablón 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.
• 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;(4):CD005161. Review.
• 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.
• 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.
• Kornberg A, Küpper 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.
• McAlister VC, Gao Z, Peltekian K, Domingues J, Mahalati K, MacDonald AS. Sirolimus-tacrolimus combination immunosuppression. Lancet. 2000 Jan 29;355(9201):376-7.
• 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.
• 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.
• 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. Epub 2005 Sep 15.
• 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.
• 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.

• Responsible Party: Vivian McAlister, Principal investigator, London Health Sciences Centre
• ClinicalTrials.gov Identifier: NCT01134952
• Other Study ID Numbers: UWO12961
• First Posted: Jun 2, 2010
• Last Update Posted: Feb 26, 2015
• Last Verified: Feb 1, 2015

• Keywords provided by Vivian McAlister, Principal investigator, London Health Sciences Centre: sirolimus; everolimus; mycophenolic acid; hepatitis C virus; tacrolimus; viral load
• Additional relevant MeSH terms: Hepatitis A; Hepatitis C; Hepatitis; Mycophenolic Acid; Sirolimus

Study Results

Participant Flow

Arm/Group Title	MMF SRL Switch
Arm/Group Description	Liver transplant recipients with Hepatitis C virus taking sirolimus (SRL) instead of mycophenolate mofetil (MMF) for 3 months
Period Title: Overall Study
STARTED	11
COMPLETED	11
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	MMF MRL Switch
Arm/Group Description	Liver transplant recipients with Hepatitis C virus switched from mycophenolate mofetil (MMF) to sirolimus (SRL) for 3 months and then switched back to MMF
Overall Participants	11
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53 (7)
Sex: Female, Male (Count of Participants)
Female	3 27.3%
Male	8 72.7%
Region of Enrollment (participants) [Number]
Canada	11 100%
Hepatitis C viral load (10^7 HCV IU/mL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [10^7 HCV IU/mL]	2.8 (2.6)
Tacrolimus trough level (ng/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng/ml]	5.5 (1.9)
Bilirubin (umol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [umol/L]	8.8 (3.2)
Alkaline phosphatase (U/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/L]	94.5 (40.2)
Alanine aminotransferase (U/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [U/ml]	86.3 (56.1)
Hemoglobin (g/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [g/L]	145.1 (13.2)
Platelet count (10^9/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [10^9/L]	165.3 (58.3)
Fasting cholesterol (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	4.9 (1.4)
Triglyceride (mmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mmol/L]	1.7 (0.5)

Outcome Measures

1. Primary Outcome

Title	Delta Hepatitis C Viral Load
Description	Percent change in HCV load determined 3 months after switch from MMF to SRL.
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MMF SRL Switch
Arm/Group Description	Liver transplant recipients with HCV 3 months after switch from mycophenolate to sirolimus
Measure Participants	11
Mean (Standard Deviation) [percent change]	15 (53)

2. Secondary Outcome

Title	Final Hepatitis C Viral Load
Description	Percent change in HCV load determined 3 months after switch from SRL to MMF
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MMF SRL Switch
Arm/Group Description	All patients switched for 3 months from mycophenolate mofetil to sirolimus and then back to mycophenolate mofetil
Measure Participants	11
Mean (Standard Deviation) [percent change]	-47 (100)

3. Secondary Outcome

Title	Sirolimus Trough Level
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	MMF SRL Switch
Arm/Group Description	All patients after switch from mycophenolate to sirolimus
Measure Participants	11
Mean (Standard Deviation) [ng/ml]	7.2 (2.2)

4. Secondary Outcome

Title	Delta Tacrolimus Trough Level
Description	Percent change determined 3 months after switch from MMF to SRL
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

2 patients did not have tacrolimus levels recorded during both time periods and are excluded

Arm/Group Title	MMF SRL Switch
Arm/Group Description	Liver transplant recipients switched from mycophenolate mofetil to sirolimus
Measure Participants	9
Mean (Standard Deviation) [percent change]	23 (82)

5. Secondary Outcome

Title	Delta Bilirubin
Description	Percent change determined 3 months after switch from MMF to SRL
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

Levels available at correct time in only 7 patients

Arm/Group Title	MMF SRL Switch
Arm/Group Description	All patients 3 months after switch from mycophenolate to sirolimus
Measure Participants	7
Mean (Standard Deviation) [percent change]	-6.0 (25)

6. Secondary Outcome

Title	Delta Alkaline Phosphatase
Description	Percent change determined 3 months after switch from MMF to SRL
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

Levels not available at appropriate times in 2 patients

Arm/Group Title	MMF SRL Switch
Arm/Group Description	All patients 3 months after switch from mycophenolate to sirolimus
Measure Participants	9
Mean (Standard Deviation) [percent change]	13.8 (3)

7. Secondary Outcome

Title	Delta Alanine Aminotransferase
Description	Percent change determined 3 months after switch from MMF to SRL
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

Levels at appropriate time not available in 2 patients

Arm/Group Title	MMF SRL Switch
Arm/Group Description	All patients 3 months after switch from mycophenolate to sirolimus
Measure Participants	9
Mean (Standard Deviation) [percent change]	9 (28)

8. Secondary Outcome

Title	Delta Hemoglobin
Description	Percent change determined 3 months after switch from MMF to SRL
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

Levels at appropriate times not available in 2 patients

Arm/Group Title	MMF SRL Switch
Arm/Group Description	All patients 3 months after switch from mycophenolate to sirolimus
Measure Participants	9
Mean (Standard Deviation) [percent change]	-2.7 (2.7)

9. Secondary Outcome

Title	Delta Platelet Count
Description	Percent change determined 3 months after switch from MMF to SRL
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

Levels not available on 2 patients at appropriate time

Arm/Group Title	MMF SRL Switch
Arm/Group Description	All patients 3 months after switch from mycophenolate to sirolimus
Measure Participants	9
Mean (Standard Deviation) [percent change]	-8.5 (20)

10. Secondary Outcome

Title	Delta Cholesterol Fasting Level
Description	Percent change determined 3 months after switch from MMF to SRL
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

Levels not available for 2 patients

Arm/Group Title	MMF SRL Switch
Arm/Group Description	All patients 3 months after switch from mycophenolate to sirolimus
Measure Participants	9
Mean (Standard Deviation) [percent change]	1.2 (55)

11. Secondary Outcome

Title	Delta Triglyceride Fasting Level
Description	Percent change determined 3 months after switch from MMF to SRL
Time Frame	3 month

Outcome Measure Data

Analysis Population Description

Levels at appropriate times not available on 2 patients

Arm/Group Title	MMF SRL Switch
Arm/Group Description	All patients 3 months after switch from mycophenolate to sirolimus
Measure Participants	9
Mean (Standard Deviation) [percent change]	23 (81)

Adverse Events

Time Frame	6 months
Arm/Group Title	MMF SRL Switch
Arm/Group Description	All patients during 3 month period of switch from mycophenolate mofetil (MMF) to sirolimus and for 3 months after switch back to MMF
All Cause Mortality
	MMF SRL Switch
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	MMF SRL Switch
	Affected / at Risk (%)	# Events
Total	0/11 (0%)
Other (Not Including Serious) Adverse Events
	MMF SRL Switch
	Affected / at Risk (%)	# Events
Total	0/11 (0%)

Limitations/Caveats

Greater than expected baseline variation; technical problems with laboratory measurement of HCV (two different platforms used); and poor recruitment over a long period make the results difficult to interpret.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.