Ribavirin Pre-treatment Followed by Combined Standard Therapy in Hepatitis C Virus (HCV) Recipients
Information source: University of Roma La Sapienza
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hepatitis C
Intervention: ribavirin pre-treatment (Drug)
Phase: Phase 4
Status: Completed
Sponsored by: University of Roma La Sapienza
Summary
The results of antiviral therapy in patients with recurrent hepatitis C after liver
transplantation are lower than standard. Ribavirin has immune-modulating effects and seems
to be crucial to optimize viral treatment. The aim of this multicenter controlled study is
to examine the effect of Ribavirin pre-treatment preceding the combination therapy with
peginterferon plus ribavirin on the sustained virological response.
Clinical Details
Official title: Phase 2 Randomized Multicenter Controlled Study of Ribavirin Pre-treatment (8 Weeks) Followed by Standard Therapy With Ribavirin and Pegylated Interferon (48 Weeks) in Transplanted Patients With Recurrence of Chronic Hepatitis C
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: HCV-RNA level, Transaminases level
Secondary outcome: liver biopsy and Transient elastography at baseline and after six month since therapy conclusion
Detailed description:
Ribavirin Pre-Treatment Study Protocol
1. Introduction:
- Recurrence of hepatitis C infection and liver transplant:
Recurrence of hepatitis C after liver transplant is almost universal. After liver
transplantation, the progression of chronic hepatitis C is more aggressive and an high
percentage of recipients develop cirrhosis and rapid liver decompensation (1). Recent
studies have shown that the long-term-survival-rate is significantly lower compared
with non-HCV infected recipients (2). Other studies founded that antiviral treatment
improves survival in these patients. Thus, the treatment of hepatitis C patients after
LT is a priority for transplant units.
To date, the rate of sustained virologic response (SVR) in patients with recurrent
hepatitis C after liver transplantation is about 20% with standard IFN and increases to
30% with pegylated IFN and Ribavirin (3). Lack in tolerability and low compliance to
the antiviral therapy may represent an important limiting factor in order to improve
the SVR. Severe myelosuppression is frequent in these patients, due to the additional
effect of immunosuppressive therapy, being an additional reason to reduce antiviral
drug dosage (3).
- Ribavirin:
Recent studies have evaluated the effects of a ribavirin priming before the standard
combined antiviral therapy in immuno-competent patients with chronic hepatitis C (4-7).
The conclusion of these studies may suggest that ribavirin pre-treatment may be a way
to improve the SVR.
2. Aim of the study:
The study is a randomized un-blind multicenter project to compare the efficacy of
antiviral treatment with a RBV priming vs standard antiviral treatment in patients with
recurrent hepatitis C after liver transplantation.
Ribavirin pre-treatment may:
- Ameliorate therapy-compliance
- Avoid a concomitant drugs-related hematological side effects
- Modify the intra-hepatic cytokine pattern toward a better antiviral action
- Improve the SVR.
This controlled trial is not sponsored by a drug company.
3. Patients:
The protocol of the study needs to be approved by the local ethic committee. Patients
are enrolled in the study after been informed of the purpose and protocol of treatment
and need to sign a written informed consent.
4. Statistical analysis, sample size and randomization:
Sample size calculations were performed using EVR as the primary outcome measure. We
assumed that 48 weeks intended treatment with pegylated interferon and ribavirin in
transplant patients with recurrent hepatitis C induced EVR in about 60% of patients
(10). In our pilot study ribavirin priming followed by 48 weeks of pegylated interferon
and ribavirin obtained EVR in 92% of patients. To show an improvement of EVR from 60 to
92% , assuming an alpha level of 0. 05, and 90% power ( beta =0. 20) fifty patients per
group are needed.
Patients will be randomized after inclusion in the study, using an opaque envelope
technique to be assigned to their treatment by a predetermined sequence at the
Coordinator Center. Randomization will be stratified for genotype 1 and non1 to
decrease the likelihood that uneven distribution of underlying disease severity would
bias the results. Randomization will occur in blocks of four.
5. Definitions:
The following definitions are going to be used; during the study:
- Rapid Virological Response: complete viral clearance at week 4
- Early Virologic Response: viral reduction > 2 log after 12 weeks of combined
therapy.
- Complete Early Virological Response: complete viral clearance after 12 weeks of
combined therapy.
- End of treatment Virologic Response: complete viral clearance at the end of the
treatment period
- Sustained Virologic Response: complete viral clearance 24 weeks after the end of
treatment
- Non Responder: Absence of virological response after 12 weeks
- Relapse: recurrence of viral replication after a complete clearance during
treatment time or after the conclusion of it.
6. Protocol of the study:
Basal Evaluation:
- Liver biopsy within the last 6 months
- Complete biochemical assessment (liver function tests, renal function, blood tests,
levels of immunosuppressive therapy)
- HCV-RNA quantitative determination
Randomization: Patient are randomized to treatment A or Treatment B):
- Treatment A:
Pre-treatment:
Ribavirin is started at 600 mg/day (or 400mg/ day if < 60 kg) and increased to 10,4 mg/kg
within week 2, the therapy is continued for 8 complete weeks.
Biochemical assessment is repeated at week 2, 4, 8. Samples are stored at the same times.
HCV-RNA quantitative determination is repeated at week 8. Drug reduction is allowed when
hemoglobin level is below 10 g/dL though EPO administration or whenever it is considered
necessary.
Combined antiviral therapy:
For 48 weeks patients are treated with Ribavirin (same dosage) and IFN alfa2b (1,5
mcg/kg/week).
Patients are followed monthly or more frequently if required. Biochemical and virological
assessment is recorded at week 4, 12, 24, 48. Surveillance is performed for any collateral
effects and dose adjustment or growth factor need.
Ribavirin reduction is required when hemoglobin level is below 10 g/dL though EPO use.
IFN weekly administration should be reduced when neutrophiles count is < 750 in spite of
G-CSF administration.
IFN interruption is required when neutrophiles are < 500 or platelets are < 35000.
- Treatment B:
For 48 weeks patients are treated with Ribavirin (10 mg/kg ) and pegylated IFN alfa2b
weekly.
Ribavirin is started at 600 mg/day and increased to 10 mg/kg within week 2. Pegylated IFN
alfa2b is administered weekly at a dose of 1,5/kg/week. Patients are followed twice monthly
in the first month and at least monthly thereafter (more frequently whenever is required).
Biochemical and virological assessment is recorded at week 4, 12, 24, 48. Surveillance is
performed for any collateral effects and dose adjustment or growth factor need.
Ribavirin reduction is required when hemoglobin level is below 10 g/dL though EPO use.
IFN weekly administration should be reduced when neutrophiles count is < 750 in spite of
G-CSF administration.
IFN interruption is required when neutrophiles are < 500 or platelets are < 35000.
End-points of the study:
- Rapid Virological Response ( week 4)
- Early Virological Response (week 12)
- Complete Early Virological Response (week 12)
- End of treatment Virological Response (week 48)
- End of treatment Biochemical Response (week 48)
- Sustained Virological Response (Six months after the end of therapy)
Collateral effects, dose adjustment and use of growth factors are recorded.
Eligibility
Minimum age: N/A.
Maximum age: 65 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
1. Liver transplantation from > 6 months
2. Positive HCV-RNA viremia
3. Elevated transaminase levels (greater than 1,2 normal values) in at least two
consecutive determinations during the last month
4. Histology pattern showing hepatitis C recurrence
Exclusion Criteria:
1. Multiple organ transplantation
2. Histology showing evidence of hepatic allograft rejection > 3/9 RAI score
3. Concomitant active biliary disease
4. Concomitant HBV infection
5. Normal transaminases levels
6. Less than 1500 neutrophiles in more than one blood test
7. Less than 50000 platelets in more than one blood test
8. Hemoglobin < 9 g/ dL
9. Creatinine clearance < 35 ml/min
10. Positive antibodies > 1: 80
11. Auto-immune thyroid pathology
12. Severe psychiatric disease
13. Diagnosis of ischemic cardiopathy in the last 12 months
14. Active alcohol abuse
15. Low compliance to other medical treatments
Locations and Contacts
Sapienza University of Rome, Rome 00100, Italy
Additional Information
Related publications: Gordon FD, Kwo P, Vargas HE. Treatment of hepatitis C in liver transplant recipients. Liver Transpl. 2009 Feb;15(2):126-35. doi: 10.1002/lt.21694. Review. Furusyo N, Kubo N, Toyoda K, Takeoka H, Nabeshima S, Murata M, Nakamuta M, Hayashi J. Helper T cell cytokine response to ribavirin priming before combined treatment with interferon alpha and ribavirin for patients with chronic hepatitis C. Antiviral Res. 2005 Jul;67(1):46-54. Feld JJ, Nanda S, Huang Y, Chen W, Cam M, Pusek SN, Schweigler LM, Theodore D, Zacks SL, Liang TJ, Fried MW. Hepatic gene expression during treatment with peginterferon and ribavirin: Identifying molecular pathways for treatment response. Hepatology. 2007 Nov;46(5):1548-63. Ogawa K, Hige S, Nakanishi M, Yamamoto Y, Chuma M, Nagasaka A, Asaka M. Immunological and mutagenic actions of ribavirin monotherapy preceding combination therapy with interferon for patients with chronic hepatitis C. Antivir Ther. 2009;14(4):513-22. Töx U, Schulte S, Heindl B, Goeser T, Drebber U, Stelzer A, Steffen HM. Ribavirin priming in patients with chronic hepatitis C and normal ALT: a pilot study. Hepatogastroenterology. 2008 Sep-Oct;55(86-87):1666-70. Cuevas JM, González-Candelas F, Moya A, Sanjuán R. Effect of ribavirin on the mutation rate and spectrum of hepatitis C virus in vivo. J Virol. 2009 Jun;83(11):5760-4. doi: 10.1128/JVI.00201-09. Epub 2009 Mar 25. Dixit NM, Perelson AS. The metabolism, pharmacokinetics and mechanisms of antiviral activity of ribavirin against hepatitis C virus. Cell Mol Life Sci. 2006 Apr;63(7-8):832-42. Review. Berenguer M. Systematic review of the treatment of established recurrent hepatitis C with pegylated interferon in combination with ribavirin. J Hepatol. 2008 Aug;49(2):274-87. doi: 10.1016/j.jhep.2008.05.002. Epub 2008 May 22. Review. Berenguer M, Prieto M, Rayón JM, Mora J, Pastor M, Ortiz V, Carrasco D, San Juan F, Burgueño MD, Mir J, Berenguer J. Natural history of clinically compensated hepatitis C virus-related graft cirrhosis after liver transplantation. Hepatology. 2000 Oct;32(4 Pt 1):852-8. Berenguer M, López-Labrador FX, Wright TL. Hepatitis C and liver transplantation. J Hepatol. 2001 Nov;35(5):666-78. Review.
Starting date: October 2009
Last updated: June 19, 2015
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