Ribavirin Pre-treatment Followed by Combined Standard Therapy in Hepatitis C Virus (HCV) Recipients (RBV)

June 19, 2015 updated by: Manuela Merli, University of Roma La Sapienza

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

100

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Rome, Italy, 00100
        • Sapienza University of Rome

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 65 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: ribavirin pre-treatment
patient will receive ribavirin in monotherapy for 8 weeks before the combined 48 weeks antiviral therapy
Drug: ribavirin pre-treatment
patients receive ribavirin (10,4 mg/kg/day) and pegylated interferon alfa-2b (1,5 mcg/kg/week).Pre-treatment arm will receive a 8-week monotherapy treatment with only ribavirin (same dosage) and the controlled arm will receive 48 week of standard combined therapy (ribavirin plus pegylated interferon)
Other Names:
  • ribavirin
  • ribavirin pre treatment
  • ribavirin priming
  • Recurrence of hepatitis c
  • hepatitis c
  • transplanted patients
  • HCV
Active Comparator: combined stardard therapy
patients will receive the standard combined therapy with ribavirin and pegylated interferon for 48 weeks
Drug: ribavirin pre-treatment
patients receive ribavirin (10,4 mg/kg/day) and pegylated interferon alfa-2b (1,5 mcg/kg/week).Pre-treatment arm will receive a 8-week monotherapy treatment with only ribavirin (same dosage) and the controlled arm will receive 48 week of standard combined therapy (ribavirin plus pegylated interferon)
Other Names:
  • ribavirin
  • ribavirin pre treatment
  • ribavirin priming
  • Recurrence of hepatitis c
  • hepatitis c
  • transplanted patients
  • HCV

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
HCV-RNA level, Transaminases level
Time Frame: 4°,12°,24°,36°48° week and six months after therapy conclusion
4°,12°,24°,36°48° week and six months after therapy conclusion

Secondary Outcome Measures

Outcome Measure
Time Frame
liver biopsy and Transient elastography at baseline and after six month since therapy conclusion
Time Frame: 0°, 72° week
0°, 72° week

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Roma La Sapienza

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2009

Primary Completion (Actual)

April 1, 2010

Study Completion (Actual)

February 1, 2012

Study Registration Dates

First Submitted

October 8, 2009

First Submitted That Met QC Criteria

October 9, 2009

First Posted (Estimate)

October 12, 2009

Study Record Updates

Last Update Posted (Estimate)

June 22, 2015

Last Update Submitted That Met QC Criteria

June 19, 2015

Last Verified

June 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Ribavirin Pre-treatment

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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