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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified October 2009 by University of Roma La Sapienza.
Recruitment status was  Recruiting
Sponsor:
Information provided by:
University of Roma La Sapienza
ClinicalTrials.gov Identifier:
NCT00993122
First received: October 8, 2009
Last updated: October 13, 2009
Last verified: October 2009

October 8, 2009
October 13, 2009
October 2009
April 2010   (final data collection date for primary outcome measure)
HCV-RNA level, Transaminases level [ Time Frame: 4°,12°,24°,36°48° week and six months after therapy conclusion ] [ Designated as safety issue: No ]
Same as current
Complete list of historical versions of study NCT00993122 on ClinicalTrials.gov Archive Site
liver biopsy and Transient elastography at baseline and after six month since therapy conclusion [ Time Frame: 0°, 72° week ] [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Ribavirin Pre-treatment Followed by Combined Standard Therapy in Hepatitis C Virus (HCV) Recipients
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.

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.

Interventional
Phase 4
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Hepatitis C
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 pre treatment
  • ribavirin priming
  • Recurrence of hepatitis c
  • hepatitis c
  • transplanted patients
  • ribavirin
  • HCV
  • Active Comparator: ribavirin pre-treatment
    patient will receive ribavirin in monotherapy for 8 weeks before the combined 48 weeks antiviral therapy
    Intervention: Drug: ribavirin pre-treatment
  • Active Comparator: combined stardard therapy
    patients will receive the standard combined therapy with ribavirin and pegylated interferon for 48 weeks
    Intervention: Drug: ribavirin pre-treatment

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
100
February 2012
April 2010   (final data collection date for primary outcome measure)

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
Both
up to 65 Years
No
Contact: manuela merli, professor +39 06 49972002 manuela.merli@uniroma1.it
Italy
 
NCT00993122
Ribavirin Pre-treatment, Ribavirin Pre-treatment
Yes
manuela merli, sapienza university of rome
University of Roma La Sapienza
Not Provided
Not Provided
University of Roma La Sapienza
October 2009

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP