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High-dose Ribavirin in Treatment of Chronic Hepatitis C Genotype 1 or 4 (VIRID)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00662220
Recruitment Status : Terminated (Due to the arrival of DAAs replacing standard of care for genotype 1 patients the VIRID study had to be terminated.)
First Posted : April 21, 2008
Last Update Posted : July 14, 2014
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Foundation for Liver Research

Tracking Information
First Submitted Date  ICMJE April 17, 2008
First Posted Date  ICMJE April 21, 2008
Last Update Posted Date July 14, 2014
Study Start Date  ICMJE April 2008
Actual Primary Completion Date June 2013   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 17, 2008)
HCV-RNA negativity by qualitative assay 24 weeks after end of treatment (sustained virological response, SVR) [ Time Frame: 72 weeks ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT00662220 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: April 17, 2008)
  • HCV-RNA negativity at week 4 (rapid virological response, RVR) [ Time Frame: 4 weeks ]
  • HCV-RNA negativity at week 12 (complete early virological response, cEVR) [ Time Frame: 12 weeks ]
  • HCV-RNA ≥ 2log10 drop at week 12, but HCV-RNA still detectable (partial early virological response, pEVR) [ Time Frame: 12 weeks ]
  • HCV- RNA negativity at week 48 (end of treatment response, ETR) [ Time Frame: 48 weeks ]
  • Relapse rate after ETR [ Time Frame: 48 weeks - end of follow up ]
  • Safety and tolerability of high-dose daily ribavirin (serious adverse events, grade 4 NCI toxicity, percentage of patients completing treatment on full or >80% of total intended dose and reasons for dose adjustments) [ Time Frame: week 0 till end of follow up ]
  • Biochemical response (normalization of serum ALT at the end of therapy and at the end of follow-up) [ Time Frame: week 0 - end of follow up ]
  • Health related quality of life and psychopathology before, during and after treatment by SF-36 and SCL-90 questionnaires [ Time Frame: week 0 - week 72 ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE High-dose Ribavirin in Treatment of Chronic Hepatitis C Genotype 1 or 4
Official Title  ICMJE High-dose Versus Standard-dose Weight-based Ribavirin in Combination With Peginterferon Alfa-2a for Patients Infected With Hepatitis C Virus Genotype 1 or 4
Brief Summary Optimal ribavirin dosages are essential in achieving SVR (sustained virological response). Several studies have shown higher SVR rates in patients receiving higher doses of ribavirin. Therefore we propose a randomized controlled open label multicenter trial to investigate wether high (25-29mg/kg) dose ribavirin can improve outcome in patients in infected with hepatitis C virus genotype 1 or 4 compared to standard dose (12-15mg/kg).
Detailed Description

Optimal ribavirin dosages are essential in achieving SVR. The initial evidence supporting higher doses of ribavirin for peginterferon alfa-2b comes from a secondary analysis of the pivotal multicenter trial of peginterferon alfa-2b and ribavirin. Patients receiving more than 10.6 mg/kg/day ribavirin experienced significantly higher SVR rates (48% vs. 38%). A large multicenter trial designed to test standard dose ribavirin (1000-1200 mg/day) versus low-dose ribavirin (800 mg/day) in combination with peginterferon alfa-2a, showed 52% SVR in the standard dose group versus 41% in the low-dose group for genotype 1 infected patients. In the pooled data from two pivotal studies with peginterferon alfa-2a and ribavirin, the probability of achieving an SVR for genotype 1 patients was influenced by the ribavirin dose per kg body weight. A 40-50% increase in the probability of SVR was found for a 12-16 mg/kg dose increase of ribavirin. For peginterferon alfa-2b it was also shown among genotype 1 patients, that weight-based ribavirin (800-1400 mg/day) leads to higher SVR rates compared to fixed dose ribavirin (800 mg/day) (34% vs. 29%). Moreover, ribavirin dosing up to 1400 mg/day was safe and the rate of treatment discontinuation was the same for both treatment groups. In a small pilot study, 10 genotype 1 patients with a high baseline load were treated with peginterferon alfa-2a and individualized high-dose ribavirin in order to achieve a ribavirin target concentration in serum of 15 μmol/l. The mean ribavirin dose of 2540 mg/day (range 1600-3600 mg/day) was high, but resulted in 90% SVR. All patients experienced severe anemia, which was treated with concomitant epoetin beta and blood transfusion.

As mentioned before, the main concern of high-dose ribavirin will be a dose-dependent hemolytic anemia and the addition of epoetin alfa has shown significant increase of haemoglobin during (peg)interferon/ribavirin therapy. Erythropoietin doses from 9,000 to 60,000 IU/week have been used in order keep the highest possible ribavirin doses. A recent trial showed a significant higher SVR rate in genotype 1 patients treated with peginterferon alfa-2b, increased dose ribavirin (15.2 mg/kg/day) and epoetin alfa than in patients treated with peginterferon alfa-2b and standard dose ribavirin (13.3 mg/kg/day) with or without epoetin alfa. Using the standard ribavirin dose, routine use of erythropoietin significantly decreased the frequency of anemia and the mean ribavirin dose reduction. Moreover, with the addition of erythropoietin, a significant higher mean dose could be given to patients in the increased ribavirin dose arm.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Chronic Hepatitis C
Intervention  ICMJE
  • Drug: ribavirin
    25-29 mg/kg/day
    Other Names:
    • Copegus
    • Pegasys
    • NeoRecormon
  • Drug: ribavirin
    12-15 mg/kg/day
    Other Names:
    • Copegus
    • Pegasys
    • NeoRecormon
Study Arms  ICMJE
  • Active Comparator: Standard dose
    Standard-dose ribavirin (12-15 mg/kg/day) in combination with peginterferon 180µg QW
    Intervention: Drug: ribavirin
  • Experimental: High dose
    High-dose ribavirin (25-29 mg/kg/day) in combination with peginterferon 180µg QW
    Intervention: Drug: ribavirin
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: July 11, 2014)
110
Original Estimated Enrollment  ICMJE
 (submitted: April 17, 2008)
170
Actual Study Completion Date  ICMJE November 2013
Actual Primary Completion Date June 2013   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • hepatitis C genotype 1 or 4
  • high viral load (>400000 IU/ml)
  • indication for antiviral treatment or patient's desire for antiviral treatment
  • hepatitis C treatment naive
  • liver biopsy within 3 years of screening visit or when biopsy is contraindicated e.g in patients with clotting diseases or when a patient refuses to undergo a new biopsy in case the liver biopsy is older than 3 years, substitution by fibroscan is allowed.
  • age 18-70 years

Exclusion Criteria:

  • serum bilirubin >35 μmol/l
  • albumin <36 g/l
  • prothrombin time >4 sec prolonged
  • platelets <90x109/l
  • decompensated cirrhosis (Child-Pugh Grade B or C)
  • hepatic imaging (ultrasound, CT or MRI) with the evidence of hepatocellular carcinoma (hepatic imaging should be performed within 3 months prior to screening for cirrhotic patients and within 6 months prior to screening for non-cirrhotic patients)
  • alcoholic liver disease (indicator: MCV>100)
  • obesity induced liver disease (indicators: steatosis proven by biopsy or ultrasound in association with a body mass index >30)
  • drug related liver disease (indicator: positive history of hepatic toxic drug intake with a causal relation)
  • auto-immune hepatitis (indicators: IgG >30g/l, anti smooth-muscle or antinuclear antibodies titer ³1:40)
  • hemochromatosis (indicator: ferritin >1000 μg/l)
  • Wilson's disease (indicator: ceruloplasmin (<0.2 g/l)
  • alpha-1 antitrypsin deficiency (indicator alpha-1 antitrypsin <0.8 g/L)
  • co-infection with hepatitis B virus or human immunodeficiency virus (HIV)
  • any cardiovascular dysfunction (e.g. cardiac decompensation, myocardial infarction, present or history of arrythmia)
  • other medical illness that might interfere with this study: significant pulmonary or renal dysfunction, malignancy other than skin basocellular carcinoma in previous 5 years, immunodeficiency syndromes (e.g.: steroid therapy, organ transplants other than cornea and hair transplant)
  • contra-indications for peginterferon and/or ribavirin:
  • severe psychiatric disorder, such as major psychoses, suicidal ideation, suicidal attempt and/or manifest depression. Severe depression would include the following: (a) subjects who have been hospitalized for depression, (b) subjects who have received electroconvulsive therapy for depression, or (c) subjects whose depression has resulted in a prolonged absence of work and/or significant disruption of daily functions. Subjects with a history of mild depression may be considered for entry into the protocol provided that a pretreatment assessment of the subject's mental status supports that the subject is clinically stable and that there is ongoing evaluation of the patient's mental status during the study
  • visual symptoms related to retinal abnormalities
  • pregnancy, breast-feeding or inadequate contraception
  • thalassemia, spherocytosis
  • females who are pregnant or intending to become pregnant or male partners of females who are pregnant or intending to become pregnant
  • absolute neutrophil count (ANC) <1.40x109/l
  • hemoglobin (Hb) <7.5 mmol/l (female) or <8.1 mmol/l (male)
  • serum creatinine concentration >1.5 times the upper limit of normal at screening
  • substance abuse, such as I.V. drugs or alcohol (indicator: >28 drinks/week). If the subject has a history of substance abuse, to be considered for inclusion into the protocol, the subject must have abstained from using the abused substance for at least 1 year
  • any other condition which in the opinion of the investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00662220
Other Study ID Numbers  ICMJE HCV07-01
2007-005344-25 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Foundation for Liver Research
Study Sponsor  ICMJE Foundation for Liver Research
Collaborators  ICMJE Hoffmann-La Roche
Investigators  ICMJE
Principal Investigator: R J de Knegt, MD PhD Erasmus Medical Center
Principal Investigator: J PH Drenth, MD PhD St Radboud Medical Center
PRS Account Foundation for Liver Research
Verification Date July 2014

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