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

This study has been terminated.
(Due to the arrival of DAAs replacing standard of care for genotype 1 patients the VIRID study had to be terminated.)
Sponsor:
Collaborator:
Hoffmann-La Roche
Information provided by (Responsible Party):
Foundation for Liver Research
ClinicalTrials.gov Identifier:
NCT00662220
First received: April 17, 2008
Last updated: July 11, 2014
Last verified: July 2014
  Purpose

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).


Condition Intervention Phase
Chronic Hepatitis C
Drug: ribavirin
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Foundation for Liver Research:

Primary Outcome Measures:
  • HCV-RNA negativity by qualitative assay 24 weeks after end of treatment (sustained virological response, SVR) [ Time Frame: 72 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • HCV-RNA negativity at week 4 (rapid virological response, RVR) [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  • HCV-RNA negativity at week 12 (complete early virological response, cEVR) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • HCV-RNA ≥ 2log10 drop at week 12, but HCV-RNA still detectable (partial early virological response, pEVR) [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • HCV- RNA negativity at week 48 (end of treatment response, ETR) [ Time Frame: 48 weeks ] [ Designated as safety issue: No ]
  • Relapse rate after ETR [ Time Frame: 48 weeks - end of follow up ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Enrollment: 110
Study Start Date: April 2008
Study Completion Date: November 2013
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Standard dose
Standard-dose ribavirin (12-15 mg/kg/day) in combination with peginterferon 180µg QW
Drug: ribavirin
12-15 mg/kg/day
Other Names:
  • Copegus
  • Pegasys
  • NeoRecormon
Experimental: High dose
High-dose ribavirin (25-29 mg/kg/day) in combination with peginterferon 180µg QW
Drug: ribavirin
25-29 mg/kg/day
Other Names:
  • Copegus
  • Pegasys
  • NeoRecormon

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00662220

Locations
Netherlands
Rijnstate
Arnhem, Gelderland, Netherlands, 6815AD
St. Radboud University Medical Center
Nijmegen, Gelderland, Netherlands, 6525GA
Canisius-Wilhelmina Ziekenhuis
Nijmegen, Gelderland, Netherlands, 6532 SZ
St. Lucas hospital
Winschoten, Groningen, Netherlands, 9670RA
Atrium Medisch Centrum
Heerlen, Limburg, Netherlands, 6401CX
Amphia hospital
Breda, Noord Brabant, Netherlands, 4818CK
Catharina hospital
Eindhoven, Noord Brabant, Netherlands, 5602ZA
St. Elisabeth hospital
Tilburg, Noord Brabant, Netherlands, 5000LC
Twee Steden hospital
Tilburg, Noord Brabant, Netherlands, 5000LA
Medisch Centrum Alkmaar
Alkmaar, Noord Holland, Netherlands, 1815JD
Onze Lieve Vrouwen Gasthuis
Amsterdam, Noord Holland, Netherlands, 1090HM
Slotervaart hospital
Amsterdam, Noord Holland, Netherlands, 1006BK
VU Medisch Centrum
Amsterdam, Noord Holland, Netherlands, 1007 MB
Spaarne Ziekenhuis
Hoofddorp, Noord Holland, Netherlands, 2130 AT
Deventer hospital
Deventer, Overijssel, Netherlands, 7415CM
ZorgSaam Hospital
Terneuzen, Zeeland, Netherlands, 4535PA
Walcheren hospital
Vlissingen, Zeeland, Netherlands, 3200
IJsselland hospital
Capelle aan de IJssel, Zuid Holland, Netherlands, 2906ZC
Reinier de Graaf Gasthuis
Delft, Zuid Holland, Netherlands, 2600GA
HAGA Ziekenhuis
Den Haag, Zuid Holland, Netherlands, 2545CH
Albert Schweitzer hospital
Dordrecht, Zuid Holland, Netherlands, 3300AK
Leids Universitair Medisch Centrum
Leiden, Zuid Holland, Netherlands, 2300 RC
Erasmus MC University Medical Center
Rotterdam, Zuid Holland, Netherlands, 3015CE
St Franciscus hospital
Rotterdam, Zuid Holland, Netherlands, 3004BA
Maasstad hospital
Rotterdam, Zuid Holland, Netherlands, 3078HT
Groningen University Medical Center
Groningen, Netherlands, 9713GZ
Universitair Medisch Centrum Utrecht
Utrecht, Netherlands, 3584CX
Sponsors and Collaborators
Foundation for Liver Research
Hoffmann-La Roche
Investigators
Principal Investigator: R J de Knegt, MD PhD Erasmus Medical Center
Principal Investigator: J PH Drenth, MD PhD St Radboud Medical Center
  More Information

Additional Information:
No publications provided

Responsible Party: Foundation for Liver Research
ClinicalTrials.gov Identifier: NCT00662220     History of Changes
Other Study ID Numbers: HCV07-01, 2007-005344-25
Study First Received: April 17, 2008
Last Updated: July 11, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by Foundation for Liver Research:
chronic
hepatitis C
ribavirin
SVR
genotype one
genotype four

Additional relevant MeSH terms:
Hepatitis
Hepatitis A
Hepatitis C
Hepatitis, Chronic
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Ribavirin
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on September 18, 2014