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

NCT ID: NCT00662220

Last Updated: 2014-07-14

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 110 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2008-04-30
• Study Completion Date: 2013-11-30

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.

Conditions

Chronic Hepatitis C

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Standard dose

Standard-dose ribavirin (12-15 mg/kg/day) in combination with peginterferon 180µg QW

Group Type: ACTIVE_COMPARATOR

ribavirin

Intervention Type: DRUG

12-15 mg/kg/day

High dose

High-dose ribavirin (25-29 mg/kg/day) in combination with peginterferon 180µg QW

Group Type: EXPERIMENTAL

ribavirin

Intervention Type: DRUG

25-29 mg/kg/day

Interventions

ribavirin

25-29 mg/kg/day

Intervention Type: DRUG

ribavirin

12-15 mg/kg/day

Intervention Type: DRUG

Other Intervention Names

Copegus; Pegasys; NeoRecormon; Copegus; Pegasys; NeoRecormon

Eligibility 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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hoffmann-La Roche

INDUSTRY

Sponsor Role: collaborator

Foundation for Liver Research

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

R J de Knegt, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Erasmus Medical Center

J PH Drenth, MD PhD

Role: PRINCIPAL_INVESTIGATOR

St Radboud Medical Center

Locations

Rijnstate

Arnhem, Gelderland, Netherlands

St. Radboud University Medical Center

Nijmegen, Gelderland, Netherlands

Canisius-Wilhelmina Ziekenhuis

Nijmegen, Gelderland, Netherlands

Atrium Medisch Centrum

Heerlen, Limburg, Netherlands

Amphia hospital

Breda, North Brabant, Netherlands

Catharina hospital

Eindhoven, North Brabant, Netherlands

Twee Steden hospital

Tilburg, North Brabant, Netherlands

St. Elisabeth hospital

Tilburg, North Brabant, Netherlands

Medisch Centrum Alkmaar

Alkmaar, North Holland, Netherlands

Slotervaart hospital

Amsterdam, North Holland, Netherlands

VU Medisch Centrum

Amsterdam, North Holland, Netherlands

Onze Lieve Vrouwen Gasthuis

Amsterdam, North Holland, Netherlands

Spaarne Ziekenhuis

Hoofddorp, North Holland, Netherlands

Deventer hospital

Deventer, Overijssel, Netherlands

Groningen University Medical Center

Groningen, Provincie Groningen, Netherlands

St. Lucas hospital

Winschoten, Provincie Groningen, Netherlands

IJsselland hospital

Capelle aan den IJssel, South Holland, Netherlands

Reinier de Graaf Gasthuis

Delft, South Holland, Netherlands

Albert Schweitzer hospital

Dordrecht, South Holland, Netherlands

Leids Universitair Medisch Centrum

Leiden, South Holland, Netherlands

St Franciscus hospital

Rotterdam, South Holland, Netherlands

Erasmus MC University Medical Center

Rotterdam, South Holland, Netherlands

Maasstad hospital

Rotterdam, South Holland, Netherlands

HAGA Ziekenhuis

The Hague, South Holland, Netherlands

Universitair Medisch Centrum Utrecht

Utrecht, Utrecht, Netherlands

Walcheren hospital

Flushing, Zeeland, Netherlands

ZorgSaam Hospital

Terneuzen, Zeeland, Netherlands

Countries

Netherlands

Related Links

http://www.virid.nl

Study website

Other Identifiers

2007-005344-25

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

HCV07-01

Identifier Type: -

Identifier Source: org_study_id