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

Chronic Hepatitis C Clinical Trial

— VIRID  

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT00662220
• Other study ID #: HCV07-01
• Secondary ID: 2007-005344-25
• Status: Terminated
• Phase: Phase 3
• First received: April 17, 2008
• Last updated: July 11, 2014
• Start date: April 2008
• Est. completion date: November 2013

Study information

• Verified date: July 2014
• Source: Foundation for Liver Research
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 110
• Est. completion date: November 2013
• Est. primary completion date: June 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Chronic Hepatitis C
• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• ribavirin
25-29 mg/kg/day
• ribavirin
12-15 mg/kg/day

Locations

Country	Name	City	State
Netherlands	Medisch Centrum Alkmaar	Alkmaar	Noord Holland
Netherlands	Onze Lieve Vrouwen Gasthuis	Amsterdam	Noord Holland
Netherlands	Slotervaart hospital	Amsterdam	Noord Holland
Netherlands	VU Medisch Centrum	Amsterdam	Noord Holland
Netherlands	Rijnstate	Arnhem	Gelderland
Netherlands	Amphia hospital	Breda	Noord Brabant
Netherlands	IJsselland hospital	Capelle aan de IJssel	Zuid Holland
Netherlands	Reinier de Graaf Gasthuis	Delft	Zuid Holland
Netherlands	HAGA Ziekenhuis	Den Haag	Zuid Holland
Netherlands	Deventer hospital	Deventer	Overijssel
Netherlands	Albert Schweitzer hospital	Dordrecht	Zuid Holland
Netherlands	Catharina hospital	Eindhoven	Noord Brabant
Netherlands	Groningen University Medical Center	Groningen
Netherlands	Atrium Medisch Centrum	Heerlen	Limburg
Netherlands	Spaarne Ziekenhuis	Hoofddorp	Noord Holland
Netherlands	Leids Universitair Medisch Centrum	Leiden	Zuid Holland
Netherlands	Canisius-Wilhelmina Ziekenhuis	Nijmegen	Gelderland
Netherlands	St. Radboud University Medical Center	Nijmegen	Gelderland
Netherlands	Erasmus MC University Medical Center	Rotterdam	Zuid Holland
Netherlands	Maasstad hospital	Rotterdam	Zuid Holland
Netherlands	St Franciscus hospital	Rotterdam	Zuid Holland
Netherlands	ZorgSaam Hospital	Terneuzen	Zeeland
Netherlands	St. Elisabeth hospital	Tilburg	Noord Brabant
Netherlands	Twee Steden hospital	Tilburg	Noord Brabant
Netherlands	Universitair Medisch Centrum Utrecht	Utrecht
Netherlands	Walcheren hospital	Vlissingen	Zeeland
Netherlands	St. Lucas hospital	Winschoten	Groningen

Sponsors (2)

Lead Sponsor	Collaborator
Foundation for Liver Research	Hoffmann-La Roche

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HCV-RNA negativity by qualitative assay 24 weeks after end of treatment (sustained virological response, SVR)		72 weeks	No
Secondary	HCV-RNA negativity at week 4 (rapid virological response, RVR)		4 weeks	No
Secondary	HCV-RNA negativity at week 12 (complete early virological response, cEVR)		12 weeks	No
Secondary	HCV-RNA = 2log10 drop at week 12, but HCV-RNA still detectable (partial early virological response, pEVR)		12 weeks	No
Secondary	HCV- RNA negativity at week 48 (end of treatment response, ETR)		48 weeks	No
Secondary	Relapse rate after ETR		48 weeks - end of follow up	No
Secondary	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)		week 0 till end of follow up	Yes
Secondary	Biochemical response (normalization of serum ALT at the end of therapy and at the end of follow-up)		week 0 - end of follow up	No
Secondary	Health related quality of life and psychopathology before, during and after treatment by SF-36 and SCL-90 questionnaires		week 0 - week 72	No