Clinical trial NCT00662220: High-dose Ribavirin in Treatment of Chronic Hepatitis C Genotype 1 or 4
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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Chronic Hepatitis C
Keywords: chronic
hepatitis C
ribavirin
SVR
genotype one
genotype four
Lead sponsor: Foundation for Liver Research
Sponsor class: OTHER
Collaborators: name: Hoffmann-La Roche
First posted: 2008-04-21
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: HCV-RNA negativity by qualitative assay 24 weeks after end of treatment (sustained virological response, SVR)
timeFrame: 72 weeks
Secondary outcomes:
measure: HCV-RNA negativity at week 4 (rapid virological response, RVR)
timeFrame: 4 weeks
measure: HCV-RNA negativity at week 12 (complete early virological response, cEVR)
timeFrame: 12 weeks
measure: HCV-RNA ≥ 2log10 drop at week 12, but HCV-RNA still detectable (partial early virological response, pEVR)
timeFrame: 12 weeks
measure: HCV- RNA negativity at week 48 (end of treatment response, ETR)
timeFrame: 48 weeks
measure: Relapse rate after ETR
timeFrame: 48 weeks - end of follow up
measure: 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)
timeFrame: week 0 till end of follow up
measure: Biochemical response (normalization of serum ALT at the end of therapy and at the end of follow-up)
timeFrame: week 0 - end of follow up
measure: Health related quality of life and psychopathology before, during and after treatment by SF-36 and SCL-90 questionnaires
timeFrame: week 0 - week 72
Other outcomes:
Locations:
city: Arnhem
country: Netherlands
facility: Rijnstate
state: Gelderland
city: Nijmegen
country: Netherlands
facility: St. Radboud University Medical Center
state: Gelderland
city: Nijmegen
country: Netherlands
facility: Canisius-Wilhelmina Ziekenhuis
state: Gelderland
city: Winschoten
country: Netherlands
facility: St. Lucas hospital
state: Groningen
city: Heerlen
country: Netherlands
facility: Atrium Medisch Centrum
state: Limburg
city: Breda
country: Netherlands
facility: Amphia hospital
state: Noord Brabant
city: Eindhoven
country: Netherlands
facility: Catharina hospital
state: Noord Brabant
city: Tilburg
country: Netherlands
facility: Twee Steden hospital
state: Noord Brabant
city: Tilburg
country: Netherlands
facility: St. Elisabeth hospital
state: Noord Brabant
city: Alkmaar
country: Netherlands
facility: Medisch Centrum Alkmaar
state: Noord Holland
city: Amsterdam
country: Netherlands
facility: Slotervaart hospital
state: Noord Holland
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum
state: Noord Holland
city: Amsterdam
country: Netherlands
facility: Onze Lieve Vrouwen Gasthuis
state: Noord Holland
city: Hoofddorp
country: Netherlands
facility: Spaarne Ziekenhuis
state: Noord Holland
city: Deventer
country: Netherlands
facility: Deventer hospital
state: Overijssel
city: Terneuzen
country: Netherlands
facility: ZorgSaam Hospital
state: Zeeland
city: Vlissingen
country: Netherlands
facility: Walcheren hospital
state: Zeeland
city: Capelle aan de IJssel
country: Netherlands
facility: IJsselland hospital
state: Zuid Holland
city: Delft
country: Netherlands
facility: Reinier de Graaf Gasthuis
state: Zuid Holland
city: Den Haag
country: Netherlands
facility: HAGA Ziekenhuis
state: Zuid Holland
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer hospital
state: Zuid Holland
city: Leiden
country: Netherlands
facility: Leids Universitair Medisch Centrum
state: Zuid Holland
city: Rotterdam
country: Netherlands
facility: St Franciscus hospital
state: Zuid Holland
city: Rotterdam
country: Netherlands
facility: Erasmus MC University Medical Center
state: Zuid Holland
city: Rotterdam
country: Netherlands
facility: Maasstad hospital
state: Zuid Holland
city: Groningen
country: Netherlands
facility: Groningen University Medical Center
city: Utrecht
country: Netherlands
facility: Universitair Medisch Centrum Utrecht
Study officials:
affiliation: Erasmus Medical Center
name: R J de Knegt, MD PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: St Radboud Medical Center
name: J PH Drenth, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: