To investigate if high-dose ribavirin in combination with peginterferon alfa-2a can improve outcome in treatment naïve hepatitis C patients with genotype 1 or 4 and a high viral load (>400.000 IU/ml).
ID
Source
Brief title
Condition
- Viral infectious disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
· To study whether 48 weeks of daily high-dose ribavirin in combination with
peginterferon alfa-2a will lead to a higher SVR rate (HCV-RNA negativity 24
weeks after end of treatment response, ETR) compared with standard-dose
weight-based ribavirin
Secondary outcome
· HCV-RNA negativity at week 4 (rapid virologic response, RVR)
· HCV-RNA negativity at week 12 (complete early virologic response, cEVR)
· HCV-RNA >= 2log10 drop at week 12, but HCV-RNA still detectable (partial early
virologic response, pEVR)
· HCV-RNA negativity at week 48 (end of treatment response, ETR)
· Relapse rate after end of treatment response
· Safety (serious adverse events, grade 4 NCI toxicity)
· Tolerability of peginterferon alfa-2a and high-dose ribavirin (percentage of
patients completing treatment on full or >80% of total intended dose and
reasons for dose adjustments)
· Normalization of serum ALT at the end of therapy and and at the end of
follow-up
· Health related quality of life assessment using SF-36 questionnaires
Background summary
Treatment of hepatitis C (HCV) has shown a remarkable success. There is
however a genotype factor, which reduces response rates in genotype 1 and 4,
especially in patients with a high baseline viral load (1). Optimal treatment
of patients with genotype 1 with peginterferon and ribavirin has led to
sustained virological response (SVR) rates between 41-52% (2, 3). Further
improvement of these results should be considered the greatest challenge.
Different strategies are proposed for optimizing treatment outcome: induction
dosing of peginterferon, prolonging therapy duration, increased weight-based
ribavirin dosing and/or experimenting with new antiviral agents. These new
agents (e.g.: protease inhibitors and polymerase inhibitors) seem promising but
will not be available for the coming years and development of antiviral
resistance may temper initial expectations. Induction dosing of peginterferon
has been studied, but did not lead to major improvement of treatment outcome.
Data on prolongation of treatment duration are contradictive; prolongation
might only be beneficial to certain subgroups of patients.
Ribavirin is an oral nucleoside analogue with antiviral activity against
several viral pathogens, although the exact mechanism of action against HCV is
not completely understood (4). Direct activity against HCV replication appears
minimal, but rapid and lethal mutation of virions and depletion of
intracellular guanosine triphosphate, necessary for viral RNA synthesis, has
been shown (5-7). Optimal ribavirin dosages are essential in achieving SVR.
For genotype 1 and 4 the current European guidelines recommend weight-based
ribavirin dosing dependent on the type of peginterferon used. If peginterferon
alfa-2b is prescribed the recommended ribavirin dosage for all genotypes is:
800 mg/day if <65 kg, 1000 mg/day if 65-85 kg or 1200 mg/day if >85 kg. If
peginterferon alfa-2a is prescribed the recommended ribavirin dosage for
genotype 1 and 4 is: 1000 mg/day if <75 kg or 1200 mg/day if >= 75 kg. 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 (8). 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 (3). 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 (9). 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 (10). 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
(11).
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 (11, 12-15). 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 (15).
A fair proportion of non-responders has been related to poor patient
compliance, probably influenced by neuropsychiatric adverse effects, and by
doctors adjusting or stopping medication on basis of cytopenia. SVR rates could
have been higher if dose reductions by either adverse events or laboratory
abnormalities would have been prevented. New guidelines have been developed
based on recent literature, in order to minimize dropout and non-response by
this route (16).
For chronic HCV patients with genotype 1 or 4 and high baseline viral load we
propose a randomized controlled clinical trial that aims to compare the
currently accepted daily ribavirin dosage of 12-15 mg/kg with that of 25-29
mg/kg in combination with peginterferon alfa-2a. Optimal management of side
effects, which includes the use of epoetin beta, will be essential in order to
maintain the highest possible dosages of both peginterferon alfa-2a and
ribavirin for 48 weeks.
Study objective
To investigate if high-dose ribavirin in combination with peginterferon alfa-2a
can improve outcome in treatment naïve hepatitis C patients with genotype 1 or
4 and a high viral load (>400.000 IU/ml).
Study design
Patients will be randomized to receive either 25-29 (mean 26.2) mg/kg/day
ribavirin (Copegus, Roche) or 12-15 (mean 13.3) mg/kg/day. Both groups will
receive once weekly 180 µg peginterferon alfa-2a (Pegasys, Roche). Ribavirin
induced anemia will be treated with epoetin beta (NeoRecormon, Roche). Therapy
will be given for a total treatment period of 48 weeks. Post treatment
follow-up will last for 24 weeks. 170 patients will be included, with 85
patients in each treatment group
Intervention
high dose ribavirin
Study burden and risks
Higher incidence of ribavirin-induced hemolytic anemia will be treated
according protocol with epoëtin beta (neorecormon) or blood transfusion when
appropriate.
's-Gravendijkwal 230
3015 CE
NL
's-Gravendijkwal 230
3015 CE
NL
Listed location countries
Age
Inclusion criteria
• Hepatitis C genotype 1 or 4
• High viral load (>400,000 IU/ml)
• Indication for antiviral treatment or patient*s desire for antiviral treatment
• Hepatitis C treatment naïve
• Liver biopsy within 3 years of the date of the screening visit or when liver
biopsy is contraindicated e.g. in patients with clotting diseases e.g hemophilia and von Willebrand disease or when a patient refuses to undergo a new liver biopsy in case the liver biopsy is older than 3 years, substitution by fibroscan is allowed.
• Age 18-70 years
Exclusion criteria
• Signs of progressive liver disease, beyond generally accepted criteria for HCV antiviral therapy:
* serum bilirubin >35 µmol/l, or albumin <36 g/l or prothrombin time >4 sec prolonged or platelets <90x109/l (if normal values are different at the local laboratory, upper and lower limits of the local laboratory should be used)
* 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)
• Thrombocytosis, defined as platelet count >500.000/mm³
• History or evidence of risk of thrombosis
• Poorly controlled hypertension
• Other acquired or inherited causes of liver disease that could explain liver disease activity (if an indicator is present at screening, additional examinations should be done to confirm or rule out the diagnoses)
* 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 >/=1:40)
* 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. decompensatio cordis, myocard infarction, present or history of arrythmia);• Other significant 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);• Creatinine clearance below 50 ml/min (Cockroft/Gault) 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;• Treatment with investigational antiviral drugs e.g. protease/polymerase inhibitors within 6 months before start of therapy;• 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
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2007-005344-25-NL |
| CCMO | NL20457.078.07 |