Chronic Hepatitis CPhase 2NCT00944684
High Dose Ribavirin in the Treatment of Chronic Hepatitis C
A Phase 2 study testing High ribavirin dose and Standard ribavirin dose in people with Chronic Hepatitis C, run by University of Bern at 5 sites in Switzerland.
Trial summary
Treatment of patients with chronic hepatitis C infected with genotype 1 hepatitis C virus (HCV) consists of combined peginterferon/ribavirin for 48 weeks. Approximately 50% of patients experience sustained virological response which equals cure. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Chronic Hepatitis C
- What is being tested?
- High ribavirin dose and Standard ribavirin dose
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 5 sitesSwitzerland
- Study dates
- Nov 2007to Apr 2011
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male and female patients aged 18-65 years
- Elevated liver enzymes levels
- Compensated liver disease
- Available liver histology confirming METAVIR F2 fibrosis
- Written consent to participation
Who cannot join
- Age <18, >65
- Prior ribavirin treatment
- Intolerance towards ribavirin, PegIFN or erythropoetin
- Pregnancy or breast feeding
- Relevant cardiovascular or pulmonary disease
- Kidney insufficiency (creatinine clearance <50ml/min)
Show all 14Show fewer
- Coinfection with HIV or hepatitis B virus
- Hepatic comorbidities (hemochromatosis, Wilson's disease, autoimmune disorders)
- Alcohol consumption > 40g/day
- Psychiatric disorders
- Malignancy (except for basalioma)
- Active consumption of illicit drugs
- Participation in another trial shorter than 3 months prior to inclusion
- Lack of consent
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
Switzerland5 sites
Dept of Gastroenterology, University of Basel
Basel, CH-4031
Institute of Clinical Pharmacology and Visceral Research, University of Bern
Bern, CH-3010
Division of Gastroenterology, University of Lausanne
Lausanne, CH-1011
Kantonsspital St.Gallen
Sankt Gallen, CH-9007
Stadtspital Waid, Zürich
Zurich, Ch-8037
About this study
Official title: Prospective, Open-label, Randomised Controlled Trial on Efficacy and Tolerability of PegIFN-alpha 2a + Serum Level-adapted RBV vs. PegIFN-alpha 2a + Weight-based RBV in Treatment-naive Patients With Chronic Hepatitis C Genotype 1
Treatment of patients with chronic hepatitis C infected with genotype 1 hepatitis C virus (HCV) consists of combined peginterferon/ribavirin for 48 weeks. Approximately 50% of patients experience sustained virological response which equals cure. All other patients either do not respond or experience recurrence of HCV virus and chronic hepatitis. Important predictors of successful treatment are sustained dosing of both peginterferon and ribavirin. With regard to the latter, clinical evidence indicates that higher ribavirin doses may in fact even improve treatment outcome. However, high ribavirin doses cause hemolytic anemia which require dose reductions. Recent clinical experience show that erythropoetic growth factors, including erythropoetin, can counteract hemolytic anemia caused by antiviral treatment in chronic hepatitis C patients. Therefore, the current trial aims to test whether higher ribavirin doses adapted to a target plasma concentrations instead of a weight-based dosing result in better healing rates, and whether ribavirin-associated hemolytic anemia can be compensated by concommitant erythropoetin treatment.
Using a randomized, controlled, open-label design, the investigators hypothesize that patients with high ribavirin doses adapted to plasma levels experience better viral clearance than patients treated with standard weight-based ribavirin doses. In addition, the investigators hypothesize that erythropoetin treatment will counteract hemolytic anemia induced by ribavirin thereby allowing maintenance of target plasma concentrations without ribavirin dose reductions.
Read the detailed description
Background
Prevalence and incidence of chronic hepatitis C (CHC) are rising worldwide. Complications include chronic liver failure and hepatocellular carcinoma, and chronic hepatitis C is a major indication for liver transplantation. Effective treatment is required to prevent these outcomes.
Current treatment consists of a combination of peginterferon (PegIFN) and ribavirin (RBV) given for 24 or 48 weeks depending on the viral genotype. While genotypes 2 and 3 respond well to 24 weeks of PegIFN/RBV with approximately 80% viral clearance, genotype 1 infected patients only achieve about 40-50% sustained viral response (SVR) with 48 weeks of combination therapy.
RBV is a nucleoside analog with structural similarities to guanosine, which modulates RNA and DNA synthesis. RBV reveals antiviral activity against respiratory syncytial (RS)-virus, influenza virus, Lassa virus uand others. The exact mode of antiviral activity is yet unknown but believed to relate to reducing survival of HCV-infected hepatocytes thereby allowing for elimination of infected cells by interferon-stimulated immune mechanisms.
Generally, RBV is well tolerated. With standard daily doses between 1.000 and 1.200mg, irritability, sleeping abnormalities, cough and pruritus. The most prevalent and typical side effect of RBV is a dose-dependent hemolytical anemia which responds well to dose reduction or interruption of RBV therapy. RBV-associated anemia impairs quality of life and, overall, 25-36% of patients require dose reductions and/or RBV cessation. However, reduction/cessation of RBV is associated with a significant drop of SVR and measures to maintain RBV doses are clearly warranted. Several recent studies have shown that erythropoetin can counteract RBV-induced hemolytic anemia, and improve quality of life.
The relevance of RBV dose with regard to therapeutic response to combination therapy is well-established and currently, RBV is dosed according to weight: patients with CHC genotype 1 are treated with 1.000mg if body weight is <65kg, and receive 1.200mg if >65kg.
Retrospective studies have shown that relapsers and non-responders to antiviral treatment with RBV had lower RBV levels than those who had a SVR. In a retrospective analysis of 4 studies investigating a total of 1105 patients treated with RBV, RBV plasma concentrations measured at 4 weeks of treatment correlated with viral clearance: SVR was 31.8% in those with RBV levels <1,000ng/ml, and increased to 62.5% with RBV concentrations at >4,000ng/ml.
A pilot trial from Sweden investigated whether dosing RBV according to a plasma level of 15mcmol/l (3.7mcg/ml) in 10 patients. Median RBV dose was 2.540mg/day and all patients received erythropoetin.SVR was achieved in 9 of 10 patients.
So far, a randomized, controlled trial comparing weight-based RBV (standard) vs. RBV dosed according to kidney function and plasma levels.
Objective
Comparison of efficacy and tolerability of treatment with PegIFN-alpha 2a + RBV dosed according plasma concentrations vs PegIFN-alpha 2a + weight-based RBV in patients with chronic hepatitis C genotype 1
Methods
Prospective, controlled, open label randomized human trial
- Conditions
- Chronic Hepatitis C
- Being tested
- High ribavirin dose, Standard ribavirin dose
- Keywords
- Chronic hepatitis C, Antiviral treatment, Ribavirin, Sustained virological response, Hemolytic anemia, Erythropoetin
- Medical subject headings
- Hepatitis C, Chronic, Anemia, Hemolytic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High ribavirin doseDrug
Ribavirin dose started according to kidney function (usually 1,800mg) and adapted according to plasma level during follow-up
Standard ribavirin doseDrug
Ribavirin dose started at 1,000mg (body weight <65kg) or 1,200mg (body weight equal or >65kg)
| Study group | Role | What they receive |
|---|---|---|
| A | Experimental | PegIFN-alpha 2a + RBV (commenced according to kidney function) adjusted to plasma levels. Treatment with erythropoetin 3x3,000IU/week up to 3x10,000IU/week in case of hemolytic anemia Receives: Drug: High ribavirin dose |
| B | Active comparator | PegIFN-alpha 2a + RBV (weight based; 1,000 or 1,200 mg/day) Receives: Drug: Standard ribavirin dose |
What is being measured
The primary outcome is the main question the study is designed to answer.
Sustained virological response
Measured: 1 Day
Secondary outcomes (3)
Adverse Events
Measured: day 1 until 24 weeks after end or treatment
Rapid virological response at 4 weeks of treatment
Measured: 4 weeks
Early virological response at 12 weeks of treatment
Measured: 12 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Jul 2009 (estimated)
- Study startNov 2007
- Primary completionApr 2011
- Study completionApr 2011
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Chronic Hepatitis CStudies of the same condition, open and under way.
- More trials run by University of BernThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Bern
- Sponsor type
- University, hospital or other
- Collaborators
- Roche Pharma AG, University of Lausanne, Cantonal Hospital of St. Gallen, Waid City Hospital, Zurich, University of Basel
- Investigators
- Felix Stickel, MD, Principal investigator, Institute for Clinical Pharmacology and Visceral Research, University of Bern
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00944684
- Sponsor's protocol ID
- 091/07
- Other IDs
- ML21071, SASL-24
- Status last verified
- Nov 2011
- First submitted
- 17 Jul 2009
- Last updated
- 11 Nov 2011
- Results posted
- No
- Data monitoring committee
- No
Publications
Pfaundler N, Kessebohm K, Blum R, Stieger M, Stickel F. Adding pancreatic panniculitis to the panel of skin lesions associated with triple therapy of chronic hepatitis C. Liver Int. 2013 Apr;33(4):648-9. doi: 10.1111/liv.12119. Epub 2013 Feb 15. No abstract available.
PubMed 23410147
Study at a glance
From the registry record, last updated by the sponsor on 11 Nov 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective, Open-label, Randomised Controlled Trial on Efficacy and Tolerability of PegIFN-alpha 2a + Serum Level-adapted RBV vs. PegIFN-alpha 2a + Weight-based RBV in Treatment-naive Patients With Chronic Hepatitis C Genotype 1
- ClinicalTrials.gov ID
- NCT00944684
- Acronym / sponsor ID
- 091/07
- Conditions
- Chronic Hepatitis C
- Keywords
- Chronic hepatitis C, Antiviral treatment, Ribavirin, Sustained virological response, Hemolytic anemia, Erythropoetin
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 32 participants (actual)
- Lead sponsor
- University of BernUniversity, hospital or other
- Collaborators
- Roche Pharma AG, University of Lausanne, Cantonal Hospital of St. Gallen, Waid City Hospital, Zurich, University of Basel
- Study start
- Nov 2007
- Primary completion
- Apr 2011 (actual)
- Study completion
- Apr 2011 (actual)
- First posted
- 23 Jul 2009 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Treatment of patients with chronic hepatitis C infected with genotype 1 hepatitis C virus (HCV) consists of combined peginterferon/ribavirin for 48 weeks. Approximately 50% of patients experience sustained virological response which equals cure. All other patients either do not respond or experience recurrence of HCV virus and chronic hepatitis. Important predictors of successful treatment are sustained dosing of both peginterferon and ribavirin. With regard to the latter, clinical evidence indicates that higher ribavirin doses may in fact even improve treatment outcome. However, high ribavirin doses cause hemolytic anemia which require dose reductions. Recent clinical experience show that erythropoetic growth factors, including erythropoetin, can counteract hemolytic anemia caused by antiviral treatment in chronic hepatitis C patients. Therefore, the current trial aims to test whether higher ribavirin doses adapted to a target plasma concentrations instead of a weight-based dosing result in better healing rates, and whether ribavirin-associated hemolytic anemia can be compensated by concommitant erythropoetin treatment.
Using a randomized, controlled, open-label design, the investigators hypothesize that patients with high ribavirin doses adapted to plasma levels experience better viral clearance than patients treated with standard weight-based ribavirin doses. In addition, the investigators hypothesize that erythropoetin treatment will counteract hemolytic anemia induced by ribavirin thereby allowing maintenance of target plasma concentrations without ribavirin dose reductions.
Detailed description
Background
Prevalence and incidence of chronic hepatitis C (CHC) are rising worldwide. Complications include chronic liver failure and hepatocellular carcinoma, and chronic hepatitis C is a major indication for liver transplantation. Effective treatment is required to prevent these outcomes.
Current treatment consists of a combination of peginterferon (PegIFN) and ribavirin (RBV) given for 24 or 48 weeks depending on the viral genotype. While genotypes 2 and 3 respond well to 24 weeks of PegIFN/RBV with approximately 80% viral clearance, genotype 1 infected patients only achieve about 40-50% sustained viral response (SVR) with 48 weeks of combination therapy.
RBV is a nucleoside analog with structural similarities to guanosine, which modulates RNA and DNA synthesis. RBV reveals antiviral activity against respiratory syncytial (RS)-virus, influenza virus, Lassa virus uand others. The exact mode of antiviral activity is yet unknown but believed to relate to reducing survival of HCV-infected hepatocytes thereby allowing for elimination of infected cells by interferon-stimulated immune mechanisms.
Generally, RBV is well tolerated. With standard daily doses between 1.000 and 1.200mg, irritability, sleeping abnormalities, cough and pruritus. The most prevalent and typical side effect of RBV is a dose-dependent hemolytical anemia which responds well to dose reduction or interruption of RBV therapy. RBV-associated anemia impairs quality of life and, overall, 25-36% of patients require dose reductions and/or RBV cessation. However, reduction/cessation of RBV is associated with a significant drop of SVR and measures to maintain RBV doses are clearly warranted. Several recent studies have shown that erythropoetin can counteract RBV-induced hemolytic anemia, and improve quality of life.
The relevance of RBV dose with regard to therapeutic response to combination therapy is well-established and currently, RBV is dosed according to weight: patients with CHC genotype 1 are treated with 1.000mg if body weight is <65kg, and receive 1.200mg if >65kg.
Retrospective studies have shown that relapsers and non-responders to antiviral treatment with RBV had lower RBV levels than those who had a SVR. In a retrospective analysis of 4 studies investigating a total of 1105 patients treated with RBV, RBV plasma concentrations measured at 4 weeks of treatment correlated with viral clearance: SVR was 31.8% in those with RBV levels <1,000ng/ml, and increased to 62.5% with RBV concentrations at >4,000ng/ml.
A pilot trial from Sweden investigated whether dosing RBV according to a plasma level of 15mcmol/l (3.7mcg/ml) in 10 patients. Median RBV dose was 2.540mg/day and all patients received erythropoetin.SVR was achieved in 9 of 10 patients.
So far, a randomized, controlled trial comparing weight-based RBV (standard) vs. RBV dosed according to kidney function and plasma levels.
Objective
Comparison of efficacy and tolerability of treatment with PegIFN-alpha 2a + RBV dosed according plasma concentrations vs PegIFN-alpha 2a + weight-based RBV in patients with chronic hepatitis C genotype 1
Methods
Prospective, controlled, open label randomized human trial
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| A | Experimental | Drug: High ribavirin dosePegIFN-alpha 2a + RBV (commenced according to kidney function) adjusted to plasma levels. Treatment with erythropoetin 3x3,000IU/week up to 3x10,000IU/week in case of hemolytic anemia |
| B | Active comparator | Drug: Standard ribavirin dosePegIFN-alpha 2a + RBV (weight based; 1,000 or 1,200 mg/day) |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- Male and female patients aged 18-65 years
- Elevated liver enzymes levels
- Compensated liver disease
- Available liver histology confirming METAVIR F2 fibrosis
- Written consent to participation
Key exclusion criteria (14 listed)
- Age <18, >65
- Prior ribavirin treatment
- Intolerance towards ribavirin, PegIFN or erythropoetin
- Pregnancy or breast feeding
- Relevant cardiovascular or pulmonary disease
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| High ribavirin doseRibavirin dose started according to kidney function (usually 1,800mg) and adapted according to plasma level during follow-up | Drug | A |
| Standard ribavirin doseRibavirin dose started at 1,000mg (body weight <65kg) or 1,200mg (body weight equal or >65kg) | Drug | B |
Primary outcome
Sustained virological response
Time frame: 1 Day
3 secondary outcomes
Adverse Events
Time frame: day 1 until 24 weeks after end or treatment
Rapid virological response at 4 weeks of treatment
Time frame: 4 weeks
Early virological response at 12 weeks of treatment
Time frame: 12 weeks
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 11 Nov 2011.
- Derived from this study: PubMed 23410147Pfaundler N, Kessebohm K, Blum R, Stieger M, Stickel F. Adding pancreatic panniculitis to the panel of skin lesions associated with triple therapy of chronic hepatitis C. Liver Int. 2013 Apr;33(4):648-9. doi: 10.1111/liv.12119. Epub 2013 Feb 15. No abstract available.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Felix Stickel, MD principal investigator
Institute for Clinical Pharmacology and Visceral Research, University of Bern
5 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing High ribavirin dose and Standard ribavirin dose in people with Chronic Hepatitis C, run by University of Bern at 5 sites in Switzerland.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 11 Nov 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 5 sites in Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Sustained virological response (time frame: 1 Day). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00944684, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 11 Nov 2011.