Hepatitis C, Chronic
Conditions
Keywords
HCV genotype 1, peginterferon alfa-2a, ribavirin, amantadine, treatment-naive
Brief summary
This was a randomized, multi-center, partially placebo-controlled Phase IV study to compare the efficacy and tolerability of a 48-week combined therapy with pegylated interferon alpha-2a, ribavirin and amantadine sulphate versus placebo in untreated patients with chronic hepatitis C virus-genotype-1-infection. The hypothesis was that there will be an increase in sustained response rate for triple therapy compared to current standard treatment.
Detailed description
Primary Objective: * Proof that a triple-therapy (peginterferon alfa-2a, ribavirin and amantadine sulphate) dispensed over a period of 50 weeks, improves the permanent virological efficacy by more than 10% as compared to a combination therapy with peginterferon alpha-2a and ribavirin, defined as negative HCV-RNA result obtained by a molecular verification method (e.g. Roche AmplicorTM HCV, v.2.0, sensitivity \<50 IE/ml) 24 weeks after the end of the therapy. Secondary Objectives: * Verification of the initial virological efficacy up to week 12, defined as negative HCV-RNA test results by means of quantitative proof methods, e.g. Roche AmplicorTM HCV Monitor v.2.0 (sensitivity \<600 IE/ml). * Biochemical efficacy, defined by the serum GPT values 24 weeks after the end of the therapy. * Virological efficacy, measured on the basis of the HCV-RNA values at the end of the therapy. * Biochemical efficacy defined by the serum GPT values at the end of the therapy.
Interventions
DRUGAmantadine sulphate (in addition to standard treatment)
Sponsors
Hoffmann-La Roche
University Hospital, Saarland
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* Female and male subjects over 18 years of age and below 70 years of age * Serological indication of chronic hepatitis C infection with positive anti-HCV test and serum HCV-RNA quantification \>600 IE/ml by means of quantitative proof methods, e.g. Roche AmplicorTM HCV Monitor test, v.2.0. * Untreated patients with HCV-induced chronic infection. * Indication of a genotype HCV-1 on the basis of the reverse hybridizing assay Inno LiPA from Bayer Versant (Innogenetics). * Increased GPT serum level on at least one determination date within the 56-day screening phase prior to start of administration of study medication. * Histological identification of inflammatory activity in the liver, with or without an indication of compensated cirrhosis, during the 24 months prior to start of the study. * Compensated liver disease (Child-Pugh Grade A). * Negative urine or serum pregnancy test in fertile female subjects within 24 hours before taking the first dose of study medication. * During the administration of study medication and for 24 weeks after the treatment has stopped, patients must apply two approved contraception methods, one of which must have a barrier effect on the male, e.g. condom. If one or more of the above inclusion criteria are not fulfilled, the patient is excluded from the study!
Exclusion criteria
* Any known sensitive reaction to interferon, ribavirin or amantadine sulphate. * Pregnant or breast-feeding women and fertile women who do not practice contraception. * Male partners of pregnant women. * Previous treatment with interferon and/or ribavirin. * Treatment with systemic anti-neoplastic or immunomodulatory medication (supraphysiologic doses of steroids or radiation included) within the last 6 months prior to the study and throughout the whole study. * Immunosuppressed/immunocompromised patients. * Participation in a clinical study within the last three months. * Infection with HCV genotype-2, -3, -4, -5 or -6. * Positive indication of HBsAg, HIV antibodies in the screening phase. * Non-hepatitis C virus-induced chronic hepatitis (e.g. hematochromatosis, autoimmune hepatitis, metabolic or alcoholic liver disease). * Decompensated liver cirrhosis or liver disease; Child-Pugh Grade B or C; or threshold compensated liver disease. * Signs of a hepatocellular carcinoma within 2 months before the randomization, coupled with existing or developing cirrhosis. * History of oesophagus varices haemorrhage. * Hemoglobin \<12 g/dl in female subjects and \<13 g/dl in male subjects in the screening phase. * Subjects with a higher risk of anemia (e.g. thalassemia, spherocytosis, history of gastrointestinal bleeding) or subjects for whom anemia could be a highly potential medical risk. * Neutropenia \<1500 /µl or thrombocytopenia \<90,000 /µl diagnosed in the screening phase. * Serum creatinine \>1.5 mg/dl in the screening phase. * History of severe psychiatric diseases, especially severe depression, whereby severe psychiatric disease is defined as any anti-depressive or anti-psychotic therapy of at least 3 months in the history, or any indication of suicidal inclination or hospitalization caused by a psychiatric disease. * Epilepsy. * Autoimmune disease (e.g. inflammatory intestinal diseases, idiopathic thrombocytopenic purpura, lupus erythematosus sclerodermia, severe psoriasis, rheumatoid arthritis, etc.). * History of thyroid disease, poorly controlled by prescribed medications * Chronic pulmonary disease with functional restriction. * History of severe cardiac disease, e.g. cardiac insufficiency New York Heart Association (NYHA) class III or IV; myocardial infarction within the last 6 months; ventricular tachyarrhythmia requiring treatment; unstable angina pectoris; cerebrovascular circulation disorders; or other significant cardiovascular diseases. * Patients with pacemakers. * Cardiomyopathy and myocarditis * Atrioventricular (AV)-block Grade II and III. * Previously known bradycardia rating under 55 strokes/minute * Known, lengthy QT-interval (QTc as per Bazett \> 420 ms) or recognizable U waves or hereditary QT-syndrome in the family history. * History of a severe ventricular arrythmia including Torsade de pointes. * Simultaneous therapy with budipine or other QT-extending medication such as: * Certain antiarrhythmias of class IA (e.g. quinidine, disopyramide, procainamide) and class III (such as amiodarone, sotalol); * Certain antipsychotics (e.g. thioridazine, chlorpromazine, haloperidol, pimozide); * Certain tri- and tetracyclic anti-depressive medications (e.g. amitriptyline); * Certain antihistaminic medications (e.g. astemizol, terfenadin); * Certain macrolide antibiotics (e.g. erythromycin, clarithromycin); * Certain gyrase inhibitors (e.g. sparfloxacin); * Azole-antimycotics and other medications such as halofantrine, cotrimoxazol, pentamidine, cisapride or bepridil; * Simultaneous treatment with Memantine. * Morbus Parkinson. * History of major organ transplantations, with the exception of cornea transplantation. * Cancer or any other disease, which, in the opinion of the investigator, is an exclusion criterion for the study. * Evidence of severe retinopathy (e.g. cytomegalovirus \[CMV\] retinitis or macular degeneration). * Patients with narrow-angle glaucoma. * Active drug abuse (excessive alcohol consumption included) within the last year prior to study (with the exception of a prescribed substitute). * Patients with state of agitation or confusion * Patients with a history of acute brain syndrome or exogenous psychosis * Patients are already enrolled in the study. * Prostate hypertrophy * Simultaneous administering of diuretics of combination type triamterene/hydrochlorothiazide. * Unwillingness or incapability to give written consent after receiving medical information; doubts about the proper protection of patient data; and general reluctance to take part in the study and to adhere to the study terms. If one or more of these
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Proof that peginterferon alfa-2a, ribavirin and amantadine sulphate over a period of 50 weeks improves the permanent virological efficacy by more than 10% compared to peginterferon alfa-2a and ribavirin | — |
Secondary
| Measure | Time frame |
|---|---|
| Verification of the initial virological efficacy up to week 12, defined as negative HCV-RNA test results by means of quantitative proof methods, e.g. Roche AmplicorTM HCV Monitor v.2.0 (sensitivity <600 IE/ml) | — |
| Biochemical efficacy, defined by the serum GPT values 24 weeks after the end of the therapy | — |
| Virological efficacy, measured on the basis of the HCV-RNA values at the end of the therapy | — |
| Biochemical efficacy defined by the serum GPT values at the end of the therapy | — |
Outcome results
None listed