Subcutaneous Continuous Infusion of Interferon Alfa-2b and Ribavirin in Hepatitis C Genotype 1 Nonresponders

Study Overview
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Brief Summary
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For chronic hepatitis C patients unresponsive to previous (PEG-)IFN/RBV combination therapy we propose continuous subcutaneous administration of high-dose IFN-a2b (Intron A®) for 48 weeks in combination with 15 mg/kg/day RBV (Rebetol®) and optimal management of side effects in order to maintain the highest possible dosages of both IFN-a2b and RBV for 48 weeks. We expect improved tolerability with continuous subcutaneous pump delivery of IFN-a2b compared to thrice weekly or daily subcutaneous injection of IFN-a2b, and increased antiviral activity and biologic potency due to sustained and higher levels of a fully potent interferon protein.

Official Title
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Subcutaneous Continuous Infusion of Interferon Alfa-2b and Ribavirin in Hepatitis C Genotype 1 Nonresponders

Conditions
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Chronic Hepatitis C

Intervention / Treatment
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* Drug: interferon alfa-2b
* Drug: interferon alfa-2b
* Drug: interferon alfa-2b


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Hepatitis C genotype 1 unresponsive to (peg)interferon /ribavirin therapy In the past, peginterferon or conventional interferon plus ribavirin combination therapy for at least 12 weeks and less than 2-log HCV RNA decrease at week 12, HCV RNA positivity at week 24, breakthrough during therapy or relapse after therapy At least 12 weeks between end of (peg)interferon/ribavirin therapy and start of high-dose IFN/ribavirin therapy Persistent indication for antiviral therapy such as persistently elevated serum ALT or histological evidence of continuing or progressive fibrosis Age 18-60 years Exclusion Criteria: Signs of progressive liver disease since end of previous therapy, beyond generally accepted criteria for HCV antiviral therapy: serum bilirubin >35 μmol/l, albumin <36 g/l, prothrombin time >4 sec prolonged or platelets <100,000/mm3 decompensated cirrhosis (defined as jaundice in the presence of cirrhosis, ascites, gastric bleeding, esophageal varices or encephalopathy) Hepatic imaging (US, CT or MRI) with the evidence of hepatocellular carcinoma (hepatic imaging should be performed within 3 months prior to screening) or an alpha fetoprotein >50 ng/ml Other acquired or inherited causes of liver disease that could explain liver disease activity Co-infection with hepatitis B virus or human immunodeficiency virus (HIV) Other significant medical illness that might interfere with this study: significant cardiovascular, pulmonary or renal dysfunction, malignancy other than skin basocellular carcinoma in previous 5 years, immunodeficiency syndromes (e.g.: HIV positivity, steroid therapy, organ transplants other than cornea and hair transplant) History of a severe seizure disorder or current anticonvulsant use History of thyroid disease poorly controlled on prescribed medications Contra-indications for IFN and/or ribavirin: Severe psychiatric disorder, such as major psychoses, suicidal ideation, suicidal attempt and/or manifest depression during previous (peg)interferon therapy. 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 Reactivation of immunological disorders during previous therapy Visual symptoms related to retinal abnormalities Pregnancy, breast-feeding or inadequate contraception Thalassemia, spherocytosis Substance abuse, such as alcohol (³80 gm/day) and I.V. drugs. 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 2 years 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>12 MU interferon alfa-2b daily continuously subcutaneous in combination with 15 mg/kg/day ribavirin | Drug: interferon alfa-2b<br>* 12 MU daily continuously subcutaneous<br>* Other names: Intron A;|
| Experimental: 2<br>9 MU interferon alfa-2b daily continuously subcutaneous in combination with 15 mg/kg/day ribavirin | Drug: interferon alfa-2b<br>* 9 MU daily continuously subcutaneous<br>* Other names: Intron A;|
| Experimental: 3<br>6 MU interferon alfa-2b daily continuously subcutaneous in combination with 15 mg/kg/day ribavirin | Drug: interferon alfa-2b<br>* 6 MU daily continuously subcutaneous<br>* Other names: Intron A;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and tolerability of high-dose continuous subcutaneous infused IFN-a2b (serious adverse events, grade 4 NCI toxicity, percentage of patients completing treatment or reasons for dose adjustments). |  | 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| HCV RNA negativity at week 48 and 24 weeks after end of treatment |  | 48 weeks | 
| Biological activity of IFN-a2b |  | 48 weeks | 
| Pharmacokinetics by IFN-a2b levels |  | 48 weeks | 
| HCV-specific immune responses |  | 48 weeks | 
| Quality of life assessment using SF-36 and SCL-90 questionnaires |  | 48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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genotype 1 nonresponders