A Phase II Study to Determine the Safety and Efficacy of Interferon-gamma in Patients With Chronic Hepatitis B

Study Overview
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Brief Summary
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Open-label, prospective, two part study evaluating IFN-γ 1b at a dose of 200μg by subcutaneous injection every day either alone or in combination with Adefovir dipivoxil or Adefovir dipivoxil alone at a dose of 10mg QD in patients with chronic Hepatitis B.

Detailed Description
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After signing the informed consent potential patients will undergo a screening medical history, physical examination, and laboratory tests. The study will consist of two parts: Part A: IFN-γ 1b monotherapy Part B: IFN-γ 1b combination therapy with Adefovir dipivoxil or Adefovir dipivoxil monotherapy Patients will be enrolled sequentially into to one of three treatment groups. In Part A, ten patients will be enrolled and will receive IFN-γ 1b 200μg, administered every day by subcutaneous injection for 4 weeks. If HBV DNA is reduced by ≥ 1 log10 copies/ mL in ≥ 30% of patients the protocol will proceed to Part B. In Part B, twenty patients will be enrolled into two cohorts (total of 10 for each cohort) and treated for four weeks. The two cohorts will be administered: IFN-γ 1b 200μg, administered every day combination therapy with Adefovir dipivoxil (10mg QD) or Adefovir dipivoxil (10mg QD) alone On the initial study visit, patients will be given instruction on self injection of IFN-γ 1b (if applicable). Patients will be monitored for safety, tolerability, HBV DNA, clinical chemistries including a standard panel of liver tests and hematologies throughout the study and for the two week post-treatment observation period.

Official Title
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Protocol Title: A Phase II Open-labeled Study to Determine the Safety and Preliminary Efficacy of Interferon-gamma 1b (IFN-γ 1b) in Patients With Chronic Hepatitis B Who Are HBV DNA Positive

Conditions
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Hepatitis B

Intervention / Treatment
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* Drug: IFN-γ 1b (Actimmune)
* Drug: Adefovir dipivoxil
* Drug: IFN-γ 1b and Adefovir dipivoxil combination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must fulfill all of the following criteria to be eligible for enrollment into the study: Men or women age 18 to 75 years Chronic hepatitis B infection based on a history of positive anti-HBsAg and positive for HBV DNA and with or without elevations in liver tests (test to be repeated on screening) Exclusion Criteria: Patients with any of the following will be excluded from randomization: Presence of clinically evident cirrhosis including: ascites requiring active diuretic therapy, history of or therapy for hepatic encephalopathy, or history of GI variceal bleeding Platelet count < 50,000/mm3 Serum ALT level > 10 times upper limit of normal Alpha-fetoprotein level ≥ 200 ng/mL or alpha-fetoprotein level between 50-200 ng/mL in association with liver ultrasound or other radiographic abnormality suspicious for hepatic neoplasm Serum creatinine level > 1.6 mg/dL Hematology outside of specified limits: neutrophil count <1000/mm3, hemoglobin <10 g/dL in males and <9 g/dL in females Unstable or uncontrolled thyroid disease Treatment with any interferon-α or nucleoside/tide analog within the previous 4 weeks Presence of clinically significant cryoglobulinemia (e.g., skin rash, arthritis, or renal insufficiency due to cryoglobuliemia) Presence or history of autoimmune hepatitis, alpha-1 anti-trypsin deficiency, hemochromatosis, Wilson's disease, drug- or toxin-induced liver disease, alcohol-related liver disease, primary biliary cirrhosis, or sclerosing cholangitis (mild-to-moderate steatosis is acceptable) Chronic hepatitis C infection Hepatits Delta infection (HDV) Known history of HIV infection or positive HIV antibody test by Western Blot (test performed within 60 days of screening can be used to determine eligibility) A disease known to cause significant alteration in immunologic function including hematological malignancy or autoimmune disorder (e.g. rheumatoid arthritis, systemic lupus erythematosis, autoimmune thyroid disease, leukemia, lymphoma, etc) Concurrent therapy with immunosuppressive drugs or cytotoxic agents such as oral prednisone, cyclosporine, azathioprine, or chemotherapeutic agent(s) (e.g., cyclophosphamide, methotrexate, or cancer chemotherapy) or radiation therapy Behavior that suggests a significant risk of poor compliance including, but not limited to: Illicit drug abuse within the past 3 years Current or history of alcohol abuse within the past 2 years Prior treatment with IFN-γ 1b History of unstable or deteriorating cardiac disease, including but not limited to: Myocardial infarction, coronary artery bypass surgery, or angioplasty within the past 6 months Congestive heart failure requiring hospitalization within the past 6 months Uncontrolled arrhythmias Transient ischemic attacks (TIAs) Any cardiac condition that, in the opinion of the site PI, might be significantly exacerbated by flu-like symptoms associated with the administration of IFN γ 1b Preexisting (within last two years) or active psychiatric condition including severe depression, major psychoses, suicidal ideation or suicidal attempts History of (within last two years) or current neurologic or psychiatric disorder that, in the opinion of the site PI, might be exacerbated by flu-like symptoms associated with the administration of IFN γ 1b. In addition, patients with the following conditions should be excluded: History of multiple sclerosis Seizures within the past 2 years Severe or poorly controlled diabetes Pregnancy or lactation. Females of childbearing potential are required to have a negative urine pregnancy test prior to treatment and must agree to practice abstinence or prevent pregnancy by at least a barrier method of birth control for the duration of the study Hemoglobinopthies (e.g. thalassemia, sickle cell disease) Any serious or chronic disease that, in the opinion of the Principal Investigator (PI), may affect the assessment of safety or efficacy parameters. This includes, but is not limited to, patients with malignancy who are receiving chemotherapy, chronic obstructive pulmonary disease or asthma requiring maintenance oral steroids, or active kidney disease Any condition which, in the opinion of the site PI, is likely to result in the death of the patient within the next year Patients who, in the opinion of the site PI, are not suitable candidates for enrollment or would not comply with the requirements of the study Patients who have had a liver transplant Patients who have Adefovir mutations on baseline tests

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br>IFN-γ 1b monotherapy: 200 micro-grams daily for 30 days | Drug: IFN-γ 1b (Actimmune)<br>* IFN-γ 1b: 200μg given SC ED = 2 vials of active drug (0.5 mL from each vial) will be mixed for a total volume of 1.0 mL per dose<br>* Other names: IFN-gamma;|
| Experimental: 2<br>IFN-γ 1b 200 micro-grams daily) combination therapy with Adefovir dipivoxil (10 mg daily) for 30 days | Drug: IFN-γ 1b and Adefovir dipivoxil combination<br>* IFN-γ 1b: 200μg given SC ED = 2 vials of active drug (0.5 mL from each vial) will be mixed for a total volume of 1.0 mL per dose Adefovir dipivoxil: 1 tablet of 10mg given orally QD<br>* Other names: Hepsera;|
| Active Comparator: 3<br>Adefovir dipivoxil monotherapy (10 mg QD) 30 days | Drug: Adefovir dipivoxil<br>* Adefovir dipivoxil: 1 tablet of 10mg given orally QD<br>* Other names: Hepsera;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective is to evaluate the safety and tolerability of IFN-γ 1b either alone or in combination with Adefovir dipivoxil in patients with chronic Hepatitis B. |  | 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate the changes in serum HBV DNA concentrations following administration of Adefovir dipivoxil alone, IFN-γ 1b either alone or in combination with Adefovir dipivoxil in patients with chronic Hepatitis B. |  | 30 days | 
| Evaluate the changes in liver tests and hematology following administration of Adefovir dipivoxil alone, IFN-γ 1b either alone or in combination with Adefovir dipivoxil in patients with chronic Hepatitis B. |  | 30 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HBV, Treatment, Interferon-gamma, combination, Hepsera, Actimmune, HBV DNA