Purpose / Objectives

Primary Outcome

To compare the virological efficacy (HDV-RNA) and safety of 96 weeks of therapy with pegylated interferon-alfa-2a plus tenofovir to 96 weeks of therapy with pegylated interferon-alfa-2a plus placebo for the treatment of patients with chronic delta hepatitis virus.

Secondary Outcomes

To explore the effects of the two treatment regimens on HDV-RNA-levels, HBsAg levels, HBV-DNA, biochemical disease activity and liver histology. Virus-specific T cell responses during therapy and after 24 weeks of the end of treatment will be analysed on stored PBMC samples if virological and biochemical efficacy has been shown. In addition, the objective of this study is to determine the virological and clinical long-term outcome of treatment of delta hepatitis.

Diagnosis

• Hepatitis
• Chronic delta hepatitis

Target population

Inclusion criteria

• Written informed consent.
• Age > 18 years.
• Positive HBsAg, for at least the prior 6 months, positive anti-HDV for at least 3 months and positive for HDV-RNA by PCR within the screening period.
• Elevated serum ALT ≥ ULN but ≤ 10X ULN as determined by two abnormal values taken > 1 month apart during the 12 months before the first dose of study drug with at least one of the determinations obtained ≤ 35 days prior to the first dose.
• A liver biopsy obtained within the past 12 months demonstrating liver disease consistent with chronic hepatitis. Patients with cirrhosis on liver biopsy must also have a liver imaging investigation to rule out hepatic carcinoma.
• Negative urine or serum pregnancy test documented within the 24 hour period prior to the first dose of test drug.
• Additionally, all fertile males with partners of childbearing age and females should use two reliable forms of effective contraception (combined) throughout the entire period of the study (treatment and for 4 months after treatment completion)
• Creatinine clearance ≥ 70 mL/min

Exclusion criteria

• Patients must not have received antiviral therapy for their chronic hepatitis D within the previous 6 months. Patients who are expected to need systemic antiviral therapy other than that provided by the study at any time during their participation in the study are also excluded.
• Positive test at screening for HAV-Ag-IgM, HCV-RNA or HCV-Ag or HIV-Ag.
• Serum concentrations of ceruloplasmin or alpha-1-antitrypsin consistent with an increased risk of metabolic liver disease.
• Evidence of decompensated liver disease (Childs B-C).
• History or other evidence of a medical condition associated with chronic liver disease (e.g., hemochromatosis, autoimmune hepatitis, alcoholic liver disease, toxin exposures, thalassemia).
• Women with ongoing pregnancy or who are breast feeding.
• WBC count of < 3.000 cells/ mm3; neutrophil count < 1.500 cells/mm3or platelet count < 90.000 cells/mm3.
• Evidence of alcohol and/or drug abuse within one year of entry.
• Patients are excluded if any history of psychiatric disease, especially depression, or of suicidal attempts is evident.
• History of immunologically mediated disease.
• History or other evidence of decompensated liver disease.
• History or other evidence of chronic pulmonary disease associated with functional limitation.
• History of severe cardiac disease
• Evidence of an active or suspected cancer or a history of malignancy where there is a risk of cancer to recur.
• History of having received any systemic anti-neoplastic (including radiation) or immunomodulatory treatment (including systemic corticosteroids) ≤ 6 months prior to the first dose of study drug or the expectation that such treatment will be needed at any time during the study.
• History of any organ transplantation with an existing functional graft
• History of thyroid disease poorly controlled on prescribed medications. Patients with elevated thyroid stimulating hormone concentrations with elevation of antibodies to thyroid peroxidase and any clinical manifestations of thyroid disease are excluded.
• History or evidence of severe retinopathy or clinically relevant ophthalmological disorder.
• Inability or unwillingness to provide informed consent or abide by the requirements of the study.
• History or other evidence of severe illness or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study.
• Patients with a value of alpha-fetoprotein >100 ng/mL are excluded, unless stability (less than 10% increase) has been documented over at least the previous 3 months.
• History or evidence for any intolerance or hypersensitivity to pegylated interferon-alfa-2a, tenofovir or other substances part of the study medication.
• Current participation in any other investigational trial and participation in another investigational trial within 3 months before the trial begins.

Study design

• Multicenter
• Double-blind
• Randomized
• Placebo-controlled

Documents (password protected)

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Responsibilities in overall study

Sponsor

MHH - Medizinische Hochschule Hannover

• Tel. +49 511 532-3556
• Fax +49 511 532-3481

Sponsor representative

Prof. Dr. med. Michael Manns

Prof. Dr. med. Heiner Wedemeyer

(National) Coordinating Investigator

Prof. Dr. med. Michael Manns

SAE management

Hep-Net Study House (Deutsche Leberstiftung)

• Tel. +49 (0)511 532 6817
• Fax +49 (0)511 532 6820

Prof. Dr. med. Heiner Wedemeyer