E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Chronic hepatitis B virus infection |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008910 |
E.1.2 | Term | Chronic hepatitis B |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To study whether a PEG-IFN add-on strategy for 24 weeks during 48 weeks of ETV therapy enhances response (HBeAg loss combined with HBV DNA < 200 IU/mL), as compared to 48 weeks of ETV monotherapy in HBeAg-positive chronic hepatitis B patients. |
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E.2.2 | Secondary objectives of the trial |
To study differences in outcome between one year ETV therapy with a PEG-IFN add-on strategy and one year of ETV monotherapy on suppression of HBV DNA (HBV DNA < 60IU/mL)
To study differences in outcome between one year ETV therapy with a PEG-IFN add-on strategy and one year of ETV monotherapy on serum HBsAg and HBeAg loss
To study differences in outcome between one year ETV therapy with a PEG-IFN add-on strategy and one year of ETV monotherapy on the emergence of entecavir-resistant mutations
To study differences in the safety and tolerability between one year ETV therapy with a PEG-IFN add-on strategy and one year of ETV monotherapy
To study differences in sustained response (HBeAg loss combined with HBV DNA < 200 IU/mL at 96 weeks) 24 weeks after discontinuation of treatment between responders at 48 weeks with 24 weeks of ETV consolidation treatment) after one year ETV therapy with a PEG-IFN add-on strategy and responders after one year of ETV monotherapy
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1) "Changes in immunology, histology and intrahepatic cccDNA levels during entecavir therapy with or without peg-interferon alpha-2a in HBeAg-positive chronic hepatitis B", version 1, 22 June 2009 - To compare liver histology in biopsies taken at baseline and at week 52 in the two treatment groups - To compare levels of intrahepatic cccDNA in biopsies taken at baseline and at week 52 in the two treatment groups - To study the use of week 52 levels of intrahepatic cccDNA in predicting sustained response up to week 96 - To asses gene expression levels, phenotype and function of peripheral blood mononuclear cells (PBMC) at baseline and at week 52 2) "The effect of HBV and/or HBV proteins on immune modulation by PEGα-2a in patients with chronic hepatitis B", 29 May 2009 To evaluate the effect of viral load reduction on the immune modulatory effect of PEGIFNα-2a as assessed by: intracellular type I IFN signalling in leukocytes DC activation and function anti-viral and IFN-induced gene and protein expression
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E.3 | Principal inclusion criteria |
•Chronic hepatitis B (HBsAg positive > 6 months) •HBeAg positive, anti-HBe negative at screening •ALT > 1.3 x ULN within 60 days prior to screening and during screening •Liver biopsy performed within 2 years prior to screening or during screening •Age > 18 years •Written informed consent •Adequate contraception for males and females during treatment and follow up; negative pregnancy test (for women of childbearing potential)
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E.4 | Principal exclusion criteria |
•Antiviral therapy against HBV within the previous 6 months •Treatment with any investigational drug within 30 days of screening •Previous treatment with lamivudine or telbivudine for more than six months •Severe hepatitis activity as documented by ALT>10 x ULN •History of decompensated cirrhosis (defined as jaundice in the presence of cirrhosis, ascites, bleeding gastric or esophageal varices or encephalopathy) •Pre-existent neutropenia (neutrophils <1,500/mm3) or thrombocytopenia (platelets <90,000/mm3) •Co-infection with hepatitis C virus or human immunodeficiency virus (HIV) •Other acquired or inherited causes of liver disease (i.e. alcoholic liver disease, obesity induced liver disease, drug related liver disease, auto-immune hepatitis, hemochromatosis, Wilson’s disease or alpha-1 antitrypsin deficiency) •Alpha fetoprotein > 50 ng/ml •Hyper- or hypothyroidism (subjects requiring medication to maintain TSH levels in the normal range are eligible if all other inclusion/exclusion criteria are met) •Immune suppressive treatment within the previous 6 months •Contra-indications for alpha-interferon therapy like suspected hypersensitivity to interferon or PEG-interferon or any known pre-existing medical condition that could interfere with the patient's participation in and completion of the study. •Pregnancy, lactation •Other significant medical illness that might interfere with this study: significant pulmonary dysfunction in the previous 6 months, malignancy other than skin basocellular carcinoma in previous 5 years, immunodeficiency syndromes (e.g. HIV positivity, auto-immune diseases, organ transplants other than cornea and hair transplant) •Any medical condition requiring, or likely to require chronic systemic administration of steroids, during the course of the study •Substance abuse, such as alcohol (80 g/day), I.V. drugs and inhaled drugs in the past 2 years. •Any other condition which in the opinion of the principal investigator would make the patient unsuitable for enrollment, or could interfere with the patient participating in and completing the study
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary outcome (response): The combined presence of HBV DNA level < 200 IU/mL and HBeAg loss at week 48 Secondary outcomes: •ALT normalization •Undetectable HBV DNA (< 60 IU/mL) •HBsAg and HBeAg loss from serum •The emergence of HBV polymerase mutations associated with reduced susceptibility to entecavir •Sustained response defined as the combined presence of HBV DNA level < 200 IU/mL and HBeAg loss at week 96
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 10 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The last visit of the last subject undergoing the trial |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |