| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
| Long term infection with the hepatitis B virus |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10008910 |
| E.1.2 | Term | Chronic hepatitis B |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
- Compare the efficacy of tenofovir DF 300 mg QD versus adefovir dipivoxil 10 mg QD for the treatment of HBeAg positive chronic hepatitis B at Week 48. The primary efficacy parameter is the proportion of patients with complete response, i.e., serum HBV DNA levels below 400 copies/mL and histologic improvement defined as at least a 2 point reduction in the Knodell necroinflammatory score without worsening in fibrosis.
- Compare the safety and tolerability of tenofovir DF 300 mg QD versus adefovir dipivoxil 10 mg QD for the treatment of HBeAg positive chronic hepatitis B at 48 weeks.
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| E.2.2 | Secondary objectives of the trial |
Compare the incidence of drug resistant mutations between treatment arms every 48 weeks.
Compare the virological, biochemical, serological and histological response to tenofovir DF 300 mg QD versus adefovir dipivoxil 10 mg QD for the treatment of HBeAg positive HBV at Week 48.
Evaluate persistent virological response (i.e., serum HBV DNA <400 copies/mL) between randomized treatment arms post Week 48.
Compare the virological, biochemical, serological and histological response of continuous treatment of tenofovir DF (early) versus sequential treatment of tenofovir DF (deferred; 48 weeks of adefovir dipivoxil followed by tenofovir DF treatment).
Evaluate durability of serological response from weeks 48 through 384 or 480 once study drug is discontinued following confirmed loss of HBsAg.
Evaluate the efficacy of combination therapy following persistent viral replication with continuous tenofovir DF treatment or sequential treatment with adefovir dipivoxil followed by tenofovir DF. |
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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 |
Note - substudy not running in Greece. Title: "A sub-study to evaluate the intra-hepatic cccDNA levels in response to long-term treatment with tenofovir DF 300 mg given continuously (early) versus treatment with adefovir dipivoxil 10 mg followed by tenofovir DF 300 mg (deferred)" Protocol amendment 2 (14-Sep-05)
In addition, an optional blood sample may be obtained for exploratory biomarker and pharmacogenomic discovery research. This sample may be collected at any time during the study or at a separate post study visit, if necessary. Subjects who agree to have blood drawn for these purposes will sign a separate informed consent form.
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| E.3 | Principal inclusion criteria |
1) Chronic HBV infection, defined as positive serum HBsAg for more than 6 months.
2) 18 through 69 years of age, inclusive.
3) Active HBeAg positive chronic HBV infection, with all of the following:
• HBeAg positive at screening
• ALT levels > 2 x ULN and ≤ 10 x ULN
• Serum HBV DNA >1000000 copies/mL at screening
• creatinine clearance ≥ 70 mL/min
• hemoglobin ≥ 8 g/dL
• neutrophils ≥ 1,000 /mm3
4) Knodell necroinflammatory score ≥ 3 and a Knodell fibrosis score < 4. However, up to 96 patients with cirrhosis, i.e., a Knodell fibrosis score equal to 4, will be eligible for enrollment.
5) Negative serum β-HCG
6) Nucleotide naïve, i.e., no prior nucleotide (tenofovir DF or adefovir dipivoxil) therapy for greater than 12 weeks.
7) Nucleoside naïve, i.e., no prior nucleoside (any nucleoside) therapy for greater than 12 weeks.
8) Willing and able to provide written informed consent.
9) Had a liver biopsy performed within 6 months of baseline and has readable biopsy slides or agrees to have a biopsy performed prior to baseline.
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| E.4 | Principal exclusion criteria |
1) Pregnant women, women who are breast feeding or who believe they may wish to become pregnant during the course of the study.
2) Males and females of reproductive potential who are unwilling to use an “effective” method of contraception during the study. For males, condoms should be used and for females, a barrier contraception method should be used.
3) Decompensated liver disease defined as conjugated bilirubin >1.5 x ULN, PT > 1.5 x ULN, platelets < 75,000/mm3, serum albumin < 3.0 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy, variceal hemorrhage).
4) Received any nucleoside, nucleotide (tenofovir DF or adefovir dipivoxil) or interferon (pegylated or not) therapy within 6 months prior of the pre-treatment biopsy.
5) Evidence of hepatocellular carcinoma (HCC), for example, α fetoprotein > 50 ng/mL or by any other standard of care measure.
6) Co-infection with HCV, HIV, or HDV.
7) Significant renal, cardiovascular, pulmonary, or neurological disease.
8) Received solid organ or bone marrow transplantation.
9) Is currently receiving therapy with immunomodulators (e.g., corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion.
10) Has proximal tubulopathy.
11) Known hypersensitivity to the study drugs, the metabolites or formulation excipients.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is the proportion of patients with a complete response (defined as having serum HBV DNA levels below 400 copies/mL and histologic improvement of at least a 2 point reduction in Knodell necroinflammatory score without worsening in the Knodell fibrosis score) at Week 48. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
| Secondary endpoints are change from baseline in log10 serum HBV DNA and ALT levels, proportion of patients with serum HBV DNA below 400 copies/mL, percentage of patients with normal ALT, incidence of drug resistant mutations, percentage of patients with HBeAg and HBsAg loss and seroconversion, percentage of patients with histological improvement, change from baseline in histological scores (to include Ishak), and ranked assessment of histological scores. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | Yes |
| 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 | Yes |
| 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) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| 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.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 69 |
| 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 | No |
| 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 |
| Australia |
| Canada |
| New Zealand |
| Turkey |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 10 |
| 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 | 10 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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