| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| 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 |
|
| 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 compare the proportion of subjects in the entecavir plus tenofovir combination therapy group to the proportion of subjects in the treatment group receiving adefovir added to continuing lamivudine therapy who achieve HBV DNA < 50 IU/mL (approximately 300 copies/mL) by PCR at Week 48 of treatment using the Roche COBAS TaqMan HBV Test for use with the High Pure System (HPS) assay |
|
| E.2.2 | Secondary objectives of the trial |
| Compare ETV+TDF treatment group with group receiving ADV+continuing LVD therapy for: Proportion of subjects -achieving HBV DNA <50 IU/mL by PCR at Week 96 of treatment using Roche COBAS TaqMan - HPS assay -achieving HBV DNA <LLD at Week 48 & 96 -with HBV DNA <LLD (4.8); LLD to <50; 50 to <172; 172 to <1.720; 1720 to <17.200; & ≥ 17.200 IU/mL (<LLD (28); 28 to <300; 300 to <103; 103 to <104; 104 to <105; & ≥ 105 copies/ml at Week 48 & 96 -with ALT normalization (≤ 1 x ULN) at Week 48 & 96 -HBeAg positive at baseline with loss of HBeAg at Week 48 & 96 -HbeAg positive at baseline with HBe seroconversion at Week 48 & 96 -with HBsAg loss at week 48 & 96 -with HBs seroconversion at Week 48 & 96 -with genotypic resistance based on analysis of samples from subjects with HBV DNA ≥50 IU/mL at Week 48 & 96; Mean log10 reduction from baseline in HBV DNA by PCR at Week 48 & 96 Frequency of AEs, SAEs, & discontinuations from study drug due to AEs or laboratory abnormalities |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| ) Signed Written Informed Consent 2) Subjects with chronic HBV infection (detectable HBsAg at screening and for at least 24 weeks prior to screening, or detectable HBsAg for < 24 weeks and negative for IgM core antibody); subjects may be either HBeAg-positive or HBeAg-negative; 3) Subjects must have a history of previous lamivudine treatment, must have LVD resistance substitutions at reverse transcriptase rtM204I/V ± rtL180M, documented by INNO-Lipa HBV-DR assay, and must be receiving lamivudine at the screening visit; 4) Subjects must have compensated liver function and must meet ALL of the following criteria; International Normalization Ratio (INR) ≤ 1.5 Serum albumin ≥ 3 g/dL (≥ 30 g/L) Serum total bilirubin ≤ 2.5 mg/dL (≤ 42.75 μmol/L) 5) HBV DNA ≥ 172,000 IU/mL HBV DNA (approximately 106 copies/mL) by PCR at screening; 6) ALT >1.0 x and ≤10 x the ULN at screening and at least once ≥ 12 weeks prior to screening with no value falling within the normal reference range in the intervening period; 7) Men and women, ≥ 18 years of age (or minimum age of consent in a given country) |
|
| E.4 | Principal exclusion criteria |
| ) WOCBP who are unwilling or unable to use an acceptable method to avoid pregnancy for the entire study period and for up to 6 weeks after the last dose of investigational product. 2) Evidence of decompensated cirrhosis including but not limited to: variceal bleeding; hepatic encephalopathy; or ascites requiring management with diuretics or paracentesis; 3) Coinfection with HIV, hepatitis C virus ([HCV]; coinfection is defined as HCV Ab-positive with detectable HCV ribonucleic acid [RNA] by PCR), or hepatitis D virus (HDV). 4) Recent history of pancreatitis (within 24 weeks prior to the first dose of study medication); 5) Currently abusing illegal drugs or alcohol sufficient in the Investigator’s opinion, to prevent adequate compliance with study therapy or to increase the risk of hepatotoxicity or pancreatitis; 6) Other serious medical conditions that might preclude completion of this study or that require chronic administration of prohibited medications (see Exclusion Criteria 13 - 15). 7) Renal impairment that precludes subject from tolerating the per protocol study drug dose levels (see Protocol section 5.3.1). 8) Serum creatinine > 1.5 mg/dL; 9) Hemoglobin < 10.0 g/dL; 10) Platelet count < 70,000/mm3; 11) Absolute neutrophil count < 1500 cells/mm3; 12) Serum alpha fetoprotein (AFP) level > 100 ng/mL. 13) Known history of allergy to nucleoside or nucleotide analogues. 14) Except lamivudine, any prior therapy with nucleoside or nucleotide analogue antiviral agents with activity against hepatitis B (e.g., adefovir, entecavir, famciclovir, tenofovir/emtricitabine, clevudine); 15) Therapy with interferon, thymosin alpha or other immuno-stimulators within 24 weeks of randomization into this study; 16) Required chronic administration of medications which cause immunosuppression or which are associated with a high risk of nephrotoxicity or hepatotoxicity or which affect renal excretion. (See Protocol Section 5.5.1 for examples.). 17) Prisoners or subjects who are involuntarily incarcerated; 18) Subject who are compulsorily detained for treatment of either a psychiatric or physical (e.g., infectious disease); 19) Unable to tolerate oral medication; 20) Poor peripheral venous access; 21) Off lamivudine therapy for greater than 7 days between the time of the screening visit and initiation of study treatment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary Efficacy Endpoints: Proportion of subjects who achieve HBV DNA < 50 IU/mL (approximately 300 copies/mL) by PCR at Week 48 of treatment using the Roche COBAS TaqMan HBV Test for use with the High Pure System (HPS) assay. Secondary Efficacy Endpoints: Proportion of subjects who achieve HBV DNA < 50 IU/mL (approximately 300 copies/mL) by PCR at Week 96 of treatment using the Roche COBAS TaqMan - HPS assay. Proportion of subjects who achieve HBV DNA < the lower limit of detection (LLD) for the Roche COBAS TaqMan - HPS assay (LLD = 4.8 IU/ml [28 copies/mL]) at Weeks 48 and 96; Proportions of subjects with HBV DNA < LLD (28); 28 to < 300; 300 to < 103; 103 - < 104; 104 - < 105; and ≥ 105 copies/ml (<LLD (4.8); LLD to < 50; 50- <172; 172 - < 1,720; 1,720 - < 17,200; and ≥ 17,200 IU/mL) at Weeks 48 and 96 using the Roche COBAS TaqMan - HPS assay; Mean log10 reduction from baseline in HBV DNA by PCR at Weeks 48 and 96 using the Roche COBAS TaqMan - HPS assay; Proportion of subjects with ALT normalization (≤ 1 x upper limit of normal [ULN]) at Weeks 48 and 96; Proportion of subjects who were HBeAg positive at baseline with loss of HBeAg at Weeks 48 and 96; Proportion of subjects who were HBeAg positive at baseline with HBe seroconversion (HBeAg loss and presence of HBeAb) at Weeks 48 and 96; Proportion of subjects with HBsAg loss and HBs seroconversion at Weeks 48 and 96; Proportion of subjects with genotypic resistance based on analysis of samples from the subjects with HBV DNA ≥ 50 IU/mL (approximately 300 copies/mL) at Weeks 48 and 96; Safety Endpoints: Number and percent of subjects with adverse events (AEs), serious adverse events (SAEs), and discontinuations from study drug due to adverse events or laboratory abnormalities |
|
| 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 | No |
| 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 | 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) | 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| ETV+TDFvsADVadded to continuingLVD therapy |
|
| 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
|
| 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 8 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 0 |
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