E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Decompensated Chronic Hepatitis B and Evidence of Cirrhosis |
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MedDRA Classification |
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 |
The primary objectives of this study are:
• To compare the antiviral and clinical efficacy of telbivudine (LdT) versus lamivudine in adults with decompensated chronic hepatitis B, over two years (104 weeks).
• To compare the safety and tolerability of telbivudine (LdT) versus lamivudine in patients with decompensated chronic hepatitis B, over two years (104 weeks). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this study are:
• To determine the comparative frequency of resistance-related virologic breakthrough during two years of treatment with LdT or lamivudine, and the clinical correlates of virologic breakthrough with regard to efficacy and safety.
• To characterize treatment-emergent HBV viral genotypes associated with virologic breakthrough, for the two study treatments. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Male or female, 16 to 70 years of age.
2. Documented decompensated chronic hepatitis B defined by all of the following: • Clinical history compatible with decompensated chronic hepatitis B related cirrhosis • Child-Turcotte-Pugh score > 7 points. • Evidence of hepatic cirrhosis or portal hypertension, documented by at least one of the following six methods: i. Evidence of cirrhosis by previous liver biopsy within 5 years prior to Screen, OR ii. Evidence of cirrhosis by liver biopsy prior to randomization, OR iii. Evidence of cirrhosis by ultrasound, CT, or MRI imaging within 2 years prior to Screen, OR iv. Evidence of cirrhosis by ultrasound, CT, or MRI imaging prior to randomization (for patients who are considered high-risk for liver biopsy, due to thrombocytopenia or bleeding diatheses), OR v. Evidence of portal hypertension by previous endoscopy demonstrating grade III or IV esophageal varices within 5 years prior to Screen, OR vi. Evidence of portal hypertension by documented previous history of related clinical complications (i.e., one or more previous episodes of clinically significant upper gastrointestinal hemorrage related to esophageal varices, or previous episode(s) of spontaneous bacterial peritonitis); OR vii. Evidence of portal hypertension by previously measured hepatic venous pressure gradient > 15 mmHg within 2 years prior to Screen • Detectable serum HBsAg at the Screening visit • Elevated serum ALT level (1.2 – 10 x ULN) at the Screening visit
3. Serum HBV DNA level ≥ 5 log10 copies/mL, as determined by the PCR assay at the central study laboratory at Screen.
4. Patient is ambulatory.
5. Patient is willing and able to comply with the study drug regimen and all other study requirements.
6. The patient is willing and able to provide written informed consent to participate in the study. |
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E.4 | Principal exclusion criteria |
1. Patient is pregnant or breastfeeding. Women of childbearing potential must have a negative serum beta-human chorionic gonadotropin (β-HCG) at Screen.
2. Patient is of childbearing potential (men and women) and unwilling to use double barrier method of contraception.
3. Patient is coinfected with hepatitis C virus (HCV), hepatitis D virus (HDV), or HIV.
4. Patient previously received lamivudine, adefovir, or an investigational anti-HBV nucleoside or nucleotide analog at any time. Precluded therapies include, but are not limited to, the following: any previous exposure to lamivudine, adefovir or other PMEA analogs (tenofovir, MCC-478), lobucavir, entecavir, emtricitabine (FTC), L-FMAU, L-Fd4C, or other investigational anti-HBV nucleosides/nucleotides.
5. Patient has received interferon or other immunomodulatory treatment for HBV infection in the 12 months before Screening for this study. Precluded therapies include, but are not limited to, interferon agents (alpha-, beta- or gamma-interferons), thymosin, IL-12, or other putative systemic immunomodulators.
6. Patient has a medical condition that requires prolonged or frequent use of systemic acyclovir or famciclovir (e.g., for recurrent herpes virus infections, etc). Prolonged use means episodic treatment with these agents for periods exceeding 10 days every 3 months, or chronic suppressive therapy.
12. Patient has evidence of renal insufficiency defined as patient requires dialysis or has an estimated creatinine clearance, below 70 mL/min, as estimated by the Cockcroft-Gault formula:
21. Patient has any of the following laboratory values at Screening: Hemoglobin < 9 g/dL for men or < 8 g/dL for women Total WBC < 1,500/ mm3 Absolute neutrophil count (ANC) < 1,000/mm3 Platelet count < 50,000/mm3 Serum amylase or lipase ≥ 1.5 x ULN Serum albumin < 2.5 g/dL Total bilirubin ≥ 3 x ULN Serum creatinine > ULN AFP > 50 ng/mL (requires further work up)
As requested, the most important exclusion criteria are listed here. Other exclusion criteria are detailed in the protocol.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is a composite endpoint called “Clinical Response” which is defined as HBV DNA < 10exp4 copies/mL AND ALT normalization AND improvement or stabilization in CTP score. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Information not present in EudraCT |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Information not present in EudraCT |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | Information not present in EudraCT |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 | 3 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |