E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
treatment in HBeAg-negative chronic hepatitis B patients |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
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 objective of the study is to compare the efficacy of Roadmap-Concept-based telbivudine treatment versus Roadmap-Concept-based tenofovir treatment in HBeAg-negative CHB patients. The rate of HBV DNA < 300 copies/mL (51 IU/mL) at week 52 will be used for the comparison of the efficacy. The hypothesis is that the aggregated rate of HBV DNA <300 copies/mL (51 IU/mL) at week 52 of Telbivudine (ARM 1) is non-inferior to Tenofovir (ARM 2). |
|
E.2.2 | Secondary objectives of the trial |
The key secondary objective of the study is to assess the antiviral
efficacy, as evaluated by rate of patients achieving HBV DNA <300
copies/mL (51 IU/mL) at Week 104, 156; and in patients who achieve
HBV DNA, <300 copies/mL at Week 104, to assess the rate of patients
with maintained HBV DNA, <300 copies/mL at Week 156.
•To compare the eGFR change in telbivudine arm versus tenofovir arm
over the course of the study
• eGFR change (absolute and percentage) from baseline to Week 52,
104, and 156 (by C-G, MDRD, CKD-EPI formula), for the overall
population (based on treatment arms) as well as sub-populations of
patients with renal function impairment at
baseline (defined as baseline eGFR 60-90 mL/min/1.73m2, or 60-80
mL/min/1.73m2)
• The percentage of patients with abnormal baseline eGFR (60-90
mL/min/1.73m2, or 60-80 mL/min/1.73m2) shifting to normal eGFR
(>90 mL/min/1.73m2 ) at Week 52, 104, and 156 |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Documented compensated HBeAg negative CHB defined by all of the
following:
•Detectable serum HBsAg at the screening visit and at least 6 months prior to the screening visit
•HBeAg negative at the screening visit with positive HBeAb
•Serum HBV DNA > 2000 IU/mL, as determined by the COBAS Taqman HBV DNA PCR assay at the central laboratory at screening visit
•Serum ALT level > 1×ULN and <10×ULN at screening visit. Patients
with normal ALT ≤ 1xULN at screening are eligible if: 1) they have at
least moderate liver inflammation or fibrosis; or 2) clinical evidence of
compensated liver cirrhosis; or 3) ALT level > 1×ULN within the last 6 months (EASL guidelines 2009; Lok and McMahon 2009)
•Available liver histology report within 12 months before screening with diagnosis of chronic hepatitis B. Patients without evaluable liver
histology report within 12 months of screening are eligible if: 1) they
have clinical evidence of compensated liver cirrhosis; or 2) non-invasive methods which are recommended by guidelines and updated clinical practice and that support diagnosis of moderate to severe liver inflammation and/or fibrosis (i.e. Fibroscan) (EASL guidelines 2009; Lok and McMahon 2009) |
|
E.4 | Principal exclusion criteria |
•Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using effective methods of contraception during dosing of study treatment.
•Sexually active males must use a condom during intercourse while
taking study drug and for 12 days after stopping study medication and should not father a child in this period.
•Patients co-infected with HCV, HDV, or HIV.
•Patient has received treatment of nucleoside or nucleotide drugs whether approved or investigational at any time.
•Patient has received IFN or other immunomodulatory treatment within six months before the screening visit. Precluded therapies include, but are not limited to any exposure to interferons, Thymosin, IL-12, or any types of immunological therapy.
•Patient has a medical condition that requires frequent use of systemic acyclovir or famcyclovir, etc.
•Patient has a medical condition that requires frequent use of systemic corticosteroids, however topical and inhaled corticosteroids are allowed.
•Patient has clinical signs/symptoms of hepatic decompensation with Child-Pugh score of B or C.
•History of malignancy of any organ system
•Patient has one or more additional known primary or secondary causes of liver disease, other than CHB, including steatohepatitis and autoimmune hepatitis among other liver diseases.
•Patient is currently abusing illicit drugs, or has a history of illicit substance abuse within the preceding two years.
•Patients with a history of alcohol abuse will be required to be abstinent from alcohol 6 months prior to screening or at the investigator’s discretion, and during the course of the study.
•Patients without a history of alcohol abuse are required to have an alcohol consumption of ≤ 30g ethanol/day for men and ≤ 15g ethanol/day for women twice a week during the course of the study.
•Patient has a history of clinical and laboratory evidence of chronic renal insufficiency defined as an estimated serum creatinine clearance < 50 mL/min using either Cockcroft-Gault or MDRD; or with a lower serum phosphate < 1.5 mg/dL.
•Patient has a medical condition requiring the chronic or prolonged use of potentially hepatotoxic drugs or nephrotoxic drugs.
•Patient has a medical condition requiring the use of chemotherapy.
•History of any other acute or chronic medical condition that in the opinion of the investigator would make the patient unsuitable for inclusion into the study.
•Patient has any other concomitant medical or social condition likely to preclude compliance with the schedule of evaluations in the protocol, or likely to confound the efficacy or safety observations of the study.
•Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
•Patient has a history of myopathy, myositis, or persistent muscle weakness.
•Patient has any of the following laboratory values during the screening period:
•Hemoglobin ≤11 g/dL(110g/L) for men or ≤10 g/dL (100g/L) for women
• Total WBC ≤3500/mm3 (3.5× 109 /L)
• Absolute neutrophil count (ANC) ≤1,500/mm3 (1.5×109/L)
• Platelet count ≤ 75,000/mm3 (75× 109 /L)
• Serum amylases or lipase ≥ 2 × ULN
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary efficacy endpoint is the rate of HBV DNA < 300 copies/mL at week 52. |
|
E.5.2 | Secondary end point(s) |
The key secondary objective of the study is to assess the antiviral
efficacy, as evaluated by rate of patients achieving HBV DNA <300
copies/mL (51 IU/mL) at Week 104, 156; and in patients who achieve
HBV DNA, <300 copies/mL at Week 104, to assess the rate of patients
with maintained HBV DNA, <300 copies/mL at Week 156.
•To compare the eGFR change in telbivudine arm versus tenofovir arm
over the course of the study
• eGFR change (absolute and percentage) from baseline to Week 52,
104, and 156 (by C-G, MDRD, CKD-EPI formula), for the overall
population (based on treatment arms) as well as sub-populations of
patients with renal function impairment at
baseline (defined as baseline eGFR 60-90 mL/min/1.73m2, or 60-80
mL/min/1.73m2)
• The percentage of patients with abnormal baseline eGFR (60-90
mL/min/1.73m2, or 60-80 mL/min/1.73m2) shifting to normal eGFR
(>90 mL/min/1.73m2 ) at Week 52, 104, and 156 |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
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 | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
- Immunology sub-study
- Renal function exploratory study
- Liver fibrosis exploratory study |
|
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.8.2.4 | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 32 |
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
|
Study completion is defined for an individual patient who meets the screening requirements, attends the Baseline Day 1 visit, completes the 156 week Treatment Phase of the study and 4 week Follow-up Phase of the study. The study recruitment is completed when at least 240 patients have been randomized to the treatment arms. |
|
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 | 6 |
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 |