| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic hepatitis due hepatitis B virus |
|
| 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, in nucleoside treatment-naïve subjects with chronic HBeAg+ HBV infection, the efficacy of clevudine 30 mg once daily and adefovir 10 mg once daily, each as monotherapy, by assessing the proportion of subjects with undetectable serum HBV DNA levels (<300 copies/mL) and ALT normalization at 48 weeks. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives characterize the nature of the efficacy responses. Comparisons will be made between the clevudine 30 mg once daily and adefovir 10 mg once daily treatment groups. The most important of the secondary objectives is to assess the histologic improvement for each treatment by comparing the proportion of subjects with a ≥ 2 point decrease from baseline in the Knodell necroinflammatory grade with no worsening of the Knodell fibrosis stage at Week 48.
Other secondary objectives further define the virological, histological and biochemical responses, compare safety and tolerability of the two treatments throughout the study, characterize clevudine’s pharmacokinetics and the viral dynamics and immunologic responses for each treatment group. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or non-pregnant and non-lactating female subjects who are 16 years of age or older (or the legal age of consent as allowed by local regulations). There is no upper age limit imposed. The investigator should consider the individual risk/benefit assessment with the subject before
considering elderly subjects eligible.
2. Female subjects may be enrolled after a negative serum pregnancy test if they are:
a) surgically sterile or menopausal (amenorrhea >1 year and FSH > 30 IU/mL) or,
b) using a reliable and appropriate contraceptive method (see Section 11.4).
3. Subjects diagnosed with chronic hepatitis B.
4. Subjects who have received previous monotherapy treatment with any form of alpha interferon must have:
a) ceased alpha interferon monotherapy at least 12 months prior to the Baseline visit, and
b) received <12 weeks of alpha interferon, and
c) developed rebound chronic hepatitis B following withdrawal of interferon monotherapy due
to tolerability issues.
5. Subjects who have compensated hepatic function despite chronic hepatitis B infection.
6. HBV DNA ≥ 5.0 log10 (≥ 100,000) copies/mL using the Roche COBAS Taqman Assay.
7. Subjects must have a screening ALT value ≥ 1.3X and ≤ 10X ULN and at least 1 additional
documented ALT value within this range during the previous 6 months.
8. HBsAg+ for ≥ 6 months prior to baseline
9. Presence of HBeAg.
10. Current liver biopsy (or an historical biopsy obtained within 6 months prior to baseline) with
evidence of chronic hepatic inflammatory injury at screening (equivalent to a Knodell HAI grade ≥ 4 and modified Ishak fibrosis score ≤ 5).
11. Total bilirubin of < 2 mg/dL.
12. INR ≤1.5
13. Serum albumin > 3 g/dL.
14. Platelet count > 90,000 /mm3.
15. Absolute neutrophil count > 1200 /mm3.
16. Hepatic ultrasound or MRI within the last 6 months without evidence of hepatocellular carcinoma.
17. ANA titer <1:320.
18. Normal electrocardiogram (ECG) or clinically non-significant changes at screening.
19. Adequate renal function to take adefovir without any dose modifications; creatinine clearance must be ≥ 50 mL/min (based on the Cockcroft-Gault equation, see Section 13.5).
20. Able and willing to undergo protocol-specified liver biopsies at Screening and Week 48. Note: subjects who have had a liver biopsy within six months prior to the baseline visit need not have a biopsy performed at screening.
21. Able to participate and willing to give written informed consent.
22. Able and willing to comply with study assessments and restrictions.
23. Able and willing to participate in the patient-reported outcomes study, Appendix D.
|
|
| E.4 | Principal exclusion criteria |
1. Subjects who are coinfected with HIV, HCV or HDV.
Note: Although subjects with anti-HCV antibodies who have responded to previous antiviral treatment may be considered cured of chronic hepatitis C infection, if there is evidence of circulating HCV RNA, these subjects are not eligible for this trial.
2. Previous or current treatment with antivirals, including approved or investigational nucleosides/nucleotides (e.g., lamivudine, adefovir, entecavir, lobucavir, famciclovir, tenofovir, telbivudine), for any duration.
3. Other chronic hepatic disease e.g., chronic alcoholism, Wilson’s disease, non-alcoholic steatotic hepatitis, non-alcoholic fatty liver disease.
4. Subjects with a history of ascites, variceal hemorrhage, hepatic encephalopathy, or other conditions consistent with decompensated liver disease.
5. History of lactic acidosis.
6. Concurrent use of nephrotoxic agents (e.g., aminoglycosides, amphotericin B, vancomycin, foscarnet, cisplatinum, pentamidine, cyclosporine, tacrolimus) or competitors of renal tubular excretion (e.g., probenecid) within 60 days prior to study screening or the expectation that the subject will receive these medications during the course of the study.
7. Poorly controlled Type 1 or Type 2 diabetes mellitus (fasting blood glucose > 300 mg/dL and/or HbA1c ≥ 8) within the 3 months prior to screening.
8. Severe chronic disease or immunocompromised subjects (including bone marrow and organ transplant subjects).
9. History of pancreatitis (other than an episode related to a documented gallstone followed by
cholecystectomy, without complications of pseudocyst, etc.).
10. Use of systemic corticosteroids, or other immunomodulatory agents, including Prednisone >10 mg/day within 30 days of Baseline or the expectation that the subject will receive these medications during the course of the study.
11. Significant chronic gastrointestinal (e.g., malabsorption syndrome) or bronchopulmonary disease (e.g., emphysema) requiring chronic therapy.
12. History or evidence of severe cardiac disease (e.g., NYHA Functional Class III or IV; see Appendix B), myocardial infarction within 6 months prior to Baseline, ventricular tachyarrythmias requiring ongoing treatment or unstable angina.
13. Malignancy diagnosed or treated within the past 5 years except for squamous cell carcinoma or basal cell carcinoma and those presenting no limitation to cancer-free survival.
14. Any medical, severe psychiatric, occupational, or social condition (including alcohol and drug abuse) currently or within 1 year prior to screening that, in the judgment of the investigator, would interfere with, or serve as a contraindication to protocol adherence, assessment of safety or treatment compliance, or a participant's ability to give informed consent (see Appendix A for alcohol abuse criteria). Severe psychiatric condition is defined as major depression or psychosis, suicidal attempt, hospitalization for psychiatric disease, or a period of disability due to a psychiatric disease.
15. Participation in a clinical trial or receipt of an investigational agent, for any reason, within 60 days of baseline.
16. Known serious allergies to nucleoside/nucleotide analogs, including adefovir or clevudine.
17. Donation or loss of more than 400 mL blood within 60 days prior to anticipated baseline visit.
18. Subjects who are pregnant, nursing, or unwilling to use appropriate forms of contraception (see Section 11.4).
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is a composite response rate defined as the proportion of subjects with both undetectable serum HBV DNA (<300 copies/mL) and normalized ALT at Week 48. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | Information not present in EudraCT |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| 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) | 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 | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 | 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
| |
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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