| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Treatment of naïve patients with HBeAg-positive compensated chronic hepatitis B |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| 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 |
| The primary objective of this study is to demonstrate the superior antiviral efficacy of the combination of peginterferon alpha-2a plus telbivudine vs peginterferon alpha-2a monotherapy as demonstrated by HBV DNA non-detectability using the COBAS Amplicor HBV Monitor™ assay (threshold for detection 300 copies/mL) at Week 52 in adult patients with HBeAg-positive CHB |
|
| E.2.2 | Secondary objectives of the trial |
The key secondary objectives of the study are
•Demonstrate that telbivudine monotherapy has superior antiviral efficacy compared to peginterferon alpha-2a monotherapy as shown via PCR non-detectability at Week 52.
•Compare the antiviral efficacy of the combination of peginterferon alpha-2a plus telbivudine to telbivudine monotherapy at Week 52
Other secondary objectives evaluated at various time points include:
•Assessment HBV DNA non-detectability, reduction from baseline and sustained reduction in HBV DNA over the course of the study.
•Assessment Virologic Breakthrough (See glossary of terms) and treatment emergent HBV resistance at Weeks 48 and 96
•Assessment of HBeAg loss and HBeAg seroconversion (defined as loss of HBeAg and development of HBeAb).
•Assessment of HBsAg loss
•Assessment of ALT normalization
|
|
| 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 |
Study title: Same as trial itself: 'A randomized, open-label, controlled, multi-center two-year study comparing efficacy and safety of telbivudine 600 mg PO in combination with pegylated interferon alpha-2a 180 micrograms with pegylated interferon alpha-2a monotherapy, and with telbivudine monotherapy in treatment-naive patient with HBeAg-positive chronic hepatitis B'.
Population pharmacokinetic exploratory objectives include the following:
•Characterization of population PK parameters and the related concentration-time profile of telbivudine.
• Investigation of the telbivudine and peginterferon alpha-2a pharmacokinetic
interaction at steady-state
•Investigation of the potential relationships between model-based, steady-state, exposure measures and HBV DNA reduction.
For characterisation of population pharmacokinetics of telbivudine and evaluation of the effect of peginterferon alpha-2a on the pharmacokinetics of telbivudine, samples will be collected at 7 various time points beginning with baseline (pre-dose, Day 1) and then at Week 4 through Week 24 (post-baseline). One post-baseline visit will collect samples at three separate time points. The samples will be collected from all patients in both telbivudine mono-therapy and the combination groups.
For evaluation of the effect of telbivudine on the pharmacokinetics of peginterferon alpha-2a, samples for the determination of trough peginterferon levels will be collected at approximately 168 hours after the last injection dose of peginterferon (just prior to next injection dose) at weeks 8, 12 and 24 (one sample per week). The samples will be collected from all patients in both peginterferon alpha-2a monotherapy and the combination groups.
Exploratory objectives of health economics include:
•Examination as to whether there would be differences in Resource Utilization with regards to outpatient visits between patients receiving peginterferon alpha-2a and telbivudine combination, peginterferon alpha-2a monotherapy and telbivudine monotherapy.
•Evaluatation of the change in the global score and the subscale scores of the HBQOL v1.0 between Baseline and various time points during treatment and the Post-study follow-up.
•Assessment of the change in the total score and subscale scores of the Psychological Well-Being Index (PGWBI) between Baseline and various time points during treatment and the Post-study follow-up. |
|
| E.3 | Principal inclusion criteria |
1. Male or female, at least 18 years of age.
2. Documented CHB defined by all of the following:
• Clinical history compatible with CHB
• Detectable serum HBsAg at the Screening visit and at least 6 months prior
• HBeAg-positive at the Screening visit
• HBeAb-negative at the Screening visit
• History of evidence of chronic liver inflammation, documented by previous history of elevated serum ALT (at least two elevated ALT values spanning six months or more, documented in available records)
• Elevated serum ALT level (1.3 – 10 x upper limit of normal (ULN)) at the Screening visit
• Serum HBV DNA level ≥ 6 log10 copies/mL, as determined by the COBAS Amplicor HBV PCR assay at the central study laboratory at Screening visit
• Chronic liver inflammation on previous liver biopsy within the previous 24 months in source documents.
|
|
| E.4 | Principal exclusion criteria |
1.Co-infection with HCV, HDV, or HIV.
2.Has any of the following drug therapy:
•Previously been treated in a trial with telbivudine
•Received nucleoside or nucleotide therapy whether approved or investigational.
•Received any immunomodulatory treatment in the 12 months before Screening for this study.
•Has a medical condition that required prolonged or frequent use of systemic acyclovir or famciclovir. Has a medical condition that requires frequent or prolonged use of systemic corticosteroids although inhaled or intra-articular corticosteroids are allowed.
•Has a medical condition requiring the chronic or prolonged use of potentially hepatotoxic drugs or nephrotoxic drugs.
•Is currently abusing alcohol or illicit drugs or has a history of alcohol abuse illicit substance abuse within the preceding two years.
•Uses other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer.
•Is currently receiving methodone.
4.Patient has any of the following:
•History of or clinical signs/symptoms of hepatic decompensation such as ascites, esophageal variceal bleeding, hepatic encephalopathy, or spontaneous bacterial peritonitis.
•History of malignancy of any organ system, treated or untreated, within the past 5 years whether or not there is evidence of local recurrence or metastases, with the exception of localized basal cell carcinoma of the skin. Patients with previous findings suggestive of possible HCC should have the disease ruled out prior to entrance into the study.
•One or more additional known primary or secondary causes of liver disease other than hepatitis B, including steatohepatitis. Note: Gilbert's syndrome and Dubin-Johnson syndrome are not considered exclusion criteria for this study.
•History of clinical and laboratory evidence of chronic pancreatitis, or demonstrates a clinical and laboratory course consistent with current pancreatitis.
•Subject has a history of myopathy, myositis, or persistent muscle weakness.
•Has in the opinion of the investigator any other concurrent 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. If in the opinion of the investigator, the patient is at risk of developing a serious or life-threatening neuropsychiatric condition
• Pre-existing retinal disorder conditions.
• Active autoimmune disorder,
• Unstable angina, MI or CVA within the past three months
5.Has any of the following laboratory values during Screening:
•HGB <11 g/dL for men or <10 g/dL for women
•Total WBC <3,500/mm3
•(ANC <1,500.mm3
•Platelet count <75,000/mm3
•Serum amylase or lipase ≥ 1.5 x ULN
•Serum albumin <3.3 g/dL
•Total bilirubin ≥ 2.0 mg/dL (34.2umol/L)
•ANA >1:320
•Prothrombin Time >3 seconds over ULN despite vitamin K administration
•Patient has TSH < 0.35microU/ml or 5.5 microU/ml
•Estimated calculated serum creatinine clearance < 50 mL/min (0.48mL/s)using the Cockcroft-Gault method using actual or ideal body weight whichever is less;
•AFP > 50 ng/mL
•Triglycerides >600mg/dl even after treatment for dyslipaemia within the screening period
6. TSH Patient is on thyroid therapy and dose is not stable for at least 5 weeks prior to Visit 2/Baseline
7. Is pregnant or breastfeeding. Women of childbearing potential must have a negative serum β-HCG during Screening.
8. Is a women of child-bearing potential (WOCBP), defined as all women physiologically capable of becoming pregnant, including women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner and women whose partners have been sterilized by vasectomy or other means, UNLESS they meet the following definition of post-menopausal: 12 months of natural (spontaneous) amenorrhea or 6 months of spontaneous amenorrhea with serum FSH levels >40 mIU/m or 6 weeks post surgical bilateral oophorectomy with or without hysterectomy or have been surgically sterilized (e.g., bilateral tubal ligation, or the patient must agree to use two methods of birth control. This is any combination of a hormonal contraception (implantable, patch, oral or injection), IUD, male or female condom with spermicidal gel, diaphragm, sponge or cervical cap.
9. Is a male capable of reproduction unless the female partner meets the definition of post-menopausal (see protocol) or agrees to use 2 methods of contraception as in 8 above. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| HBV DNA non-detectability at Week 52 |
|
| 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 | Yes |
| 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) | 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.8.3 |
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.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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