| 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 assess the safety of longer-term treatment with telbivudine (LdT), for two years (104 weeks), in patients who have received approximately 1-3 years of previous anti-HBV treatment with telbivudine or a comparator antiviral drug in the global telbivudine clinical development program | |
| E.2.2 | Secondary objectives of the trial | To longitudinally assess the longer-term antiviral efficacy achieved with telbivudine treatment
To longitudinally assess the clinical efficacy of longer-term treatment with telbivudine
To longitudinally assess the durability of HBeAg responses achieved with telbivudine treatment and other previous treatments in patients’ qualifying clinical trials or in the present study
To determine the longitudinal frequency of virologic breakthrough and characterize the associated mutations in the HBV polymerase gene in HBV DNA amplified from sera of patients with virologic breakthrough | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | The study population will comprise patients with chronic hepatitis B who have successfully completed a previous Idenix-sponsored study, as follows. Patients must meet all of the following inclusion criteria:
1. Patient completed a previous qualifying Idenix-sponsored Phase IIb, III, or IIIb trial in the telbivudine clinical development program, and will be available to immediately rollover into this study with no discontinuation of study drug.
For patients who have achieved efficacy responses in their previous trial and are eligible to enter Group C in this study, rollover into the present study should be immediate whenever possible and in any case must be within 30 days of completion of the previous trial. The previous qualifying trials include the following:
Phase IIB trial
1. NV-02B-010
Phase IIb extension trial Phase III-IIIb trials
1. NV-02B-007 trial, for patients with compensated chronic hepatitis B
2. NV-02B-011 trial, for patients with decompensated HBV cirrhosis
3. NV-02B-015 trial, supplemental Phase III trial in China
4. NV-02B-018 trial, telbivudine vs. adefovir
5. NV-02B-019 trial, “switch” trial for lamivudine-treated patients
(Other qualifying trials may be added by amendment, as the telbivudine global clinical development program advances).
2. Patient was not discontinued from the previous Idenix-sponsored study due to a serious adverse event (SAE), other adverse event, laboratory abnormality, disease progression, virologic breakthrough, or treatment failure.
3. Patients in Groups A and B must be HBsAg-positive.
4. Patient is willing and able to comply with the study drug regimen and all other study requirements.
5. The patient is willing and able to provide written informed consent to participate in the study | |
| E.4 | Principal exclusion criteria | Patients will be excluded from the study for any of the following reasons:
1. Patient is pregnant or breastfeeding. Women of childbearing potential must have a negative urine test at Baseline.
2. Patient is of reproductive potential (men and women) and unwilling to use double barrier method of contraception. It is required that double barrier method of contraception be used (i.e. condom with spermicide or diaphragm with spermicide) by patients of reproductive potential (men and women) regardless of whether a hormonal agent also is used as a method of contraception.
3. Patient is coinfected with hepatitis C virus (HCV), hepatitis D virus (HDV), or HIV. Patients will be tested for antibodies to HCV, HIV, and HDV in the Baseline assessments performed at the central laboratory. If the patient is found to be coinfected with HDV, HCV or HIV they will be discontinued from the study at or before the next scheduled study visit.
4. Patient has evidence of renal insufficiency defined as patient requiring dialysis or having an estimated creatinine clearance below 50 mL/min, as estimated by the Cockcroft-Gault formula: • Calculation for Males: CrCl (mL/min) = [(140-age in yr)×(wt. in kg)]/[(serum creatinine in g/dL)×(72)] • Calculation for Females: CrCl (mL/min) = 0.85 x [(140-age in yr)×(wt. in kg)]/[(serum creatinine in mg/dL)×(72)]
5. Since entry into the qualifying prior study, patient has developed a concurrent medical or psychosocial condition that will confound the efficacy or safety assessments in the current study, or may preclude the patient’s compliance with the visit schedule or study drug regimen in the present study. Examples of such intercurrent conditions include, but are not limited to: unstable cardiovascular or pulmonary disease; active malignancy requiring intensive surgical or medical management; unstable diabetes or other poorly controlled endocrine disease; poorly controlled seizure disorder, neuropsychiatric disorder associated with severe depression, suicidal ideation, or psychosis; or change in social or geographic circumstances that would likely interfere with compliance with the protocol requirements.
6. Patient is currently abusing alcohol or illicit drugs. For the purposes of the present study, alcohol abuse is defined as frequent consumption of alcoholic beverages with an average daily intake of more than 40g of ethanol or any lesser amount that would, in the investigator’s opinion, interfere with the study evaluations.
7. Patient is enrolled or plans to enroll in another clinical trial of an investigational agent while participating in this study.
8. All other treatments for hepatitis B, including commercially available treatments indicated for conditions other than chronic hepatitis B that are being investigated to treat or may have activity against HBV (e.g., ribavirin, famciclovir, ganciclovir, etc).
9. Prolonged use of systemic acyclovir or famciclovir defined as episodic treatment with these agents for periods exceeding 10 days every 3 months, or chronic suppressive therapy.
10. Systemic immunomodulators of any type.
11. Systemic corticosteroids (topical and inhaled corticosteroids are permitted).
12. Herbal medications known to cause hepatotoxicity ( e.g., St. John’s Wart, Kava, Jin Bu Huan, Yuzhitang, germander, chaparral, shark cartilage, mistletoe, slim 10, Lipokinetix, etc.).
13. Patient has any of the following laboratory values: • Hemoglobin < 9 g/dL for men or < 8 g/dL for women • Total WBC < 1,500/ mm 3 • Absolute neutrophil count (ANC) < 1,000/mm 3 • Platelet count < 30,000/mm 3 • Serum albumin < 2.5 g/dL • Total bilirubin ≥4 x ULN • Serum creatinine > 1.5 x ULN | |
| E.5 End points |
| E.5.1 | Primary end point(s) | Primary Efficacy Endpoint for Patients with Compensated Chronic Hepatitis B.
The three patient Groups in this study have different natural histories. Therefore the assessments of treatment efficacy and safety in this study will be conducted by Group.
For the data analyses within each Group, patients will be sub-grouped by treatment type (i.e., previous study drug identity), by duration of previous treatment (in weeks), and by entry HBeAg status in the previous qualifying trial. Group A comprises patients (HBeAg-positive or HBeAg-negative) with compensated liver disease; it is expected that the vast majority of patients in Group C will also be patients with compensated liver disease. Therefore the primary endpoint for Groups A and C will be Maintained Therapeutic Response, here defined as serum HBV DNA < 5 log10 copies/ml by the COBAS Amplicor PCR, and either HBeAg loss or normal serum ALT level on at least two consecutive study visits, with this composite efficacy response subsequently maintained to the patient’s last treatment visit with no two consecutive disqualifying values and with a qualifying value at last treatment visit.
Primary Efficacy Endpoint for Patients with Decompensated Chronic Hepatitis B Group B comprises patients with decompensated HBV cirrhosis, who previously completed the NV-02B-011 Phase III trial.
For this patient Group, the primary efficacy endpoint will be Maintained Clinical Response, here defined as achievement of the following three efficacy criteria: serum HBV DNA < 4 log10 copies/mL and normal serum ALT level and improvement or stabilization in Childs-Turcotte-Pugh (CTP) score, on at least two consecutive study visits and maintained to last treatment visit with no two intervening consecutive disqualifying values; the value at last treatment visit must also be a qualifying value.
“Improvement” is defined as a 2-point or greater reduction in CTP score, and “stabilization” is defined as a less than 2-point change in CTP score, compared to the patient’s Baseline value | |
| 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 | Information not present in EudraCT |
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| 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) | Information not present in EudraCT |
| 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 | 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.8.6 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 | 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 | 5 |
