E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
E.1.1.1 | Medical condition in easily understood language |
Long term infection with the hepatits B virus |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008910 |
E.1.2 | Term | Chronic hepatitis B |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
|
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 evaluate the efficacy of tenofovir disoproxil fumarate (TDF) plus peginterferon α-2a (PEG) combination therapy for 48 weeks versus standard of care TDF monotherapy or PEG monotherapy for 48 weeks in non-cirrhotic CHB subjects as determined by loss of HBsAg. |
|
E.2.2 | Secondary objectives of the trial |
Efficacy of TDF (48 weeks) plus PEG (16 weeks) combination therapy versus standard of care TDF monotherapy or PEG monotherapy for 48 weeks in non-cirrhotic CHB subjects as determined by loss of HBsAg.
virological response (HBV DNA < 117 IU/mL).
Serological responses (HBeAg loss and seroconversion, and HBsAg seroconversion).
Biochemical response (ALT < 30 for males and <19 for
females (based on AASLD 2008 guidelines); ALT <42 for
males and <32 for females (based on central lab ULN for ALT) |
|
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 |
At selected sites, subjects who consent to participate in a liver biopsy substudy will undergo biopsy at Baseline and week 96 (+/- 2 weeks). Liver biopsies will be evaluated for clinical/histological, and, if appropriate and possible, for molecular correlates of treatment outcome. |
|
E.3 | Principal inclusion criteria |
Adult subjects (aged 18-75) with CHB (e.g., positive for either serum HBsAg or HBV DNA for at least 6 months) prior to baseline.
Anti-HBV treatment naïve subjects and subjects who have taken oral anti-HBV nucleoside therapy with the last dose greater than or equal to 24 weeks prior to screening are also eligible).
HBV DNA ≥ 20,000 IU/ml for HBeAg+ subjects and HBV
DNA ≥ 2,000 IU/ml for HBeAg- subjects.
ALT > 54 U/L and ≤ 400 U/L for men and > 36 U/L and
≤ 300 U/L for women.
Creatinine clearance rate ≥ 80 mL/min.
A negative serum pregnancy test is required for female subjects of childbearing potential.
All sexually active female subjects of childbearing potential must agree to use a protocol-recommended method of contraception during heterosexual intercourse throughout the study and for 30 days following the last dose of study medication.
Lactating female subjects must agree to discontinue nursing before initiation of study investigational medicinal product. |
|
E.4 | Principal exclusion criteria |
Evidence of bridging fibrosis or cirrhosis at screening as confirmed by liver biopsy within 12 months prior to first visit. In countries where Fibroscan is approved for clinical
use, Fibroscan (< 8 kPa) may be used to verify absence of bridging fibrosis and cirrhosis. Patients with Fibroscan data of > 8 kPa will be excluded, unless biopsy within the 12 months prior to first visit confirms the absence of bridging fibrosis and cirrhosis.
Decompensated liver disease defined as direct (conjugated) bilirubin > 1.2 × ULN, PT > 1.2 × ULN, serum albumin < 3.5 g/dL, or prior history of clinical hepatic decompensation (e.g., ascites, jaundice, encephalopathy, variceal hemorrhage). Isolated
increase in direct bilirubin >6.1 μmol/L but < 10.2 μmol/L, in the presence of platelet count >100,000/mm3 and normal INR, may qualify for the trial.
Absolute neutrophil count < 1,500/mm3, platelet < 100,000/mm3, hemoglobin < 10 g/dL for female subjects or < 11 g/dL for male subjects Evidence of hepatocellular carcinoma.
Evidence of hepatocellular carcinoma.
History of severe depression or known severe psychiatric disease.
History of significant renal disease (e.g., nephrotic syndrome, renal dysgenesis, polycystic kidney disease, congenital nephrosis, acute tubular necrosis, other renal
disease).
Thyroid dysfunction.
History of autoimmune disease (e.g., lupus, rheumatoid arthritis, autoimmune thyroiditis).
Significant bone disease (e.g., osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochrondroses, history of multiple bone fractures).
Pregnant.
Previous treatment with any form of interferons and anti-HBV nucleotides.
Co-infection with HIV, HCV or HDV.
Ongoing therapy with any of the following:
• Nephrotoxic agents
— Parenteral aminoglycoside antibiotics (e.g., gentamicin, tobramycin,amikacin).
— Cidofovir
— Cisplatin
— Foscarnet
— IV amphotericin B
— IV pentamidine
— Oral or IV ganciclovir
— Cyclosporine
— Tacrolimus
— IV vancomycin
— Chronic daily non-steroidal anti-inflammatory drug therapy
• Hepatotoxic agents such as anabolic steroids, isoniazid, itraconazole, ketoconazole, rifabutin, rifampin and other agents with significant hepatotoxic potential
• Competitors of renal excretion (e.g., probenecid)
• Systemic chemotherapeutic agents
• Systemic corticosteroids
• Interleukin-2 (IL-2) and other immunomodulating agents
• Investigational agents (except with the expressed approval of the Sponsor)
Administration of any of the above mentioned medications must be discontinued at least 30 days prior to the Baseline Visit and for the duration of the study period.
Known hypersensitivity to the study investigational medicinal product, metabolites, or formulation excipients.
Any other condition (including alcohol or substance abuse) or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for the study or unable to comply with dosing requirements
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
The proportion of subjects with HBsAg loss at Week 72 following treatment with 48 weeks of TDF plus PEG combination versus PEG alone for 48 weeks or TDF alone. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
The proportion of subjects with HBsAg loss at Week 72 following treatment with TDF (48 weeks) plus PEG (16 weeks) combination versus PEG alone for 48 weeks or TDF alone
The proportion of subjects who experience HBsAg loss at Week 96 and Week 120
The proportion of subjects with virological response (HBV DNA level < 117 IU/mL) at Weeks 72, 96 and 120
The proportion of subjects with serological response (HBeAg loss and seroconversion, and HBsAg seroconversion) at Weeks 72, 96 and 120
The proportion of subjects who experience biochemical response (ALT < 30 for males and < 19 for females (based on AASLD 2008 guidelines); ALT < 42 for males and < 32 for females (based on central lab ULN for ALT) at Weeks 72, 96, and 120
The proportion of subjects who require re-initiation or change of therapy while on therapy or post-treatment |
|
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 | Yes |
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) | 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 | 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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
|
E.8.2.4 | Number of treatment arms in the trial | 4 |
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 | 61 |
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 | No |
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 |
Australia |
Canada |
France |
Germany |
Greece |
Hong Kong |
Italy |
Korea, Republic of |
Netherlands |
Poland |
Portugal |
Romania |
Singapore |
Spain |
Taiwan |
Turkey |
United Kingdom |
United States |
|
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
|
Last patient last visit at Week 120 |
|
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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |