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 hepatitis 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 | 20.0 |
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 objectives of this study are as follows:
To compare the efficacy of tenofovir alafenamide (TAF) 25 mg QD versus tenofovir disoproxil fumarate (TDF) 300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at Week 48 in treatment naïve and treatment experienced subjects. The primary efficacy parameter is the proportion of subjects with plasma HBV DNA levels below 29 IU/mL.
To compare the safety and tolerability of TAF 25 mg QD versus TDF 300 mg QD for the treatment of HBeAg-negative, chronic hepatitis B at Week 48 in treatment naïve and treatment experienced subjects |
|
E.2.2 | Secondary objectives of the trial |
Key secondary objectives:
To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the percent change from baseline in hip and spine BMD at Week 48
To compare the safety of TAF 25 mg QD versus TDF 300 mg QD as determined by the change from baseline in serum creatinine at Week 48 |
|
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 |
Intensive PK Substudy (Optional)
For subjects who provide a separate informed consent (n=16 and upto n=32), an intensive pharmacokinetic substudy will be performed once at either of the Week 4, 8 or 12 visits, at select sites to assess intensive PK profiling in plasma.
Subjects participating in the PK substudy (at sites which can process PBMCs) will also be asked to provide a PBMC (pre-dose) sample at the intensive PK substudy visit. This will be used to evaluate PBMC concentrations of tenofovir diphosphate (TFV-DP), the active form of tenofovir (TFV).
Opthalmologic Substudy (Optional)
For subjects who provide a separate informed consent (n = 30), a substudy will be conducted to assess ophthalmologic findings, including fundoscopic examination with retinal photographs (both eyes), anytime during the screening period, but must be completed prior to the first dose of study drug, and at Weeks 24, 48, 72, 96, 144, 192 and 240/ED visits at select sites.
An examination of the full retinal field should be conducted noting changes or abnormalities. Photographs of the retina must be taken at each exam and filed in the subject’s source medical records. A central vendor will be used to assess the retinal photographs. |
|
E.3 | Principal inclusion criteria |
1) Must have the ability to understand and sign a written informed consent form
2) Male and non-pregnant, non-lactating female subjects, 18 years of age and older, based on the date of the screening visit. A negative serum pregnancy test at Screening is required for female subjects of childbearing potential.
3) Documented evidence of chronic HBV infection
4) HBeAg-negative, chronic hepatitis B
5) Treatment naïve subjects or treatment experienced subjects will be eligible for enrollment. Treatment experienced subjects receiving oral antiviral treatment at Screening must continue their treatment regimen until the time of randomization, when it will be discontinued.
6) Any previous treatment with interferon (pegylated or non-pegylated) must have ended at least 6 months prior to the baseline visit.
7) Estimated creatinine clearance (CLCr) >= 50 mL/min (using the Cockcroft-Gault method) based on serum creatinine and actual body weight as measured at the Screening evaluation.
8) Normal ECG.
9) Willing and able to comply with all study requirements. |
|
E.4 | Principal exclusion criteria |
1) Pregnant women, women who are breastfeeding or who believe they may wish to become pregnant during the course of the study.
2) Males and females of reproductive potential who are unwilling to use an “effective”, protocol-specified method(s) of contraception during the study.
3) Co-infection with HCV, HIV, or HDV.
4) Evidence of hepatocellular carcinoma.
5) Any history of, or current evidence of, clinical hepatic decompensation.
6) Abnormal hematological and biochemical parameters.
7) Received solid organ or bone marrow transplant
8) Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the investigator
9) Significant bone disease (eg, osteomalacia, chronic osteomyelitis, osteogenesis imperfecta, osteochrondroses), or multiple bone fractures. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy endpoint is the proportion of subjects with plasma HBV DNA < 29 IU/mL at Week 48. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
The secondary endpoints are:
• The percent change from baseline at Week 48 in spine and hip BMD
• The change from baseline at Week 48 in creatinine clearance (measured by Cockcroft-Gault method) |
|
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 | Yes |
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 | 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 | 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.8.2.4 | 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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 55 |
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 |
Argentina |
Australia |
Brazil |
Bulgaria |
Canada |
China |
France |
Hong Kong |
Indonesia |
Italy |
Japan |
Korea, Republic of |
New Zealand |
Nigeria |
Pakistan |
Poland |
Romania |
Singapore |
Spain |
Taiwan |
Turkey |
United Kingdom |
|
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 | 9 |
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 | 9 |
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 |