E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Long term infection with hepatitis B virus |
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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 | 20.1 |
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 |
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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 switch study are as follows:
-To evaluate the safety and tolerability of TAF 25 mg QD at Week 24
-To measure the proportion of subjects achieving virologic response (HBV DNA < 20 IU/mL) at Week 24 |
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E.2.2 | Secondary objectives of the trial |
-To evaluate the safety and tolerability of TAF 25 mg QD at Weeks 48 and 96
-To measure the proportion of subjects achieving virologic response (HBV DNA < 20 IU/mL) at Weeks 48 and 96
-To evaluate biochemical and serological (loss of HBeAg with seroconversion to anti-HBe in HBeAg-positive subjects and loss of HBsAg with seroconversion to anti-HBs) responses at Weeks 24, 48, and 96
-To evaluate the effect of TAF 25 mg QD on renal parameters at Weeks 24, 48, and 96 in subjects with moderate or severe renal impairment and hepatically impaired subjects
-To evaluate the safety of TAF 25 mg QD as determined by percentage change from Baseline in hip and spine bone mineral density at Weeks 24, 48, and 96
-To evaluate the effect of TAF 25 mg QD on fibrosis as assessed by Fibrotest® at Weeks 24, 48, and 96
-To evaluate the effect of TAF 25 mg QD on changes in Child-Pugh-Turcotte and Model for End-stage Liver Disease scores at Weeks 24, 48, and 96 in hepatically impaired subjects |
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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 Pharmacokinetic Substudy (Optional)
A PK substudy will be performed in a subset of subjects (Part A, Cohort 2 [ESRD subjects on HD at selected study sites, target n = 10 to 15] and Part B subjects [hepatic impairment, target n = 10 to 15]). Separate consent for the PK substudy is required. The substudy will include intensive PK profiling in plasma and serial blood samples will be collected at one of the Week 4, 8, or 12 on-treatment visits (on the day prior to hemodialysis for Part A, Cohort 2 subjects [ESRD subjects on HD]). |
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E.3 | Principal inclusion criteria |
Subjects must meet all of the following inclusion criteria to be eligible to participate in the study:
All Subjects (Parts A and B):
1) Must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
2) Adult male or non-pregnant female subjects, ≥ 18 years of age 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 (e.g. HBsAg positive for ≥ 6 months)
4) Normal ECG (or if abnormal, determined by the Investigator not to be clinically significant)
5) ALT ≤ 10 × upper limit of normal (ULN) at Screening by central laboratory
6) Must be willing and able to comply with all study requirements
Part A Only (renal impairment):
1) Maintained on TDF and/or other OAV treatment(s) for CHB for at least 48 weeks and with viral suppression (HBV DNA < LLOQ) for ≥ 6 months prior to Screening
2) Moderate renal impairment (30 mL/min ≤ eGFRCG ≤ 59 mL/min), severe renal impairment (15 mL/min ≤ eGFRCG < 30 mL/min) using the Cockcroft-Gault equation, or ESRD (eGFR < 15 mL/min) maintained on HD
Part B Only (hepatic impairment):
1) Maintained on TDF and/or other OAV(s) for CHB for at least 48 weeks and with viral suppression (HBV DNA < LLOQ) for ≥ 6 months prior to Screening
2) CPT score (Appendix 7) of 7-12 (inclusive) OR a past history of CPT score ≥ 7 and any CPT score ≤ 12 at Screening
3) eGFRCG ≥ 30 mL/min using the Cockcroft-Gault equation |
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E.4 | Principal exclusion criteria |
All Subjects (Parts A & B):
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
-Subjects who are HCV positive, but have a documented negative HCV RNA, are eligible
4) Prior Interferon (IFN) use within 6 months of Screening
5) Evidence of hepatocellular carcinoma (i.e. evidenced by imaging within 6 months of Screening)
6) Received solid organ or bone marrow transplant
7) Significant cardiovascular, pulmonary, or neurological disease in the opinion of the investigator
8) Malignancy within 5 years prior to screening, with the exception of specific cancers that are cured by surgical resection (basal cell skin cancer, etc.). Subjects under evaluation for possible malignancy are not eligible
9) Currently receiving therapy with immunomodulators (e.g. corticosteroids), nephrotoxic agents, or agents capable of modifying renal excretion
10) Known hypersensitivity to study drugs, metabolites, or formulation excipients
11) Current alcohol or substance abuse judged by the investigator to potentially interfere with subject compliance
12) Any other clinical condition 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.
13) Use of investigational agents within 3 months of Screening, unless allowed by the Sponsor
14) Use of any prohibited medication
Part A Only (renal impairment):
1) Current or historical evidence of clinical hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage)
2) Abnormal hematological and biochemical parameters
3) Subjects with ESRD (i.e. eGFRCG < 15 mL/min) not on HD, or those on other forms of renal replacement therapy (i.e. peritoneal dialysis)
Part B Only (hepatic impairment):
1) Active variceal bleeding within 6 months or prior placement of a portosystemic shunt (such as transjugular intrahepatic portosystemic shunt [TIPS])
2) History of hepatorenal syndrome, hepatopulmonary syndrome, Grade 3 or Grade 4 hepatic encephalopathy, or spontaneous bacterial peritonitis within 6 months of Screening
3) Grade 2 hepatic encephalopathy at Screening
4) MELD score ≥ 30
5) Abnormal hematological and biochemical parameters |
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E.5 End points |
E.5.1 | Primary end point(s) |
-The primary safety endpoint is the incidence of graded adverse events and graded laboratory abnormalities at Week 24.
-The primary efficacy endpoint is the proportion of subjects achieving virologic response (plasma HBV DNA < 20 IU/mL) at Week 24. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
The Secondary safety endpoints are:
-Incidence of graded adverse events and graded laboratory abnormalities at Week 48 and 96
-Change from baseline in eGFRCG at Weeks 24, 48, and 96 in subjects with moderate or severe renal impairment and hepatically impaired subjects
-Percent change from baseline in hip and spine bone mineral density (BMD) at Weeks 24, 48, and 96
The Secondary efficacy endpoints are:
-Proportion of subjects achieving virologic response (plasma HBV DNA < 20 IU/mL ) at Weeks 48 and 96
-Proportion of subjects with plasma HBV DNA < 20 IU/mL and target detected/not detected (i.e. < LLOD) at Weeks 24, 48, and 96
-Proportion of subjects with serological response (loss of HBsAg and seroconversion to anti-HBs, loss of HBeAg and seroconversion to anti-HBe in HBeAg-positive subjects) at Weeks 24, 48, and 96
-Proportion of subjects with biochemical response (normal ALT and normalized ALT) at Weeks 24, 48, and 96
-Change in fibrosis as assessed by FibroTest® at Weeks 24, 48, and 96
-Change from baseline in CPT score (Appendix 7) and MELD score at Weeks 24, 48, and 96 in hepatically impaired subjects |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 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) | No |
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 | 8 |
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 |
Canada |
Hong Kong |
Korea, Republic of |
Taiwan |
United States |
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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
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The end of the study will be the last subjects’ last observation or visit. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
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 | 3 |
E.8.9.2 | In all countries concerned by the trial months | 9 |