Chronic Hepatitis b
Conditions
Brief summary
Treatment with Tenofovir Alafenamide(TAF) in Chronic Hepatitis B (CHB) patients classified as beyond treatment indication of current international guidelines (e.g. aged more than 40 years old and 4 ≤ log HBV-DNA IU/mL \< 8) is expected to bring improvement in long-term clinical outcomes. This expected result may expand the treatment indications in patients with CHB based on age and HBV-DNA in contrast to current international guidelines of CHB.
Detailed description
Study objectives: To investigate whether TAF treatment reduce clinical events (HCC, death, liver decompensation, portal hypertensive complications, and liver transplantation) in CHB patients beyond treatment indications by current guidelines Study procedure: 780 subjects will be randomized in a 1:1 ratio (A:B) either to receive TAF 25 mg QD or to receive best supportive care after stratification according to the HBeAg status. The study duration is 12 years. During treatment period, among treatment arm B, subjects who are indicated for antiviral treatment will be treated with TAF as follows: 1. Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female) 2. 40≤ALT levels\<70 IU/L (males) or 40≤ ALT levels\<50 IU/L (females) with evidence of significant fibrosis(F2; ≥7.2 kPa) as measured by either liver biopsy, Fibroscan or MR elastograpy performed within 3 months. 3. If they were clinically judged to have cirrhosis by investigators and confirmed with Fibroscan (≥ 12.0 kPa). * Treatment Arm A: 390 subjects administered TAF 25 mg once daily * Treatment Arm B: 390 subjects received best supportive care The primary analysis will occur at Year 4 with the primary endpoint being occurrence of composite events during follow-up observation
Interventions
DRUGTenofovir Alafenamide
Tenofovir Alafenamide 25mg, Tablet, Oral, Daily
Sponsors
Samsung Medical Center
Kyunghee University Medical Center
Chung-Ang University Hosptial, Chung-Ang University College of Medicine
Seoul National University Hospital
Ulsan University Hospital
Konkuk University Medical Center
Kyungpook National University Hospital
Korea University Guro Hospital
Seoul St. Mary's Hospital
Kaohsiung Medical University
Chang Gung Memorial Hospital
E-DA Hospital
Taitung Mackay Memorial Hospital
National Cheng-Kung University Hospital
Chi Mei Medical Hospital
Chiayi Christian Hospital
St. Martin De Porress Hospital
Dalin Tzu Chi General Hospital
Taichung Veterans General Hospital
China Medical University Hospital
Seoul National University Bundang Hospital
Young-Suk Lim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
40 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Patients must meet all of the following criteria to be eligible to participate in the study 1. Patient must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures 2. Male or female, 40 to 80 years of age 3. Positive for HBsAg or HBV DNA for at least 6 months or more 4. HBeAg positive or negative 5. No evidence of liver cirrhosis (platelet count ≥100,000/mm3) 6. serum HBV DNA ≥ 4 log10 IU/mL and ≤ 8 log10 IU/mL 7. Serum ALT level \<70 if male, \<50 if female 8. Estimated creatinine clearance ≥ 30 ml/min based on serum creatinine as measured at the screening evaluation 9. Patient is willing and able to comply with all study requirements
Exclusion criteria
Patients who meet any of the following
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| the occurrence of composite events during follow-up observation | At year 4 | the occurrence of composite events during follow-up observation(including death, liver transplantation, or decompensated liver diseases \[Child-Pugh score≥7\], complications of portal hypertension \[ascites, gastroesophageal varices\] or HCC |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of ALT normalization | At year 4, 8 and 12 | Rate of ALT normalization if baseline ALT is elevated |
| Rate of HBeAg seroclearance and seroconversion | At year 4, 8 and 12 | Rate of HBeAg seroclearance and seroconversion among HBeAg-positive patients |
| Cumulative rate of patients with clinical events | At year 4, 8 and 12 | Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) |
| Cumulative incidence rate of HCC | At year 4, 8 and 12 | Cumulative incidence rate of HCC |
| All-cause mortality | At year 4, 8 and 12 | All-cause mortality |
| Cumulative incidence rate of liver transplantation | At year 4, 8 and 12 | Cumulative incidence rate of liver transplantation |
| Cumulative incidence rate of liver decompensation | At year 4, 8 and 12 | Cumulative incidence rate of liver decompensation |
| Cumulative incidence rate of portal hypertensive complications | At year 4, 8 and 12 | Cumulative incidence rate of portal hypertensive complications |
| Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B subjects | At year 4, 8 and 12 | Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B subjects |
| Change of fibroscan | At year 4, 8 and 12 | Change of fibroscan |
| Change of APRI index | At year 4, 8 and 12 | Change of APRI index |
| Change of FIB-4 | At year 4, 8 and 12 | Change of FIB-4 |
| Cumulative incidence rate of HCC among HBeAg-positive or HBeAg-negative Patients | At year 4, 8 and 12 | Cumulative incidence rate of HCC among HBeAg-positive or HBeAg-negative Patients |
| Virologic response defined as HBV DNA less than 15 IU/mL | At year 4, 8 and 12 | Virologic response defined as HBV DNA less than 15 IU/mL |
| Cumulative incidence rate of liver transplantation among HBeAg-positive or HBeAg-negative | At year 4, 8 and 12 | Cumulative incidence rate of liver transplantation among HBeAg-positive or HBeAg-negative |
| Cumulative incidence rate of liver decompensation among HBeAg-positive or HBeAg-negative | At year 4, 8 and 12 | Cumulative incidence rate of liver decompensation among HBeAg-positive or HBeAg-negative |
| Cumulative incidence rate of portal hypertensive complications among HBeAg-positive or HBeAg-negative | At year 4, 8 and 12 | Cumulative incidence rate of portal hypertensive complications amongHBeAg-positive or HBeAg-negative |
| Cumulative incidence rate of HCC among subjects according to baseline ALT level (normal ALT and elevated ALT) | At year 4, 8 and 12 | Cumulative incidence rate of HCC amongsubjects according to baseline ALT level (normal ALT and elevated ALT) |
| All cause-mortality among subjects according to baseline ALT level (normal ALT and elevated ALT) | At year 4, 8 and 12 | All cause-mortality among subjects according to baseline ALT level (normal ALT and elevated ALT) |
| Cumulative incidence rate of liver transplantation among subjects according to baseline ALT level (normal ALT and elevated ALT) | At year 4, 8 and 12 | Cumulative incidence rate of liver transplantation among subjects according to baseline ALT level (normal ALT and elevated ALT) |
| Cumulative incidence rate of liver decompensation among subjects according to baseline ALT level (normal ALT and elevated ALT) | At year 4, 8 and 12 | Cumulative incidence rate of liver decompensation among subjects according to baseline ALT level (normal ALT and elevated ALT) |
| Cumulative incidence rate of portal hypertensive complications among subjects according to baseline ALT level (normal ALT and elevated ALT) | At year 4, 8 and 12 | Cumulative incidence rate of portal hypertensive complications among subjects according to baseline ALT level (normal ALT and elevated ALT) |
| Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 6 months of enrollment | At year 4, 8 and 12 | Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 6 months of enrollment |
| Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 12 months of enrollment | At year 4, 8 and 12 | Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) after excluding patients who occurrs clinical events within 12 months of enrollment |
| Cumulative and annual rate of patients with clinical events in patients with normal ALT (<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical | At year 4, 8 and 12 | Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (\<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical events within 6 months of enrollment |
| Cumulative and annual rate of patients with clinical events in patients with normal ALT (<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical events within 12 months of enrollment | At year 4, 8 and 12 | Cumulative and annual rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) in patients with normal ALT (\<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical events within 12 months of enrollment |
| All cause-mortality among HBeAg-positive or HBeAg-negative | At year 4, 8 and 12 | All cause-mortality among HBeAg-positive or HBeAg-negative |
Countries
South Korea
Outcome results
None listed