Effectiveness of TAF in Reducing Clinical Events in CHB Patients Beyond Treatment Indications by Current Guidelines
- Registration Number
- NCT03753074
- Lead Sponsor
- Young-Suk Lim
- 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
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 780
Patients must meet all of the following criteria to be eligible to participate in the study
- Patient must have the ability to understand and sign a written informed consent form; consent must be obtained prior to initiation of study procedures
- Male or female, 40 to 80 years of age
- Positive for HBsAg or HBV DNA for at least 6 months or more
- HBeAg positive or negative
- No evidence of liver cirrhosis (platelet count ≥100,000/mm3)
- serum HBV DNA ≥ 4 log10 IU/mL and ≤ 8 log10 IU/mL
- Serum ALT level <70 if male, <50 if female
- Estimated creatinine clearance ≥ 30 ml/min based on serum creatinine as measured at the screening evaluation
- Patient is willing and able to comply with all study requirements
Patients who meet any of the following exclusion criteria are not to be enrolled in this study
- Co-infection with HCV, HDV, HIV (Confirmed by nucleic acid tests)
- Abusing alcohol (more than 60 g/day) or illicit drugs
- Patients with history of hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage)
4-1) Evidence of cirrhosis, including any of follows:
- Platelet count <100,000/mm3
- Esophagogastric varices on endoscopy
- Evidence of clinically significant portal hypertension
- Fibroscan ≥ 12.0 kPa (If the test was done in 3 months before the time of screening.) and confirmed to have liver cirrhosis by an investigator
4-2) 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.
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Received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study
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Medical condition that requires concurrent use of systemic corticosteroid or other immunosuppressive agents
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Received solid organ or bone marrow transplant
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Known hypersensitivity to study drugs, metabolites, or formulation excipients
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Any other clinical condition or prior therapy that, in the opinion of the Investigator, would make the patient unsuitable for the study or unable to comply with dosing requirements
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Use of investigational agents within 6 months of screening, unless allowed by the Sponsor or Investigator
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Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the Investigator
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Any malignant tumor in the preceding five years. However, a history of treated malignancy (other than HCC) is allowable if the patient's malignancy has been in complete remission, off chemotherapy and without additional surgical intervention, during the preceding three years
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Pregnant or breastfeeding or willing to be pregnant
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Participating in other clinical trials to administer medication. However, it is possible to participate if it is not an antiviral agent or immunosuppressant related clinical trial.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Treatment Arm A (TAF) Tenofovir Alafenamide 390 subjects administered Tenofovir Alafenamide 25 mg once daily
- Primary Outcome Measures
Name Time Method 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 Outcome Measures
Name Time Method 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 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
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
All cause-mortality among HBeAg-positive or HBeAg-negative At year 4, 8 and 12 All cause-mortality 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 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)
Change of FIB-4 At year 4, 8 and 12 Change of FIB-4
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 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 incidence rate of liver decompensation At year 4, 8 and 12 Cumulative incidence rate of liver decompensation
Rate of HBeAg seroclearance and seroconversion At year 4, 8 and 12 Rate of HBeAg seroclearance and seroconversion among HBeAg-positive patients
Change of APRI index At year 4, 8 and 12 Change of APRI index
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 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 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
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
Rate of ALT normalization At year 4, 8 and 12 Rate of ALT normalization if baseline ALT is elevated
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)
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 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
Trial Locations
- Locations (10)
Konkuk University Hospital
🇰🇷Seoul, Korea, Republic of
Kyungpook National University Hospital
🇰🇷Daegu, Korea, Republic of
Asan Medical Center
🇰🇷Seoul, Korea, Republic of
Seoul National University Bundang Hospital
🇰🇷Seongnam, Korea, Republic of
Chung-Ang University Hospital
🇰🇷Seoul, Korea, Republic of
Korea University Guro Hospital
🇰🇷Seoul, Korea, Republic of
Kyung-Hee University Hospital
🇰🇷Seoul, Korea, Republic of
Samsung Medical center
🇰🇷Seoul, Korea, Republic of
Seoul National University Hospital
🇰🇷Seoul, Korea, Republic of
Ulsan University Hospital
🇰🇷Ulsan, Korea, Republic of