Effectiveness of TAF in Reducing Clinical Events in CHB Patients Beyond Treatment Indications by Current Guidelines

Study Overview
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Brief Summary
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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
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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: Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female) 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. 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

Official Title
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A Multinational, Multicenter, Open-label, Randomized Controlled Trial to Investigate the Effectiveness of Tenofovir Alafenamide in Reducing Clinical Events in Chronic Hepatitis B Patients Beyond Treatment Indications by Current Guidelines

Conditions
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Chronic Hepatitis b

Intervention / Treatment
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* Drug: Tenofovir Alafenamide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 Exclusion Criteria: 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. 5. Received interferon or other immunomodulatory treatment for HBV infection in the 12 months before screening for this study 6. Medical condition that requires concurrent use of systemic corticosteroid or other immunosuppressive agents 7. Received solid organ or bone marrow transplant 8. Known hypersensitivity to study drugs, metabolites, or formulation excipients 9. 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 10. Use of investigational agents within 6 months of screening, unless allowed by the Sponsor or Investigator 11. Significant renal, cardiovascular, pulmonary, or neurological disease in the opinion of the Investigator 12. 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 13. Pregnant or breastfeeding or willing to be pregnant 14. 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Arm A (TAF)<br>390 subjects administered Tenofovir Alafenamide 25 mg once daily | Drug: Tenofovir Alafenamide<br>* Tenofovir Alafenamide 25mg, Tablet, Oral, Daily<br>* Other names: Vemlidy;|
| No Intervention: Treatment Arm B (Best supportive care)<br>390 subjects received best supportive care During treatment period, among treatment arm B, subjects who are indicated for antiviral treatment will be treated with TAF as follows: Based on the AASLD 2018 Guidelines of CHB (ALT 70≥ for male, 50≥ for female) 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. If they were clinically judged to have cirrhosis by investigators and confirmed with Fibroscan (≥ 12.0 kPa). | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the occurrence of composite events during follow-up observation | 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 | At year 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative rate of patients with clinical events | Cumulative rate of patients with clinical events (death, liver transplantation, liver decompensation, portal hypertensive complications, and HCC) | At year 4, 8 and 12 | 
| Cumulative incidence rate of HCC | Cumulative incidence rate of HCC | At year 4, 8 and 12 | 
| All-cause mortality | All-cause mortality | At year 4, 8 and 12 | 
| Cumulative incidence rate of liver transplantation | Cumulative incidence rate of liver transplantation | At year 4, 8 and 12 | 
| Cumulative incidence rate of liver decompensation | Cumulative incidence rate of liver decompensation | At year 4, 8 and 12 | 
| Cumulative incidence rate of portal hypertensive complications | Cumulative incidence rate of portal hypertensive complications | At year 4, 8 and 12 | 
| Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B subjects | Rate of receiving nucleos(t)ide analogue by meeting reimbursement criteria of treatment among Treatment ARM B subjects | At year 4, 8 and 12 | 
| Virologic response defined as HBV DNA less than 15 IU/mL | Virologic response defined as HBV DNA less than 15 IU/mL | At year 4, 8 and 12 | 
| Rate of ALT normalization | Rate of ALT normalization if baseline ALT is elevated | At year 4, 8 and 12 | 
| Rate of HBeAg seroclearance and seroconversion | Rate of HBeAg seroclearance and seroconversion among HBeAg-positive patients | At year 4, 8 and 12 | 
| Change of fibroscan | Change of fibroscan | At year 4, 8 and 12 | 
| Change of APRI index | Change of APRI index | At year 4, 8 and 12 | 
| Change of FIB-4 | Change of FIB-4 | At year 4, 8 and 12 | 
| Cumulative incidence rate of HCC among HBeAg-positive or HBeAg-negative Patients | Cumulative incidence rate of HCC among HBeAg-positive or HBeAg-negative Patients | At year 4, 8 and 12 | 
| All cause-mortality among HBeAg-positive or HBeAg-negative | All cause-mortality 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 transplantation 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 liver decompensation among HBeAg-positive or HBeAg-negative | At year 4, 8 and 12 | 
| Cumulative incidence rate of portal hypertensive complications among HBeAg-positive or HBeAg-negative | Cumulative incidence rate of portal hypertensive complications amongHBeAg-positive or HBeAg-negative | At year 4, 8 and 12 | 
| Cumulative incidence rate of HCC among subjects according to baseline ALT level (normal ALT and elevated ALT) | Cumulative incidence rate of HCC amongsubjects 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) | All cause-mortality 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 transplantation 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 liver decompensation 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 portal hypertensive complications among subjects according to baseline ALT level (normal ALT and elevated ALT) | 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 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 12 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 in patients with normal ALT (<40 U/L) at the time of enrollment, after excluding patients who occurrs clinical | 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 | At year 4, 8 and 12 | 
| 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 | 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 | At year 4, 8 and 12 |