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

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

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.

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

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 exclusion criteria are not to be enrolled in this study

1. Co-infection with HCV, HDV, HIV (Confirmed by nucleic acid tests)
2. Abusing alcohol (more than 60 g/day) or illicit drugs
3. Patients with history of hepatic decompensation (e.g., ascites, encephalopathy or variceal hemorrhage)

4-1) Evidence of cirrhosis, including any of follows:

1. Platelet count <100,000/mm3
2. Esophagogastric varices on endoscopy
3. Evidence of clinically significant portal hypertension
4. 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.