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

Chronic Hepatitis b Clinical Trial

— ATTENTION  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03753074
• Other study ID #: IN-KR-320-5358
• Status: Recruiting
• Phase: Phase 4
• Start date: February 18, 2019
• Est. completion date: December 31, 2031

Study information

• Verified date: November 2023
• Source: Asan Medical Center
• Contact: Young-Suk Lim, M.D, Ph D
• Phone: +82-2-3010-5933
• Email: limys[@]amc.seoul.kr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Recruiting
• Enrollment: 780
• Est. completion date: December 31, 2031
• Est. primary completion date: December 31, 2031
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years to 80 Years

Eligibility

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.

Related Conditions & MeSH terms

• Chronic Hepatitis b
• Hepatitis
• Hepatitis B
• Hepatitis B, Chronic
• Hepatitis, Chronic

Intervention

Drug:
• Tenofovir Alafenamide
Tenofovir Alafenamide 25mg, Tablet, Oral, Daily

Locations

Country	Name	City	State
Korea, Republic of	Kyungpook National University Hospital	Daegu
Korea, Republic of	Asan Medical Center	Seoul
Korea, Republic of	Chung-Ang University Hospital	Seoul
Korea, Republic of	Konkuk 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	The Catholic University of Korea, Seoul ST. Mary's Hospital	Seoul
Korea, Republic of	Ulsan University Hospital	Ulsan

Sponsors (21)

Lead Sponsor

Collaborator

Young-Suk Lim

Chang Gung Memorial Hospital, Chi Mei Medical Hospital, Chiayi Christian Hospital, China Medical University Hospital, Chung-Ang University Hosptial, Chung-Ang University College of Medicine, Dalin Tzu Chi General Hospital, E-DA Hospital, Kaohsiung Medical University, Konkuk University Medical Center, Korea University Guro Hospital, Kyunghee University Medical Center, Kyungpook National University Hospital, National Cheng-Kung University Hospital, Samsung Medical Center, Seoul National University Hospital, Seoul St. Mary's Hospital, St. Martin De Porress Hospital, Taichung Veterans General Hospital, Taitung Mackay Memorial Hospital, Ulsan University Hospital

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (13)

Andreani T, Serfaty L, Mohand D, Dernaika S, Wendum D, Chazouilleres O, Poupon R. Chronic hepatitis B virus carriers in the immunotolerant phase of infection: histologic findings and outcome. Clin Gastroenterol Hepatol. 2007 May;5(5):636-41. doi: 10.1016/j.cgh.2007.01.005. Epub 2007 Apr 11. — View Citation

Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH; REVEAL-HBV Study Group. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006 Jan 4;295(1):65-73. doi: 10.1001/jama.295.1.65. — View Citation

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18. — View Citation

Hui CK, Leung N, Yuen ST, Zhang HY, Leung KW, Lu L, Cheung SK, Wong WM, Lau GK; Hong Kong Liver Fibrosis Study Group. Natural history and disease progression in Chinese chronic hepatitis B patients in immune-tolerant phase. Hepatology. 2007 Aug;46(2):395-401. doi: 10.1002/hep.21724. — View Citation

Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ; Risk Evaluation of Viral Load Elevation and Associated Liver Disease/Cancer-In HBV (the REVEAL-HBV) Study Group. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006 Mar;130(3):678-86. doi: 10.1053/j.gastro.2005.11.016. — View Citation

Kennedy PTF, Sandalova E, Jo J, Gill U, Ushiro-Lumb I, Tan AT, Naik S, Foster GR, Bertoletti A. Preserved T-cell function in children and young adults with immune-tolerant chronic hepatitis B. Gastroenterology. 2012 Sep;143(3):637-645. doi: 10.1053/j.gastro.2012.06.009. Epub 2012 Jun 15. — View Citation

Kim GA, Lim YS, Han S, Choi J, Shim JH, Kim KM, Lee HC, Lee YS. High risk of hepatocellular carcinoma and death in patients with immune-tolerant-phase chronic hepatitis B. Gut. 2018 May;67(5):945-952. doi: 10.1136/gutjnl-2017-314904. Epub 2017 Oct 21. — View Citation

Kumar M, Sarin SK, Hissar S, Pande C, Sakhuja P, Sharma BC, Chauhan R, Bose S. Virologic and histologic features of chronic hepatitis B virus-infected asymptomatic patients with persistently normal ALT. Gastroenterology. 2008 May;134(5):1376-84. doi: 10.1053/j.gastro.2008.02.075. Epub 2008 Feb 29. — View Citation

Lai M, Hyatt BJ, Nasser I, Curry M, Afdhal NH. The clinical significance of persistently normal ALT in chronic hepatitis B infection. J Hepatol. 2007 Dec;47(6):760-7. doi: 10.1016/j.jhep.2007.07.022. Epub 2007 Sep 24. — View Citation

Lin ZH, Xin YN, Dong QJ, Wang Q, Jiang XJ, Zhan SH, Sun Y, Xuan SY. Performance of the aspartate aminotransferase-to-platelet ratio index for the staging of hepatitis C-related fibrosis: an updated meta-analysis. Hepatology. 2011 Mar;53(3):726-36. doi: 10.1002/hep.24105. Epub 2011 Feb 11. — View Citation

Sterling RK, Lissen E, Clumeck N, Sola R, Correa MC, Montaner J, S Sulkowski M, Torriani FJ, Dieterich DT, Thomas DL, Messinger D, Nelson M; APRICOT Clinical Investigators. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006 Jun;43(6):1317-25. doi: 10.1002/hep.21178. — View Citation

Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. No abstract available. — View Citation

Tseng TC, Kao JH. Treating Immune-tolerant Hepatitis B. J Viral Hepat. 2015 Feb;22(2):77-84. doi: 10.1111/jvh.12370. Epub 2014 Nov 25. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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
Secondary	Cumulative incidence rate of HCC	Cumulative incidence rate of HCC	At year 4, 8 and 12
Secondary	All-cause mortality	All-cause mortality	At year 4, 8 and 12
Secondary	Cumulative incidence rate of liver transplantation	Cumulative incidence rate of liver transplantation	At year 4, 8 and 12
Secondary	Cumulative incidence rate of liver decompensation	Cumulative incidence rate of liver decompensation	At year 4, 8 and 12
Secondary	Cumulative incidence rate of portal hypertensive complications	Cumulative incidence rate of portal hypertensive complications	At year 4, 8 and 12
Secondary	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
Secondary	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
Secondary	Rate of ALT normalization	Rate of ALT normalization if baseline ALT is elevated	At year 4, 8 and 12
Secondary	Rate of HBeAg seroclearance and seroconversion	Rate of HBeAg seroclearance and seroconversion among HBeAg-positive patients	At year 4, 8 and 12
Secondary	Change of fibroscan	Change of fibroscan	At year 4, 8 and 12
Secondary	Change of APRI index	Change of APRI index	At year 4, 8 and 12
Secondary	Change of FIB-4	Change of FIB-4	At year 4, 8 and 12
Secondary	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
Secondary	All cause-mortality among HBeAg-positive or HBeAg-negative	All cause-mortality among HBeAg-positive or HBeAg-negative	At year 4, 8 and 12
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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