Regression of Liver Fibrosis by Tenofovir Alafenamide (TAF)

Regression of Liver Fibrosis by Tenofovir Alafenamide (TAF) in Treatment-Naive CHB Related Fibrosis/Cirrhosis: a 96w Open-label Multicenter Study

Tenofovir alafenamide (TAF) is a new prodrug of tenofovir developed to treat patients with chronic hepatitis B virus (HBV) infection. Whereas, the long-term effect of TAF to liver fibrosis is still unknown. Here, we enrolled treatment naive CHB patients with biopsy-proven significant fibrosis (METAVIR fibrosis stage ≥ F2). All enrolled subjects will be treated with TAF monotherapy for 96 weeks. After 96 weeks of therapy, the second liver biopsy will be performed to evaluate the rate of liver fibrosis regression. During this study, all subjects will be assessed for laboratory tests, imaging examination at baseline, first 12-week and every 24-week during follow-up.

Study Overview

• Status: Active, not recruiting
• Conditions: Chronic Hepatitis B
• Intervention / Treatment: Drug: Tenofovir alafenamide

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jidong Jia; Phone Number: 86-010-63139246; Email: jia_jd@ccmu.edu.cn
• Study Contact Backup: Name: Jialing Zhou; Phone Number: 86-010-63138665; Email: zhoujialing11@126.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100015
      • Beijing Ditan Hospital, Capital Medical University
  • Shanghai
    • Shanghai, Shanghai, China, 200040
      • Huashan Hospital Fudan University
    • Shanghai, Shanghai, China, 200021
      • ShuGuang Hospital
    • Shanghai, Shanghai, China, 201199
      • Ruijin Hospital
    • Shanghai, Shanghai, China, 310000
      • Shanghai East Hospital
  • Tianjin
    • Tianjin, Tianjin, China, 300170
      • Tianjin Third Central Hospital
    • Tianjin, Tianjin, China, 300192
      • Tianjin Second People's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 69 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 18-69 years old (inclusive);
• BMI (18-30 kg/m2);
• Chronic hepatitis B virus (HBV) infection, defined as positive serum hepatitis B s-antigen (HBsAg) for more than 6 months; or chronic hepatitis B proven by live biopsy;
• Not received nucleoside (acid) analogue and/or interferon therapy (treatment-naive);
• Liver biopsy performed within 6 months before treatment and had readable biopsy slides or agrees to have a biopsy performed prior to baseline;
• METAVIR fibrosis stage ≥ F2;
• For patients without cirrhosis (F2/3), HBV DNA levels >2000 IU/mL before treatment; For patients with cirrhosis (F4), HBV DNA >20 IU/mL before treatment;
• ALT≤10 ULN before treatment;
• Creatinine clearance ≥ 50 mL/min;
• Agreement not to undertake other HBV systemic antiviral or interferon (IFN) regimens during participation in this study;
• Willing and able to provide written informed consent.

Exclusion Criteria:

• Patients with Child-Turcotte-Pugh（CTP）score ≥ 7;
• Patients with decompensated cirrhosis: including ascites, hepatic encephalopathy, esophageal varices bleeding or other complications of decompensated cirrhosis or liver transplantation;
• Patients co-infection with hepatitis C virus (HCV), human immunodeficiency virus (HIV), or hepatitis delta virus (HDV), or alcoholic liver diseases, autoimmune liver disease, genetic liver disease, drug-induced liver injury, non-alcoholic fatty liver disease or other chronic liver diseases;
• Patients with evidence of hepatocellular carcinoma (HCC) by imaging with or without AFP;
• Patients with other uncured malignant tumors;
• Patients with organ or bone marrow transplantation;
• Patients currently receiving therapy with immunomodulators (eg, corticosteroids, etc.), investigational agents, nephrotoxic agents, or agents susceptible of modifying renal excretion;
• Patients who are allergic to any component of TAF;
• Patients who recently or newly started bisphosphate (within 1 month);
• Patients with active alcohol or drug abuse or history of alcohol or drug abuse (hinder compliance with treatment, or participation in the study or interpretation of results considered by the Investigator);
• Patients with significant renal, cardiovascular, pulmonary, or neurological disease
• Males and females of reproductive potential who are unwilling to use an effective method of contraception during the study;
• Pregnant women, women who are breast feeding or who believe they may wish to become pregnant during the course of the study;
• Not suitable for this study identified by researchers.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: TAF group; TAF [Vemlidy® 25mg QD] monotherapy	Drug: Tenofovir alafenamide; Subjects will be treated for 96 weeks with TAF [Vemlidy® 25mg QD] monotherapy; Other Names: Vemlidy®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with fibrosis regression	Fibrosis stage decrease at least 1 point by Ishak score or "Predominantly Regressive" by "Beijing classification"	Week 96
HBV DNA undetectable rate	Serum HBV DNA <20 IU/mL	Week 96

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of liver stiffness decrease >= 30%	Proportion of patients with liver stiffness decrease >= 30% from baseline to week 48 and 96	Week 48 and Week 96
HBV DNA undetectable rate	HBV DNA undetectable rate at week 24, 48, and 72	Week 24, Week 48 and Week 72
ALT normalization rate	Proportion of patients with ALT <= 1.0xULN	Week 48 and Week 96
HBeAg and HBsAg loss and seroconversion rate	Proportions of patients with HBsAg loss and seroconversion to anti-HBs, and proportions of patients with HBeAg loss and seroconversion to anti-HBe.	Week 48 and Week 96
Changes in renal function	Changes of eGFR (estimated Glomerular Filtration rate) from baseline to week 48 and 96	Week 48 and Week 96
Changes of bone mineral density	Percentage changes in spine BMD and hip BMD from baseline to week 48 and 96	Week 48 and Week 96
Incidence of liver-related endpoint events	liver-related endpoint events: decompensation, HCC, liver transplantation, liver-related death	Week 96

Collaborators and Investigators

• Sponsor: Jidong Jia
• Collaborators: Beijing Ditan Hospital; Huashan Hospital; Ruijin Hospital; Shanghai East Hospital; Tianjin Third Central Hospital; ShuGuang Hospital; Tianjin Second People's Hospital; The Sixth Peoples Hospital of Zhengzhou
• Investigators: Principal Investigator: Jidong Jia, Beijing Friendship Hospital, Capital Medical Hospital

Publications and helpful links

General Publications

• Chan HL, Fung S, Seto WK, Chuang WL, Chen CY, Kim HJ, Hui AJ, Janssen HL, Chowdhury A, Tsang TY, Mehta R, Gane E, Flaherty JF, Massetto B, Gaggar A, Kitrinos KM, Lin L, Subramanian GM, McHutchison JG, Lim YS, Acharya SK, Agarwal K; GS-US-320-0110 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):185-195. doi: 10.1016/S2468-1253(16)30024-3. Epub 2016 Sep 22. Erratum In: Lancet Gastroenterol Hepatol. 2016 Nov;1(3):e2.
• Buti M, Gane E, Seto WK, Chan HL, Chuang WL, Stepanova T, Hui AJ, Lim YS, Mehta R, Janssen HL, Acharya SK, Flaherty JF, Massetto B, Cathcart AL, Kim K, Gaggar A, Subramanian GM, McHutchison JG, Pan CQ, Brunetto M, Izumi N, Marcellin P; GS-US-320-0108 Investigators. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016 Nov;1(3):196-206. doi: 10.1016/S2468-1253(16)30107-8. Epub 2016 Sep 22. Erratum In: Lancet Gastroenterol Hepatol. 2016 Nov;1(3):e2.
• Agarwal K, Brunetto M, Seto WK, Lim YS, Fung S, Marcellin P, Ahn SH, Izumi N, Chuang WL, Bae H, Sharma M, Janssen HLA, Pan CQ, Celen MK, Furusyo N, Shalimar D, Yoon KT, Trinh H, Flaherty JF, Gaggar A, Lau AH, Cathcart AL, Lin L, Bhardwaj N, Suri V, Mani Subramanian G, Gane EJ, Buti M, Chan HLY; GS-US-320-0110; GS-US-320-0108 Investigators. 96 weeks treatment of tenofovir alafenamide vs. tenofovir disoproxil fumarate for hepatitis B virus infection. J Hepatol. 2018 Apr;68(4):672-681. doi: 10.1016/j.jhep.2017.11.039. Epub 2018 Jan 17.

Study record dates

Study Major Dates

• Study Start (Actual): April 20, 2021
• Primary Completion (Anticipated): May 1, 2024
• Study Completion (Anticipated): May 1, 2025

Study Registration Dates

• First Submitted: June 17, 2021
• First Submitted That Met QC Criteria: June 17, 2021
• First Posted (Actual): June 25, 2021

Study Record Updates

• Last Update Posted (Actual): May 23, 2023
• Last Update Submitted That Met QC Criteria: May 20, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Chronic Hepatitis B; Tenofovir alafenamide; Liver fibrosis, Liver cirrhosis
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Disease Attributes; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Chronic Disease; Fibrosis; Hepatitis B; Hepatitis; Hepatitis B, Chronic; Hepatitis, Chronic; Liver Cirrhosis; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Reverse Transcriptase Inhibitors; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Tenofovir
• Other Study ID Numbers: IN-CN-320-5613

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No