Clinical trial NCT04939441: Regression of Liver Fibrosis by Tenofovir Alafenamide (TAF)
Official title: Regression of Liver Fibrosis by Tenofovir Alafenamide (TAF) in Treatment-Naive CHB Related Fibrosis/Cirrhosis: a 96w Open-label Multicenter Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Chronic Hepatitis B
Keywords: Chronic Hepatitis B
Liver fibrosis, Liver cirrhosis
Tenofovir alafenamide
Lead sponsor: Beijing Friendship Hospital
Sponsor class: OTHER
Collaborators: name: Beijing Ditan Hospital
name: ShuGuang Hospital
name: Tianjin Third Central Hospital
name: Huashan Hospital
name: The Sixth Peoples Hospital of Zhengzhou
name: Tianjin Second People's Hospital
name: Ruijin Hospital
name: Shanghai East Hospital
First posted: 2021-06-25
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Maximum age (years): 69
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Subjects will be treated for 96 weeks with TAF \[Vemlidy® 25mg QD\] monotherapy
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Proportion of patients with fibrosis regression
timeFrame: Week 96
measure: HBV DNA undetectable rate
timeFrame: Week 96
Secondary outcomes:
measure: Percentage of liver stiffness decrease >= 30%
timeFrame: Week 48 and Week 96
measure: HBV DNA undetectable rate
timeFrame: Week 24, Week 48 and Week 72
measure: ALT normalization rate
timeFrame: Week 48 and Week 96
measure: HBeAg and HBsAg loss and seroconversion rate
timeFrame: Week 48 and Week 96
measure: Changes in renal function
timeFrame: Week 48 and Week 96
measure: Changes of bone mineral density
timeFrame: Week 48 and Week 96
measure: Incidence of liver-related endpoint events
timeFrame: Week 96
Other outcomes:
Locations:
city: Beijing
country: China
facility: Beijing Ditan Hospital, Capital Medical University
state: Beijing
city: Shanghai
country: China
facility: Shuguang Hospital
state: Shanghai
city: Shanghai
country: China
facility: Huashan Hospital Fudan University
state: Shanghai
city: Shanghai
country: China
facility: Ruijin Hospital
state: Shanghai
city: Shanghai
country: China
facility: Shanghai East Hospital
state: Shanghai
city: Tianjin
country: China
facility: Tianjin Third Central Hospital
state: Tianjin
city: Tianjin
country: China
facility: Tianjin Second People's Hospital
state: Tianjin
Study officials:
affiliation: Beijing Friendship Hospital, Capital Medical Hospital
name: Jidong Jia
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.