Finite Versus Continuous Nucleos(t)Ide Analogues for Chronic Hepatitis B

NCT05793268 | Active Not Recruiting

• 1 other identifier: EMRP26111N
• Study Type: interventional
• Target: 360
• Locations: 1 country
• Sites: 6

Brief Summary

BACKGROUND: Finite nucleos(t)ide analogue (Nuc) therapy was proposed as an alternative strategy in the management of chronic hepatitis B (CHB) but there remained not data from randomized controlled trials to clarify safety and efficacy of this treatment strategy. AIMS: The investigators aimed to evaluate the safety and efficacy of finite Nuc therapy versus continuous treatment in CHB patients without liver cirrhosis and also to identify factors that may predict therapeutic responses and clinical outcomes after withdrawal of Nuc treatment for CHB MATERIAL AND METHODS: This is a multicenter randomized controlled trial conducted in Taiwan. Eligible patients are adults (age≥20 years) with CHB (chronic infection ≥ 6 months) who fulfill the APASL guideline 2016 to stop NA therapy. Those with cirrhosis, malignancy, organ transplant, autoimmune disorder, or serious underlying diseases including renal impairment were excluded. A total of 360 patients will be enrolled. Enrolled patients are randomly allocated with a 1:1 ratio to continue viral suppression with entecavir (0.5mg once daily) or tenofovir disoproxil fumarate (300mg once daily) or stop the treatment. All patients will be followed up according to the protocol recommended by a panel of APASL experts. The primary analysis for study outcomes is scheduled at 3 years after randomization and the primary outcome is seroclearance of HBsAg. There will be interim analyses scheduled at one- and two-years following randomization of the first 200 patients, and also one-and two years following randomization of the planned 360 patients, to determine whether early termination of the trial may be justified by attainment of the efficacy endpoint (10% vs 1% of HBsAg seroclearance) or concerns of the safety outcomes (significant between-group difference in mortality, acute on chronic liver failure, or acute flares with hepatic decompensation).

Conditions

Chronic Hepatitis b

Keywords

hepatitis b virus infection; antiviral therapy; randomized trial

Outcome Measures

Primary Outcomes (1)

• Number of Participants with seroclearance of HBsAg

  Serology of HBsAg was negative by the laboratory report

  The time from randomization to seroclearance of HBsAg, up to 3 years after randomization

Secondary Outcomes (12)

• Number of Participants with liver-related mortality or liver transplantation

  The time from randomization to this secondary outcome, up to 3 years after randomization

• Number of Participants with acute on chronic liver failure

  The time from randomization to this secondary outcome, up to 3 years after randomization

• Number of Participants with severe acute exacerbation of chronic hepatitis B

  The time from randomization to this secondary outcome, up to 3 years after randomization

• Number of Participants with clinical relapse of active hepatitis B

  The time from randomization to this secondary outcome, up to 3 years after randomization

• Number of Participants with incident hepatocellular carcinoma

  The time from randomization to this secondary outcome, up to 3 years after randomization

Study Arms (2)

Finite Therapy

EXPERIMENTAL

Discontinuation of nucleos(t)ide analog (Nuc) therapy

Other: Nuc Discontinuation

Continuous Therapy

ACTIVE COMPARATOR

Continuation of oral Nuc monotherapy using entecavir (0.5mg/tab, once per day), tenofovir disoproxil fumarate (300mg/tab, once per day), or tenofovir alafenamide (25mg/tab, once per day) for 3 years

Drug: Entecavir or Tenofovir

Interventions

Nuc Discontinuation OTHER

Eligible patients are randomly allocated with a 1:1 ratio to continue viral suppression or stop the treatment (entecavir or tenofovir). Patients will be followed up for 3 years. For patients who are assigned to the finite Nuc therapy, they should be monitored monthly for the initial 3 months and then every 3-6 months thereafter for relapse.

Finite Therapy

Entecavir or Tenofovir DRUG

Continuation of either entecavir or tenofovir treatment for 3 years

Continuous Therapy

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age ≥ 20 years
• Chronic hepatitis B virus infection (defined as positive HBsAg for ≥ 6 months)
• Entecavir or tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) for at least two years and still on therapy at screening for this trial.
• Fulfillment of the stopping rules recommended by the Asian-Pacific guidelines 2016:
• For patients with positive HBeAg prior to their antiviral treatment, HBeAg seroconversion needs to be documented and followed by consolidation treatment for at least one year). Besides, serum ALT is within normal limits and HBV DNA is undetectable.
• For those with negative HBeAg prior to the antiviral therapy, undetectable HBV DNA documented on three separate occasions (at least 6 months apart)
• At screening for this study, HBsAg serology is positive, HBeAg negative, and HBV DNA undetectable in serum.

You may not qualify if:

• Liver cirrhosis (either clinical or pathological diagnosis) at screening
• Serious underlying disease (with valid certification of catastrophic illness) at screening
• Manifestations and concerns of hepatic decompensation, including serum bilirubin \>2mg/dL and/or prolongation of prothrombin time \> 3 seconds at screening
• Hepatitis C virus (if anti-HCV serology is positive, confirmation with detectable HCV RNA is required), human immunodeficiency virus (HIV) or hepatitis delta virus (HDV) coinfection at screening.
• Prior history of any malignancy including liver cancer
• Prior history of any organ transplantation
• Prior history of drug resistance to any Nuc agent
• Any patient condition that the treating physician deems inappropriate for enrollment in this trial

Sponsors & Collaborators

• E-DA Hospital: lead

Study Sites (6)

Chia-Yi Christian Hospital

Chiayi City, Taiwan

Location

E-Da Hospital

Kaohsiung City, 824, Taiwan

Location

Taichung Veterans General Hospital

Taichung, Taiwan

Location

Fu-Jen Catholic University Hospital

Taipei, Taiwan

Location

Taitung Mackay Memorial Hospital

Taitung, Taiwan

Location

Lotung Poh-Ai Hospital

Yilan, Taiwan

Location

Related Publications (6)

• Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, Chen DS, Chen HL, Chen PJ, Chien RN, Dokmeci AK, Gane E, Hou JL, Jafri W, Jia J, Kim JH, Lai CL, Lee HC, Lim SG, Liu CJ, Locarnini S, Al Mahtab M, Mohamed R, Omata M, Park J, Piratvisuth T, Sharma BC, Sollano J, Wang FS, Wei L, Yuen MF, Zheng SS, Kao JH. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016 Jan;10(1):1-98. doi: 10.1007/s12072-015-9675-4. Epub 2015 Nov 13.

  PMID: 26563120 BACKGROUND

• Kao JH, Jeng WJ, Ning Q, Su TH, Tseng TC, Ueno Y, Yuen MF. APASL guidance on stopping nucleos(t)ide analogues in chronic hepatitis B patients. Hepatol Int. 2021 Aug;15(4):833-851. doi: 10.1007/s12072-021-10223-5. Epub 2021 Jul 23.

  PMID: 34297329 BACKGROUND

• Hsu YC, Yeh ML, Wong GL, Chen CH, Peng CY, Buti M, Enomoto M, Xie Q, Trinh H, Preda C, Liu L, Cheung KS, Yeo YH, Hoang J, Huang CF, Riveiro-Barciela M, Kozuka R, Istratescu D, Tsai PC, Accarino EV, Lee DH, Wu JL, Huang JF, Dai CY, Cheung R, Chuang WL, Yuen MF, Wong VW, Yu ML, Nguyen MH. Incidences and Determinants of Functional Cure During Entecavir or Tenofovir Disoproxil Fumarate for Chronic Hepatitis B. J Infect Dis. 2021 Dec 1;224(11):1890-1899. doi: 10.1093/infdis/jiab241.

  PMID: 33999179 BACKGROUND

• Berg T, Simon KG, Mauss S, Schott E, Heyne R, Klass DM, Eisenbach C, Welzel TM, Zachoval R, Felten G, Schulze-Zur-Wiesch J, Cornberg M, Op den Brouw ML, Jump B, Reiser H, Gallo L, Warger T, Petersen J; FINITE CHB study investigators [First investigation in stopping TDF treatment after long-term virological suppression in HBeAg-negative chronic hepatitis B]. Long-term response after stopping tenofovir disoproxil fumarate in non-cirrhotic HBeAg-negative patients - FINITE study. J Hepatol. 2017 Nov;67(5):918-924. doi: 10.1016/j.jhep.2017.07.012. Epub 2017 Jul 21.

  PMID: 28736139 BACKGROUND

• Jeng WJ, Chen YC, Chien RN, Sheen IS, Liaw YF. Incidence and predictors of hepatitis B surface antigen seroclearance after cessation of nucleos(t)ide analogue therapy in hepatitis B e antigen-negative chronic hepatitis B. Hepatology. 2018 Aug;68(2):425-434. doi: 10.1002/hep.29640. Epub 2018 May 6.

  PMID: 29108132 BACKGROUND

• Hall SAL, Vogrin S, Wawryk O, Burns GS, Visvanathan K, Sundararajan V, Thompson A. Discontinuation of nucleot(s)ide analogue therapy in HBeAg-negative chronic hepatitis B: a meta-analysis. Gut. 2022 Aug;71(8):1629-1641. doi: 10.1136/gutjnl-2020-323979. Epub 2021 Sep 7.

  PMID: 34493592 BACKGROUND

MeSH Terms

Conditions

Hepatitis B, Chronic; Hepatitis B

Interventions

entecavir; Tenofovir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Adenine; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Yao-Chun Hsu, MD, PhD

  E-Da Hospital/I-Shou University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 19, 2022
• First Posted: March 31, 2023
• Study Start: December 20, 2022
• Primary Completion: December 1, 2025
• Study Completion (Estimated): December 1, 2026
• Last Updated: March 31, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: Data will become available beginning with full publication of the study results in an academic peer-reviewed journal and for at least a year.

Locations

TW (6)