Chronic Hepatitis b Clinical Trial
Official title:
Safety and Efficacy of Finite Versus Continuous Nucleos(t)Ide Analogues Therapy in Patients With Chronic Hepatitis B: A Multicenter Randomized Controlled Trial
Verified date | March 2023 |
Source | E-DA Hospital |
Contact | n/a |
Is FDA regulated | No |
Health authority | |
Study type | Interventional |
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).
Status | Active, not recruiting |
Enrollment | 360 |
Est. completion date | December 2026 |
Est. primary completion date | December 2025 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 20 Years and older |
Eligibility | Inclusion Criteria: 1. Age = 20 years 2. Chronic hepatitis B virus infection (defined as positive HBsAg for = 6 months) 3. Entecavir or tenofovir (either tenofovir disoproxil fumarate or tenofovir alafenamide) for at least two years and still on therapy at screening for this trial. 4. 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) 5. At screening for this study, HBsAg serology is positive, HBeAg negative, and HBV DNA undetectable in serum. Exclusion Criteria: 1. Liver cirrhosis (either clinical or pathological diagnosis) at screening 2. Serious underlying disease (with valid certification of catastrophic illness) at screening 3. Manifestations and concerns of hepatic decompensation, including serum bilirubin >2mg/dL and/or prolongation of prothrombin time > 3 seconds at screening 4. 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. 5. Prior history of any malignancy including liver cancer 6. Prior history of any organ transplantation 7. Prior history of drug resistance to any Nuc agent 8. Any patient condition that the treating physician deems inappropriate for enrollment in this trial |
Country | Name | City | State |
---|---|---|---|
Taiwan | Chia-Yi Christian Hospital | Chiayi City | |
Taiwan | E-Da Hospital | Kaohsiung | |
Taiwan | Taichung Veterans General Hospital | Taichung | |
Taiwan | Fu-Jen Catholic University Hospital | Taipei | |
Taiwan | Taitung Mackay Memorial Hospital | Taitung | |
Taiwan | Lotung Poh-Ai Hospital | Yilan |
Lead Sponsor | Collaborator |
---|---|
E-DA Hospital |
Taiwan,
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. — View Citation
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. — View Citation
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. — View Citation
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. — View Citation
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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. — View Citation
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Primary | 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 | Number of Participants with liver-related mortality or liver transplantation | Death from liver failure or liver transplantation because of liver failure | The time from randomization to this secondary outcome, up to 3 years after randomization | |
Secondary | Number of Participants with acute on chronic liver failure | According to the definition of Asian-Pacific Association for the Study of Liver Diseases | The time from randomization to this secondary outcome, up to 3 years after randomization | |
Secondary | Number of Participants with severe acute exacerbation of chronic hepatitis B | Serum alanine aminotransferase > 5 times the upper limit of normal with either serum bilirubin =2mg/dL or prolongation of prothrombin time =3 seconds, in the presence of serum HBV DNA >2000 IU/mL | The time from randomization to this secondary outcome, up to 3 years after randomization | |
Secondary | Number of Participants with clinical relapse of active hepatitis B | Serum alanine aminotransferase > 2 times the upper limit of normal in the presence of serum HBV DNA >2000 IU/mL | The time from randomization to this secondary outcome, up to 3 years after randomization | |
Secondary | Number of Participants with incident hepatocellular carcinoma | Diagnosis of hepatocellular carcinoma after randomization | The time from randomization to this secondary outcome, up to 3 years after randomization | |
Secondary | Changes in the FIB4 index from baseline | The formula for FIB-4 is: Age ([yr] x AST [U/L]) / ((PLT [10(9)/L]) x (ALT [U/L])(1/2)). | At three years after randomization | |
Secondary | Changes in serum concentration of quantitative HBsAg from the baseline at randomization | Quantitative HBsAg measured in log IU/mL | At three years after randomization | |
Secondary | Changes in serum concentration of HBcrAg from the baseline at randomization | Quantitative HBcrAg measured in log U/mL | At three years after randomization | |
Secondary | Changes in the quality of life as measured by Short Form-36 Inventory from the baseline | Chinese version of the Short-form 36. Responses in each domain are transformed into a 0-100 scale, with a higher score indicating better health or functioning. | At each follow-up visit during the study period, up to 3 years after randomization | |
Secondary | Changes in the scores measured by the General Anxiety Disorder-7 from baseline | Chinese version of the questionnaire. The total score can range from 0 to 21, with a higher score indicating more severe anxiety | At each follow-up visit during the study period, up to 3 years after randomization | |
Secondary | Direct expenditure on healthcare | Money (measured in US dollars) that is paid for all sort of healthcare | At three years after randomization | |
Secondary | Changes in the scores measured by the Perceived Stress Scale - 14 from baseline | Chinese version of the questionnaire. The total score can range from 0 to 56, with a higher score indicating a higher level of perceived stress. | At each follow-up visit during the study period, up to 3 years after randomization |
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