Clinical trial NCT05793268: Finite Versus Continuous Nucleos(t)Ide Analogues for Chronic Hepatitis B
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Chronic Hepatitis b
Keywords: hepatitis b virus infection
antiviral therapy
randomized trial
Lead sponsor: E-DA Hospital
Sponsor class: OTHER
First posted: 2023-03-31
Enrollment: 360
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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).

Detailed description: Chronic hepatitis B virus (HBV) infection imposes a serious threat to global public health, affecting more than 250 million individuals around the world. In the management of patients with chronic hepatitis B (CHB), treatment with nucleos(t)ide analog (Nuc) has been shown to improve clinical outcomes including occurrence and recurrence of hepatocellular carcinoma (HCC), liver-related mortality, and overall mortality. Nuc therapy, however, cannot exterminate HBV and so continuous treatment is usually required to sustain viral inhibition. Seroclearance of hepatitis B surface antigen (HBsAg) predicts durable remission off Nuc and may serve as the treatment endpoint, but it rarely occurs with current regimen. Therefore, long-term to indefinite treatment is currently recommended.

In view of various concerns such as drug exposure, adherence, and expense for a treatment course that could be lifelong, a finite strategy of Nuc therapy was proposed to allow treatment withdrawal prior to HBsAg seroclearance. Another major reason for the finite strategy is a higher chance of HBsAg seroclearance following treatment cessation. Nevertheless, viral replication almost always reactivates and often leads to clinical flares. While an episode of acute flare might be self-limited or even conducive to HBsAg seroclearance, it could progress to acute on chronic liver failure with fatal consequences. Risks of these serious outcomes following treatment withdrawal need to be accurately quantified in order to inform the practice of finite Nuc therapy.

Existent literature on the efficacy and safety of finite Nuc therapy remained very limited, as recently shown in a systematic review and meta-analysis by Hall and colleagues. In order to close the gaps in current knowledge, the investigators conduct this multicenter randomized controlled trial to examine if cessation of Nuc is safe and conducive to HBsAg seroclearance.

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants with seroclearance of HBsAg
timeFrame: The time from randomization to seroclearance of HBsAg, up to 3 years after randomization
Secondary outcomes:
measure: Number of Participants with liver-related mortality or liver transplantation
timeFrame: The time from randomization to this secondary outcome, up to 3 years after randomization
measure: Number of Participants with acute on chronic liver failure
timeFrame: The time from randomization to this secondary outcome, up to 3 years after randomization
measure: Number of Participants with severe acute exacerbation of chronic hepatitis B
timeFrame: The time from randomization to this secondary outcome, up to 3 years after randomization
measure: Number of Participants with clinical relapse of active hepatitis B
timeFrame: The time from randomization to this secondary outcome, up to 3 years after randomization
measure: Number of Participants with incident hepatocellular carcinoma
timeFrame: The time from randomization to this secondary outcome, up to 3 years after randomization
measure: Changes in the FIB4 index from baseline
timeFrame: At three years after randomization
measure: Changes in serum concentration of quantitative HBsAg from the baseline at randomization
timeFrame: At three years after randomization
measure: Changes in serum concentration of HBcrAg from the baseline at randomization
timeFrame: At three years after randomization
measure: Changes in the quality of life as measured by Short Form-36 Inventory from the baseline
timeFrame: At each follow-up visit during the study period, up to 3 years after randomization
measure: Changes in the scores measured by the General Anxiety Disorder-7 from baseline
timeFrame: At each follow-up visit during the study period, up to 3 years after randomization
measure: Direct expenditure on healthcare
timeFrame: At three years after randomization
measure: Changes in the scores measured by the Perceived Stress Scale - 14 from baseline
timeFrame: At each follow-up visit during the study period, up to 3 years after randomization
Other outcomes:
Locations:
city: Chiayi City
country: Taiwan
facility: Chia-Yi Christian Hospital
city: Kaohsiung
country: Taiwan
facility: E-Da Hospital
city: Taichung
country: Taiwan
facility: Taichung Veterans General Hospital
city: Taipei
country: Taiwan
facility: Fu-Jen Catholic University Hospital
city: Taitung
country: Taiwan
facility: Taitung Mackay Memorial Hospital
city: Yilan
country: Taiwan
facility: Lotung Poh-Ai Hospital
Study officials:
affiliation: E-Da Hospital/I-Shou University
name: Yao-Chun Hsu, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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