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Halting Nucleoside Analogues in Chronic Hepatitis B (HALT-NUCS)

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ClinicalTrials.gov Identifier: NCT04102176
Recruitment Status : Recruiting
First Posted : September 25, 2019
Last Update Posted : September 26, 2019
Sponsor:
Collaborators:
Tan Tock Seng Hospital
Singapore General Hospital
Changi General Hospital
Information provided by (Responsible Party):
Seng Gee Lim, National University Health System, Singapore

Brief Summary:
Most patients with Chronic Hepatitis B are on nucleoside analogy (NA) long term, but this leads to HBsAg loss (defined as functional cure) of only 2% at 6 years. Recently a number of studies have shown significant HBsAg loss rates after stopping nucleoside analogues (NA). However, no criteria to select such patients have been evaluated. Consequently, the objective of the study is not only to determine the proportion of patients able to achieve HBsAg loss in those with qHBsAg≤100IU/ml. The study is designed as a randomised control trial with 1:2 parallel arm randomisation to continuing NA or stopping therapy. Patients will be monitored after stopping therapy for Hepatitis B flares and also to document HBsAg loss.

Condition or disease Intervention/treatment Phase
Chronic Hepatitis B Other: stopping nucleos(t)ide therapy Other: Continue nucleos(t)ide analogue Not Applicable

Detailed Description:
Chronic Hepatitis B (CHB) affects over 250 million persons and is considered one of the major causes of mortality and morbidity globally. Standard treatment consists of nucleos(t)ide analogues (NA) or peginterferon (PEG). There has been increasing interested in HBsAg loss, defined as functional cure. However this has been difficult to achieve with NA, and although rates of HBsAg loss are higher with PEG, they are still <10%. However, a number of studies have shown that HBsAg loss rates were significantly higher in those who stopped NA. A study from Greece by Hadziyannis had a 39% HBsAg loss after patients stopped adefovir therapy. Further studies have shown similar results, and those not able to clear HBsAg have had quiescent disease, although some patients had to restart therapy usually due to hepatitis B flares. No deaths have been reported. Consequently, while stopping therapy has led to HBsAg loss in some patients, it is not clear which patients would benefit the most. The prior studies have indicated that patients most likely to lose HBsAg had low qHBsAg levels and a level ≤100 IU/ml had a high possibility of HBsAg loss. Consequently, we propose to test whether patients with CHB on NA >1year and without liver cirrhosis and with qHBsAg≤100 IU/ml are able to lose HBsAg compared to those who continue NA. The study is designed as a parallel arm RCT randomised 1:2 to continue NA versus stop NA. Patients will be monitored regularly for clinical status, virological markers, and liver markers. The primary endpoint is HBsAg loss at the end of the study in those who stop versus those who continue NA. Additional outcomes will be hepatitis B flares, inactive hepatitis B status, virological relapse, and restarting therapy.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Parallel arm study randomised 1:2
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: HALT NUCs: Halting Nucleoside Analogue Therapy in Chronic Hepatitis B
Actual Study Start Date : January 29, 2019
Estimated Primary Completion Date : March 2021
Estimated Study Completion Date : March 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Continue nucleos(t)ide analogue
patients will be given open label tenofovir alafenamide
Other: Continue nucleos(t)ide analogue
Continue nucleos(t)ide analogue

Experimental: Stopping nucleos(t)ide analogue
patients will stop nucleos(t)ide therapy (such as entecavir, tenofovir, lamivudine or adefovir)
Other: stopping nucleos(t)ide therapy
patients taking nucleoside(t)ide therapy will stop treatment




Primary Outcome Measures :
  1. HBsAg loss [ Time Frame: Through year 3 ]
    Absence of HBsAg by ELISA


Secondary Outcome Measures :
  1. Hepatitis B flare [ Time Frame: Through year 3 ]
    increase in ALT associated with increase in HBV DNA

  2. virological relapse [ Time Frame: Through year 3 ]
    increase in HBV DNA without increase in ALT

  3. Restarting antiviral therapy [ Time Frame: Through year 3 ]
    Those who have to start therapy based on clinical indications after stopping therapy



Information from the National Library of Medicine

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Ages Eligible for Study:   21 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • • Between 21 and 75 years old.

    • Documented to be HBsAg positive for ≥ 6 months.
    • On any NA (lamivudine, adefovir, entecavir, telbivudine tenofovir) for ≥ 1 year
    • HBV DNA <15 IU/ml at screening (undetectable)
    • Quantitative HBsAg <100 IU/ml
    • Patient has agreed not to take any other investigational drug or systemic anti-viral, cytotoxic, corticosteroid, immunomodulatory agents or Chinese traditional remedies unless clinically indicated.
    • Patient is able to give written consent prior to study start and to comply with the study requirements.
    • Women of childbearing age must have a negative serum (ß-HCG) pregnancy test taken with 14 days of starting therapy

Exclusion Criteria:

  • • Evidence of liver cirrhosis based on liver biopsy, fibroscan score >10.5 kpa, or MRE score>5.5kpa, or clinical evidence of cirrhosis demonstrated by presence of esophageal varices, obvious features of cirrhosis on ultrasound within the last 12 months

    • Evidence of decompensated liver disease or hepatocellular carcinoma.
    • HIV antibody or HCV antibody or HDV antibody positivity
    • Creatinine > 1.5 times upper limit of normal
    • INR > 1.5, uncorrected by Vitamin K therapy.
    • Any interferon, Immunomodulators, systemic cytotoxic agents, or systemic corticosteroids within 6 months before trial entry.
    • Prolonged exposure to known hepatotoxins such as alcohol or drugs.
    • History of clinically relevant psychiatric disease, seizures, central nervous system dysfunction, severe pre-existing cardiac, renal, hematological disease or medical illness that in the investigator's opinion might interfere with therapy.
    • Malignant disease within 5 years of trial entry.
    • Women who are pregnant and who are not practicing adequate birth control measures, or who are lactating

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04102176


Contacts
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Contact: Chris Lee, BSc (65)67726123 mdclywc@nus.edu.sg

Locations
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Singapore
National University Hospital Recruiting
Singapore, Singapore, 119228
Contact: Chris Lee, BSc    67726123    mdclywc@nus.edu.sg   
Sponsors and Collaborators
Seng Gee Lim
Tan Tock Seng Hospital
Singapore General Hospital
Changi General Hospital
Investigators
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Principal Investigator: Seng Gee Lim, MBBS MD National University Health System

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Responsible Party: Seng Gee Lim, Director of Hepatology, National University Health System, Singapore
ClinicalTrials.gov Identifier: NCT04102176    
Other Study ID Numbers: CIRG17may042
First Posted: September 25, 2019    Key Record Dates
Last Update Posted: September 26, 2019
Last Verified: September 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Seng Gee Lim, National University Health System, Singapore:
chronic hepatitis B
nucleoside analogues
stopping
discontinuing
Additional relevant MeSH terms:
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Hepatitis A
Hepatitis B
Hepatitis B, Chronic
Hepatitis
Hepatitis, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human
Virus Diseases
Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Hepadnaviridae Infections
DNA Virus Infections
Tin Fluorides
Cariostatic Agents
Protective Agents
Physiological Effects of Drugs