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NCT Number: NCT03681132

The Norwegian Nucleoside Analogue Stop Study

Globally, an estimated 257 million individuals have chronic hepatitis B-virus infection (CHB). In the absence of treatment 15-40% of these will progress to liver cirrhosis and/or hepatocellular carcinoma. Oral antiviral treatment suppresses the virus and improves prognosis, but less than 0.5% per year achieve a "functional cure" (i.e. HBsAg loss). One remaining controversy, therefore, is whether antiviral treatment must continue life-long. Observational studies have assessed stopping antiviral treatment after years of viral suppression; however, HBsAg loss has rarely been seen. But interestingly, a few small trials that chose watchful waiting instead of re-initiation of treatment when reactivation occurred, achieved 40% HBsAg loss during 6 years follow-up.

The present proposal is a randomized controlled trial that will assess the safety, efficacy, and cost-effectiveness of treatment discontinuation - and delayed restart - in HBeAg negative CHB. The study is sufficiently powered to address the hypotheses, and a pilot study that demonstrates feasibility has been performed. Patients will be enrolled at 12 Norwegian hospitals, in addition to our collaborating institution in Ethiopia - the largest CHB treatment center in sub-Saharan Africa. If the study shows that discontinuation is safe and effective, it will directly impact both national and international treatment guidelines.

Main objective:

-To study whether stopping nucleoside analogue (NA) therapy - and delaying re-start - can trigger an immune response and set off a functional cure (viz HBsAg loss)

Secondary objectives:

* Assess whether stopping NA therapy - and delaying re-start - leads to a higher chance of HBsAg loss * Assess the safety of stopping NA therapy - and delaying re-start - in terms of hepatic decompensation, fibrosis progression, and/or adverse events * Study whether stopping NA therapy - and delaying re-start - leads to a higher chance of sustained off-therapy immune control (low viral load and normal ALT) * Assess the quality of life and cost-effectiveness of stopping NA therapy - and delaying re-start * Identify predictors of HBsAg loss

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Key information

Conditions

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

Age range

18 year–70 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Hvidovre Hospital, Copenhagen, Denmark

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • Adults (18-70 years) with HBeAg negative chronic hepatitis B
  • HBeAg negative at start of antiviral therapy
  • Treated minimum 2 years with either tenofovir or entecavir without interruption (i.e. no self-reported episodes of ≥2 weeks off therapy)
  • Full viral suppression >2 years: at least 3 measurements at least 6 months apart with at least 24 months between the first and last measurement.
  • Most recent liver fibrosis assessment, performed within the past 12 months, does not show advanced fibrosis (i.e. Metavir score <F3 or Fibroscan <9 kPa). For the (few) patients who lack pre-treatment fibrosis assessment, a more conservative Fibroscan threshold of <8 kPa will apply.

Exclusion criteria

  • A history of decompensated liver disease, either by clinical signs (ascites, encephalopathy, portal hypertension, jaundice) or suggestive laboratory results (total bilirubin >38 umol/L, INR >1.5, platelets <75,000/mm3, serum albumin <30 g/L).
  • Any previous diagnosis of cirrhosis, either by liver biopsy (Metavir score F4) or elastography (Fibroscan >12 kPa). Elastography results with concomitant ALT >200 U/L are not considered.
  • Previous hepatocellular carcinoma (HCC).
  • Co-infections with HIV, hepatitis C or hepatitis D.
  • Other disease or medication that can interfere with the study (e.g. ongoing alcohol or illicit drug abuse, immunosuppressive medication, other active liver disease, or any other condition which in the opinion of the physician is incompatible with participation)

Treatment and study plan

Stop of therapy

Other

The active intervention is to stop antiviral therapy, and delay re-start in the high-threshold group.

Primary outcomes

  1. HBsAg loss

    Time frame: Within 3 years after stopping therapy

    Undetectable HBsAg measured by a standard assay

Secondary outcomes

  1. Time to HBsAg loss

    Time frame: Within 3 years after stopping therapy

    Time from randomization to undetectable HBsAg

  2. Time to re-start of antiviral therapy

    Time frame: Within 3 years after stopping therapy

    Time from randomization to re-start of therapy according to the specified criteria

  3. Severe unintended medical events

    Time frame: Within 3 years after stopping therapy

    Liver failure or other liver-related grade 4/5 SAEs

  4. Immune control

    Time frame: Within 3 years after stopping therapy

    Sustained off-therapy response viz HBV DNA <2000 IU/ml and ALT <40 U/L

  5. Changes in health-related quality of life

    Time frame: Within 3 years after stopping therapy

    Changes in the EuroQol standardized measure of health status (EQ-5D-5L) score. The summary index (from 0 to 1) as described by the manufacturer (euroqol.org) will be employed.

  6. Liver fibrosis evolution

    Time frame: Within 3 years after stopping therapy

    Changes in transient elastography from baseline

Sponsors and collaborators

Lead sponsor

Oslo University Hospital

Other

Collaborators

  • Addis Ababa University
  • Bodø Hospital, Norway
  • Bærum Hospital, Norway
  • Drammen Hospital, Norway
  • Helse Stavanger HF
  • Hvidovre University Hospital
  • Karolinska University Hospital
  • South-Eastern Norway Regional Health Authority
  • St. Paul's Hospital Millennium Medical College, Ethiopia
  • Tønsberg Hospital, Norway
  • University Hospital, Akershus
  • Ålesund Hospital, Norway

Registry information

Official study title

The Norwegian Nucleoside Analogue Stop Study: a Randomized Open-label Trial in HBeAg Negative Chronic Hepatitis B, Aiming at Achieving a Functional Cure.

Acronym: Nuc-Stop

Important dates

Study start
2018
Primary completion
2023
Study completion
2023
First posted
Sep 21, 2018
Registry last updated
Mar 20, 2023

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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