The Norwegian Nucleoside Analogue Stop Study (Nuc-Stop)

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

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

Study Overview

• Status: Completed
• Conditions: Hepatitis B, Chronic
• Intervention / Treatment: Other: Stop of therapy

• Study Type: Interventional
• Enrollment (Actual): 127
• Phase: Phase 4

Contacts and Locations

Study Locations

• Denmark
  • København, Denmark
    • Hvidovre Hospital
• Ethiopia
  • Addis Abeba, Ethiopia
    • St Paul Hospital Millennium Medical College
• Norway
  • Bodø, Norway
    • Bodø Hospital
  • Drammen, Norway
    • Drammen Hospital
  • Lørenskog, Norway
    • Akershus University Hospital
  • Oslo, Norway
    • Oslo University Hospital
  • Sandvika, Norway
    • Bærum Hospital
  • Stavanger, Norway
    • Stavanger University Hospital
  • Tønsberg, Norway
    • Tønsberg Hospital
  • Ålesund, Norway
    • Alesund Hospital
• Sweden
  • Stockholm, Sweden
    • Karonlinska University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Low-threshold re-start; Re-start antiviral therapy if HBV DNA viral load >2000 IU/ml and ALT >80 U/L.	Other: Stop of therapy; The active intervention is to stop antiviral therapy, and delay re-start in the high-threshold group.
Other: High-threshold re-start; Re-start antiviral therapy if: ALT >100 U/L persisting for more than 4 months without any spontaneous decline toward normal; OR; ALT >400 U/L persisting for more than 2 months in consecutive assays.	Other: Stop of therapy; The active intervention is to stop antiviral therapy, and delay re-start in the high-threshold group.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HBsAg loss	Undetectable HBsAg measured by a standard assay	Within 3 years after stopping therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to HBsAg loss	Time from randomization to undetectable HBsAg	Within 3 years after stopping therapy
Time to re-start of antiviral therapy	Time from randomization to re-start of therapy according to the specified criteria	Within 3 years after stopping therapy
Severe unintended medical events	Liver failure or other liver-related grade 4/5 SAEs	Within 3 years after stopping therapy
Immune control	Sustained off-therapy response viz HBV DNA <2000 IU/ml and ALT <40 U/L	Within 3 years after stopping therapy
Changes in health-related quality of life	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.	Within 3 years after stopping therapy
Liver fibrosis evolution	Changes in transient elastography from baseline	Within 3 years after stopping therapy

Collaborators and Investigators

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

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2018
• Primary Completion (Actual): January 31, 2023
• Study Completion (Actual): January 31, 2023

Study Registration Dates

• First Submitted: September 20, 2018
• First Submitted That Met QC Criteria: September 20, 2018
• First Posted (Actual): September 21, 2018

Study Record Updates

• Last Update Posted (Actual): March 20, 2023
• Last Update Submitted That Met QC Criteria: March 17, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Liver Diseases; Hepatitis, Viral, Human; Hepadnaviridae Infections; DNA Virus Infections; Hepatitis, Chronic; Hepatitis B; Hepatitis; Hepatitis B, Chronic
• Other Study ID Numbers: 2018/988

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No