The Norwegian Nucleoside Analogue Stop Study

NCT03681132 | Completed Phase 4 DMC

• 1 other identifier: 2018/988
• Study Type: interventional
• Target: 127
• Locations: 4 countries
• Sites: 11

Brief Summary

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

Conditions

Hepatitis B, Chronic

Outcome Measures

Primary Outcomes (1)

• HBsAg loss

  Undetectable HBsAg measured by a standard assay

  Within 3 years after stopping therapy

Secondary Outcomes (6)

• Time to HBsAg loss

  Within 3 years after stopping therapy

• Time to re-start of antiviral therapy

  Within 3 years after stopping therapy

• Severe unintended medical events

  Within 3 years after stopping therapy

• Immune control

  Within 3 years after stopping therapy

• Changes in health-related quality of life

  Within 3 years after stopping therapy

Study Arms (2)

Low-threshold re-start

OTHER

Re-start antiviral therapy if HBV DNA viral load \>2000 IU/ml and ALT \>80 U/L.

Other: Stop of therapy

High-threshold re-start

OTHER

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

Interventions

Stop of therapy OTHER

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

High-threshold re-start; Low-threshold re-start

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

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

Study Sites (11)

Hvidovre Hospital

Copenhagen, Denmark

Location

St Paul Hospital Millennium Medical College

Addis Ababa, Ethiopia

Location

Ålesund Hospital

Ålesund, Norway

Location

Bodø Hospital

Bodø, Norway

Location

Drammen Hospital

Drammen, Norway

Location

Akershus University Hospital

Lørenskog, Norway

Location

Oslo University Hospital

Oslo, Norway

Location

Bærum Hospital

Sandvika, Norway

Location

Stavanger University Hospital

Stavanger, Norway

Location

Tønsberg Hospital

Tønsberg, Norway

Location

Karonlinska University Hospital

Stockholm, Sweden

Location

Related Publications (2)

• Johannessen A, Reikvam DH, Aleman S, Berhe N, Weis N, Desalegn H, Stenstad T, Heggelund L, Samuelsen E, Karlsen LN, Lindahl K, Pettersen FO, Iversen J, Kleppa E, Bollerup S, Winckelmann AA, Brugger-Synnes P, Simonsen HE, Svendsen J, Kran AB, Holmberg M, Olsen IC, Rueegg CS, Dalgard O. Clinical trial: An open-label, randomised trial of different re-start strategies after treatment withdrawal in HBeAg negative chronic hepatitis B. Aliment Pharmacol Ther. 2024 Aug;60(4):434-445. doi: 10.1111/apt.18147. Epub 2024 Jul 5.

  PMID: 38970293 DERIVED

• Holmberg M, Aass HCD, Dalgard O, Samuelsen E, Sun D, Bjorkstrom NK, Johannessen A, Reikvam DH. Treatment cessation in HBeAg-negative chronic hepatitis B: clinical response is associated with increase in specific proinflammatory cytokines. Sci Rep. 2023 Dec 18;13(1):22590. doi: 10.1038/s41598-023-50216-y.

  PMID: 38114718 DERIVED

MeSH Terms

Conditions

Hepatitis B, Chronic

Condition Hierarchy (Ancestors)

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

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Consultant/ researcher

Study Record Dates

• First Submitted: September 20, 2018
• First Posted: September 21, 2018
• Study Start: September 20, 2018
• Primary Completion: January 31, 2023
• Study Completion: January 31, 2023
• Last Updated: March 20, 2023

Record last verified: 2023-03

Locations

NO (8); SE (1); DK (1); ET (1)