The Norwegian Nucleoside Analogue Stop Study

NCT ID: NCT03681132

Last Updated: 2023-03-20

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 127 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-09-20
• Study Completion Date: 2023-01-31

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Low-threshold re-start

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

Group Type: OTHER

Stop of therapy

Intervention Type: OTHER

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

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.

Group Type: OTHER

Stop of therapy

Intervention Type: OTHER

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

Interventions

Stop of therapy

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

Intervention Type: OTHER

Eligibility Criteria

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)

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Akershus

OTHER

Sponsor Role: collaborator

Addis Ababa University

OTHER

Sponsor Role: collaborator

St. Paul's Hospital Millennium Medical College, Ethiopia

OTHER

Sponsor Role: collaborator

South-Eastern Norway Regional Health Authority, Norway

UNKNOWN

Sponsor Role: collaborator

Bærum Hospital, Norway

UNKNOWN

Sponsor Role: collaborator

Drammen Hospital, Norway

UNKNOWN

Sponsor Role: collaborator

Tønsberg Hospital, Norway

UNKNOWN

Sponsor Role: collaborator

Helse Stavanger HF

OTHER_GOV

Sponsor Role: collaborator

Ålesund Hospital, Norway

UNKNOWN

Sponsor Role: collaborator

Bodø Hospital, Norway

UNKNOWN

Sponsor Role: collaborator

Hvidovre University Hospital

OTHER

Sponsor Role: collaborator

Karolinska University Hospital

OTHER

Sponsor Role: collaborator

Oslo University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Asgeir Johannessen

Consultant/ researcher

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Hvidovre Hospital

Copenhagen, , Denmark

St Paul Hospital Millennium Medical College

Addis Ababa, , Ethiopia

Ålesund Hospital

Ålesund, , Norway

Bodø Hospital

Bodø, , Norway

Drammen Hospital

Drammen, , Norway

Akershus University Hospital

Lørenskog, , Norway

Oslo University Hospital

Oslo, , Norway

Bærum Hospital

Sandvika, , Norway

Stavanger University Hospital

Stavanger, , Norway

Tønsberg Hospital

Tønsberg, , Norway

Karonlinska University Hospital

Stockholm, , Sweden

Countries

Denmark; Ethiopia; Norway; Sweden

References

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.

Reference Type: DERIVED

PMID: 38114718 (View on PubMed)

Other Identifiers

2018/988

Identifier Type: -

Identifier Source: org_study_id