The Norwegian Nucleoside Analogue Stop Study

Hepatitis B, Chronic Clinical Trial

— Nuc-Stop  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03681132
• Other study ID #: 2018/988
• Status: Completed
• Phase: Phase 4
• Start date: September 20, 2018
• Est. completion date: January 31, 2023

Study information

• Verified date: March 2023
• Source: Oslo University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 127
• Est. completion date: January 31, 2023
• Est. primary completion date: January 31, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

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)

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis B
• Hepatitis B, Chronic

Intervention

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

Locations

Country	Name	City	State
Denmark	Hvidovre Hospital	København
Ethiopia	St Paul Hospital Millennium Medical College	Addis Abeba
Norway	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
Sweden	Karonlinska University Hospital	Stockholm

Sponsors (13)

Lead Sponsor

Collaborator

Oslo University Hospital

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

Countries where clinical trial is conducted

Denmark,  Ethiopia,  Norway,  Sweden, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HBsAg loss	Undetectable HBsAg measured by a standard assay	Within 3 years after stopping therapy
Secondary	Time to HBsAg loss	Time from randomization to undetectable HBsAg	Within 3 years after stopping therapy
Secondary	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
Secondary	Severe unintended medical events	Liver failure or other liver-related grade 4/5 SAEs	Within 3 years after stopping therapy
Secondary	Immune control	Sustained off-therapy response viz HBV DNA <2000 IU/ml and ALT <40 U/L	Within 3 years after stopping therapy
Secondary	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
Secondary	Liver fibrosis evolution	Changes in transient elastography from baseline	Within 3 years after stopping therapy