The Norwegian Nucleoside Analogue Stop Study (Nuc-Stop)

• ClinicalTrials.gov Identifier: NCT03681132
• Recruitment Status: Active, not recruiting
• First Posted: September 21, 2018
• Last Update Posted: September 14, 2021
• Sponsor: Oslo University Hospital
• Collaborators: Akershus University Hospital, Norway; Addis Ababa University; St. Paul's Hospital Millennium Medical College, Ethiopia; 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; Hvidovre University Hospital; Karolinska University Hospital
• Information provided by (Responsible Party): Asgeir Johannessen, Oslo University Hospital

Study Description

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

Condition or disease	Intervention/treatment	Phase
Hepatitis B, Chronic	Other: Stop of therapy	Phase 4

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 120 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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.
• Actual Study Start Date: September 20, 2018
• Estimated Primary Completion Date: January 31, 2023
• Estimated Study Completion Date: January 31, 2023

Arms and Interventions

Arm	Intervention/treatment
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.
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.

Outcome Measures

Primary Outcome Measures :

1. HBsAg loss [ Time Frame: Within 3 years after stopping therapy ]
   Undetectable HBsAg measured by a standard assay

Secondary Outcome Measures :

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

Eligibility Criteria

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

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)

Contacts and Locations

Locations

Denmark

Hvidovre Hospital

København, Denmark

Ethiopia

St Paul Hospital Millennium Medical College

Addis Abeba, Ethiopia

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

Ålesund Hospital

Ålesund, Norway

Sweden

Karonlinska University Hospital

Stockholm, Sweden

Sponsors and Collaborators

Oslo University Hospital

Akershus University Hospital, Norway

Addis Ababa University

St. Paul's Hospital Millennium Medical College, Ethiopia

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

Hvidovre University Hospital

Karolinska University Hospital

More Information

• Responsible Party: Asgeir Johannessen, Consultant/ researcher, Oslo University Hospital
• ClinicalTrials.gov Identifier: NCT03681132
• Other Study ID Numbers: 2018/988
• First Posted: September 21, 2018
• Last Update Posted: September 14, 2021
• Last Verified: September 2021

• 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

Additional relevant MeSH terms:

Hepatitis B; Hepatitis B, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Hepadnaviridae Infections; DNA Virus Infections; Hepatitis, Chronic