Clinical trial NCT03681132: The Norwegian Nucleoside Analogue Stop Study
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.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hepatitis B, Chronic
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: University Hospital, Akershus
name: Addis Ababa University
name: St. Paul's Hospital Millennium Medical College, Ethiopia
name: South-Eastern Norway Regional Health Authority, Norway
name: Bærum Hospital, Norway
name: Drammen Hospital, Norway
name: Tønsberg Hospital, Norway
name: Helse Stavanger HF
name: Ålesund Hospital, Norway
name: Bodø Hospital, Norway
name: Hvidovre University Hospital
name: Karolinska University Hospital
First posted: 2018-09-21
Enrollment: 127
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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


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)

Primary outcomes:
measure: HBsAg loss
timeFrame: Within 3 years after stopping therapy
Secondary outcomes:
measure: Time to HBsAg loss
timeFrame: Within 3 years after stopping therapy
measure: Time to re-start of antiviral therapy
timeFrame: Within 3 years after stopping therapy
measure: Severe unintended medical events
timeFrame: Within 3 years after stopping therapy
measure: Immune control
timeFrame: Within 3 years after stopping therapy
measure: Changes in health-related quality of life
timeFrame: Within 3 years after stopping therapy
measure: Liver fibrosis evolution
timeFrame: Within 3 years after stopping therapy
Other outcomes:
Locations:
city: København
country: Denmark
facility: Hvidovre Hospital
city: Addis Abeba
country: Ethiopia
facility: St Paul Hospital Millennium Medical College
city: Bodø
country: Norway
facility: Bodø Hospital
city: Drammen
country: Norway
facility: Drammen Hospital
city: Lørenskog
country: Norway
facility: Akershus University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Sandvika
country: Norway
facility: Bærum Hospital
city: Stavanger
country: Norway
facility: Stavanger University Hospital
city: Tønsberg
country: Norway
facility: Tønsberg Hospital
city: Ålesund
country: Norway
facility: Ålesund Hospital
city: Stockholm
country: Sweden
facility: Karonlinska University Hospital
Study officials:
References: