Hepatitis B, ChronicPhase 4Nuc-StopNCT03681132
The Norwegian Nucleoside Analogue Stop Study
A Phase 4 study testing Stop of therapy in people with Hepatitis B, Chronic, run by Oslo University Hospital at 11 sites in 4 countries.
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. Read more about this study
- Who is it for?
- Ages 18 to 70 years
- Conditions the study is for
- Hepatitis B, Chronic
- What is being tested?
- Stop of therapy
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 127 participants
- Where
- 11 sitesin 4 countries
- Study dates
- 20 Sep 2018to 31 Jan 2023
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 70 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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)
Trial locations and contacts
11 sites in 4 countries.
11 sites in 4 countries
Norway8 sites
Ålesund Hospital
Ålesund
Bodø Hospital
Bodø
Drammen Hospital
Drammen
Akershus University Hospital
Lørenskog
Oslo University Hospital
Oslo
Bærum Hospital
Sandvika
Stavanger University Hospital
Stavanger
Tønsberg Hospital
Tønsberg
About this 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.
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.
Read more
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
- Being tested
- Stop of therapy
- Medical subject headings
- Hepatitis B, Chronic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Stop of therapyOther
The active intervention is to stop antiviral therapy, and delay re-start in the high-threshold group.
| Study group | Role | What they receive |
|---|---|---|
| Low-threshold re-start | Other | Re-start antiviral therapy if HBV DNA viral load >2000 IU/ml and ALT >80 U/L. Receives: 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. Receives: Other: Stop of therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
HBsAg loss
Undetectable HBsAg measured by a standard assay
Measured: Within 3 years after stopping therapy
Secondary outcomes (6)
Time to HBsAg loss
Time from randomization to undetectable HBsAg
Measured: Within 3 years after stopping therapy
Time to re-start of antiviral therapy
Time from randomization to re-start of therapy according to the specified criteria
Measured: Within 3 years after stopping therapy
Severe unintended medical events
Liver failure or other liver-related grade 4/5 SAEs
Measured: Within 3 years after stopping therapy
Immune control
Sustained off-therapy response viz HBV DNA <2000 IU/ml and ALT <40 U/L
Measured: Within 3 years after stopping therapy
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.
Measured: Within 3 years after stopping therapy
Liver fibrosis evolution
Changes in transient elastography from baseline
Measured: Within 3 years after stopping therapy
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted21 Sep 2018
- Study start20 Sep 2018
- Primary completion31 Jan 2023
- Study completion31 Jan 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Hepatitis B, ChronicStudies of the same condition, open and under way.
- More trials run by Oslo University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 127 participants (actual)
Sponsor and investigators
- Lead sponsor
- Oslo University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- University Hospital, Akershus, Addis Ababa University, St. Paul's Hospital Millennium Medical College, Ethiopia, South-Eastern Norway Regional Health Authority, Bærum Hospital, Norway, Drammen Hospital, Norway, Tønsberg Hospital, Norway, Helse Stavanger HF, Ålesund Hospital, Norway, Bodø Hospital, Norway, Hvidovre University Hospital, Karolinska University Hospital
- Responsible party
- Principal investigator, Asgeir Johannessen, Oslo University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03681132
- Sponsor's protocol ID
- 2018/988
- Acronym
- Nuc-Stop
- Status last verified
- Mar 2023
- First submitted
- 20 Sep 2018
- Last updated
- 20 Mar 2023
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Holmberg M, Niehrs A, Dalgard O, Berhe N, Desalegn H, Aleman S, Weis N, Stenstad T, Heggelund L, Samuelsen E, Karlsen LN, Lindahl K, Kleppa E, Winckelmann AA, Brugger-Synnes P, Simonsen HE, Svendsen J, Bjorkstrom NK, Reikvam DH, Johannessen A. Hepatic flares, their immune signatures, and ALT variability after nucleos(t)ide analogue cessation in HBeAg-negative hepatitis B. JHEP Rep. 2026 Jul;8(7):101875. doi: 10.1016/j.jhepr.2026.101875. Epub 2026 Apr 29.
PubMed 42067192Ghorbani M, Kvedaraite A, Al-Manei K, Too CB, Cederberg S, Johannessen A, Reikvam DH, Valentini D, Maucourant C, Bjorkstrom NK, Aleman S, Sallberg Chen M. Oral Microbiome Diversity Matters on Nucleos(t)ide Analogue Cessation in Chronic Hepatitis B. J Infect Dis. 2026 Mar 17;233(3):e630-e640. doi: 10.1093/infdis/jiaf591.
PubMed 41328917Johannessen 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.
PubMed 38970293Holmberg 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.
PubMed 38114718
Study at a glance
From the registry record, last updated by the sponsor on 20 Mar 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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.
- ClinicalTrials.gov ID
- NCT03681132
- Acronym / sponsor ID
- Nuc-Stop / 2018/988
- Conditions
- Hepatitis B, Chronic
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 127 participants (actual)
- Lead sponsor
- Oslo University HospitalUniversity, hospital or other
- Collaborators
- University Hospital, Akershus, Addis Ababa University, St. Paul's Hospital Millennium Medical College, Ethiopia, South-Eastern Norway Regional Health Authority, Bærum Hospital, Norway, Drammen Hospital, Norway, Tønsberg Hospital, Norway, Helse Stavanger HF, Ålesund Hospital, Norway, Bodø Hospital, Norway, Hvidovre University Hospital, Karolinska University Hospital
- Study start
- 20 Sep 2018 (actual)
- Primary completion
- 31 Jan 2023 (actual)
- Study completion
- 31 Jan 2023 (actual)
- First posted
- 21 Sep 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Low-threshold re-start | Other | Other: Stop of therapyRe-start antiviral therapy if HBV DNA viral load >2000 IU/ml and ALT >80 U/L. |
| High-threshold re-start | Other | Other: Stop of therapyRe-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. |
Who may qualify
- Ages
- 18 to 70 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
Key exclusion criteria (5 listed)
- 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)
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Stop of therapyThe active intervention is to stop antiviral therapy, and delay re-start in the high-threshold group. | Other | High-threshold re-start, Low-threshold re-start |
Primary outcome
HBsAg loss
Time frame: Within 3 years after stopping therapy
Undetectable HBsAg measured by a standard assay
6 secondary outcomes
Time to HBsAg loss
Time frame: Within 3 years after stopping therapy
Time to re-start of antiviral therapy
Time frame: Within 3 years after stopping therapy
Severe unintended medical events
Time frame: Within 3 years after stopping therapy
Immune control
Time frame: Within 3 years after stopping therapy
Changes in health-related quality of life
Time frame: Within 3 years after stopping therapy
Liver fibrosis evolution
Time frame: Within 3 years after stopping therapy
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 20 Mar 2023.
- Derived from this study: PubMed 42067192Holmberg M, Niehrs A, Dalgard O, Berhe N, Desalegn H, Aleman S, Weis N, Stenstad T, Heggelund L, Samuelsen E, Karlsen LN, Lindahl K, Kleppa E, Winckelmann AA, Brugger-Synnes P, Simonsen HE, Svendsen J, Bjorkstrom NK, Reikvam DH, Johannessen A. Hepatic flares, their immune signatures, and ALT variability after nucleos(t)ide analogue cessation in HBeAg-negative hepatitis B. JHEP Rep. 2026 Jul;8(7):101875. doi: 10.1016/j.jhepr.2026.101875. Epub 2026 Apr 29.
- Derived from this study: PubMed 41328917Ghorbani M, Kvedaraite A, Al-Manei K, Too CB, Cederberg S, Johannessen A, Reikvam DH, Valentini D, Maucourant C, Bjorkstrom NK, Aleman S, Sallberg Chen M. Oral Microbiome Diversity Matters on Nucleos(t)ide Analogue Cessation in Chronic Hepatitis B. J Infect Dis. 2026 Mar 17;233(3):e630-e640. doi: 10.1093/infdis/jiaf591.
- Derived from this study: PubMed 38970293Johannessen 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.
- Derived from this study: PubMed 38114718Holmberg 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
11 sites in 4 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Stop of therapy in people with Hepatitis B, Chronic, run by Oslo University Hospital at 11 sites in 4 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 20 Mar 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 11 sites in Norway, Denmark, Ethiopia, Sweden. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
HBsAg loss (time frame: Within 3 years after stopping therapy). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03681132, which also lists 4 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 20 Mar 2023.