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Halting Nucleoside Analogues in Chronic Hepatitis B (HALT-NUCS)

Primary Purpose

Chronic Hepatitis B

Status

Unknown status

Phase

Not Applicable

Locations

Singapore

Study Type

Interventional

Intervention

stopping nucleos(t)ide therapy

Continue nucleos(t)ide analogue

About this trial

This is an interventional treatment trial for Chronic Hepatitis B focused on measuring chronic hepatitis B, nucleoside analogues, stopping, discontinuing

Eligibility Criteria

21 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

• Between 21 and 75 years old.
- Documented to be HBsAg positive for ≥ 6 months.
- On any NA (lamivudine, adefovir, entecavir, telbivudine tenofovir) for ≥ 1 year
- HBV DNA <15 IU/ml at screening (undetectable)
- Quantitative HBsAg <100 IU/ml
- Patient has agreed not to take any other investigational drug or systemic anti-viral, cytotoxic, corticosteroid, immunomodulatory agents or Chinese traditional remedies unless clinically indicated.
- Patient is able to give written consent prior to study start and to comply with the study requirements.
- Women of childbearing age must have a negative serum (ß-HCG) pregnancy test taken with 14 days of starting therapy

Exclusion Criteria:

• Evidence of liver cirrhosis based on liver biopsy, fibroscan score >10.5 kpa, or MRE score>5.5kpa, or clinical evidence of cirrhosis demonstrated by presence of esophageal varices, obvious features of cirrhosis on ultrasound within the last 12 months
- Evidence of decompensated liver disease or hepatocellular carcinoma.
- HIV antibody or HCV antibody or HDV antibody positivity
- Creatinine > 1.5 times upper limit of normal
- INR > 1.5, uncorrected by Vitamin K therapy.
- Any interferon, Immunomodulators, systemic cytotoxic agents, or systemic corticosteroids within 6 months before trial entry.
- Prolonged exposure to known hepatotoxins such as alcohol or drugs.
- History of clinically relevant psychiatric disease, seizures, central nervous system dysfunction, severe pre-existing cardiac, renal, hematological disease or medical illness that in the investigator's opinion might interfere with therapy.
- Malignant disease within 5 years of trial entry.
- Women who are pregnant and who are not practicing adequate birth control measures, or who are lactating

Sites / Locations

National University HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Continue nucleos(t)ide analogue

Stopping nucleos(t)ide analogue

Arm Description

patients will be given open label tenofovir alafenamide

patients will stop nucleos(t)ide therapy (such as entecavir, tenofovir, lamivudine or adefovir)

Outcomes

Primary Outcome Measures

HBsAg loss

Absence of HBsAg by ELISA

Secondary Outcome Measures

Hepatitis B flare

increase in ALT associated with increase in HBV DNA

virological relapse

increase in HBV DNA without increase in ALT

Restarting antiviral therapy

Those who have to start therapy based on clinical indications after stopping therapy

Full Information

NCT ID

NCT04102176

First Posted

May 27, 2019

Last Updated

September 24, 2019

Sponsor

Seng Gee Lim

Collaborators

Tan Tock Seng Hospital, Singapore General Hospital, Changi General Hospital

1. Study Identification

Unique Protocol Identification Number

NCT04102176

Brief Title

Halting Nucleoside Analogues in Chronic Hepatitis B

Acronym

HALT-NUCS

Official Title

HALT NUCs: Halting Nucleoside Analogue Therapy in Chronic Hepatitis B

Study Type

Interventional

2. Study Status

Record Verification Date

September 2019

Overall Recruitment Status

Unknown status

Study Start Date

January 29, 2019 (Actual)

Primary Completion Date

March 2021 (Anticipated)

Study Completion Date

March 30, 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Seng Gee Lim

Collaborators

Tan Tock Seng Hospital, Singapore General Hospital, Changi General Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Most patients with Chronic Hepatitis B are on nucleoside analogy (NA) long term, but this leads to HBsAg loss (defined as functional cure) of only 2% at 6 years. Recently a number of studies have shown significant HBsAg loss rates after stopping nucleoside analogues (NA). However, no criteria to select such patients have been evaluated. Consequently, the objective of the study is not only to determine the proportion of patients able to achieve HBsAg loss in those with qHBsAg≤100IU/ml. The study is designed as a randomised control trial with 1:2 parallel arm randomisation to continuing NA or stopping therapy. Patients will be monitored after stopping therapy for Hepatitis B flares and also to document HBsAg loss.

Detailed Description

Chronic Hepatitis B (CHB) affects over 250 million persons and is considered one of the major causes of mortality and morbidity globally. Standard treatment consists of nucleos(t)ide analogues (NA) or peginterferon (PEG). There has been increasing interested in HBsAg loss, defined as functional cure. However this has been difficult to achieve with NA, and although rates of HBsAg loss are higher with PEG, they are still <10%. However, a number of studies have shown that HBsAg loss rates were significantly higher in those who stopped NA. A study from Greece by Hadziyannis had a 39% HBsAg loss after patients stopped adefovir therapy. Further studies have shown similar results, and those not able to clear HBsAg have had quiescent disease, although some patients had to restart therapy usually due to hepatitis B flares. No deaths have been reported. Consequently, while stopping therapy has led to HBsAg loss in some patients, it is not clear which patients would benefit the most. The prior studies have indicated that patients most likely to lose HBsAg had low qHBsAg levels and a level ≤100 IU/ml had a high possibility of HBsAg loss. Consequently, we propose to test whether patients with CHB on NA >1year and without liver cirrhosis and with qHBsAg≤100 IU/ml are able to lose HBsAg compared to those who continue NA. The study is designed as a parallel arm RCT randomised 1:2 to continue NA versus stop NA. Patients will be monitored regularly for clinical status, virological markers, and liver markers. The primary endpoint is HBsAg loss at the end of the study in those who stop versus those who continue NA. Additional outcomes will be hepatitis B flares, inactive hepatitis B status, virological relapse, and restarting therapy.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Hepatitis B

Keywords

chronic hepatitis B, nucleoside analogues, stopping, discontinuing

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Model Description

Parallel arm study randomised 1:2

Masking

None (Open Label)

Allocation

Randomized

Enrollment

150 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Continue nucleos(t)ide analogue

Arm Type

Active Comparator

Arm Description

patients will be given open label tenofovir alafenamide

Arm Title

Stopping nucleos(t)ide analogue

Arm Type

Experimental

Arm Description

patients will stop nucleos(t)ide therapy (such as entecavir, tenofovir, lamivudine or adefovir)

Intervention Type

Other

Intervention Name(s)

stopping nucleos(t)ide therapy

Intervention Description

patients taking nucleoside(t)ide therapy will stop treatment

Intervention Type

Other

Intervention Name(s)

Continue nucleos(t)ide analogue

Intervention Description

Continue nucleos(t)ide analogue

Primary Outcome Measure Information:

Title

HBsAg loss

Description

Absence of HBsAg by ELISA

Time Frame

Through year 3

Secondary Outcome Measure Information:

Title

Hepatitis B flare

Description

increase in ALT associated with increase in HBV DNA

Time Frame

Through year 3

Title

virological relapse

Description

increase in HBV DNA without increase in ALT

Time Frame

Through year 3

Title

Restarting antiviral therapy

Description

Those who have to start therapy based on clinical indications after stopping therapy

Time Frame

Through year 3

10. Eligibility

Sex

All

Minimum Age & Unit of Time

21 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: • Between 21 and 75 years old. Documented to be HBsAg positive for ≥ 6 months. On any NA (lamivudine, adefovir, entecavir, telbivudine tenofovir) for ≥ 1 year HBV DNA <15 IU/ml at screening (undetectable) Quantitative HBsAg <100 IU/ml Patient has agreed not to take any other investigational drug or systemic anti-viral, cytotoxic, corticosteroid, immunomodulatory agents or Chinese traditional remedies unless clinically indicated. Patient is able to give written consent prior to study start and to comply with the study requirements. Women of childbearing age must have a negative serum (ß-HCG) pregnancy test taken with 14 days of starting therapy Exclusion Criteria: • Evidence of liver cirrhosis based on liver biopsy, fibroscan score >10.5 kpa, or MRE score>5.5kpa, or clinical evidence of cirrhosis demonstrated by presence of esophageal varices, obvious features of cirrhosis on ultrasound within the last 12 months Evidence of decompensated liver disease or hepatocellular carcinoma. HIV antibody or HCV antibody or HDV antibody positivity Creatinine > 1.5 times upper limit of normal INR > 1.5, uncorrected by Vitamin K therapy. Any interferon, Immunomodulators, systemic cytotoxic agents, or systemic corticosteroids within 6 months before trial entry. Prolonged exposure to known hepatotoxins such as alcohol or drugs. History of clinically relevant psychiatric disease, seizures, central nervous system dysfunction, severe pre-existing cardiac, renal, hematological disease or medical illness that in the investigator's opinion might interfere with therapy. Malignant disease within 5 years of trial entry. Women who are pregnant and who are not practicing adequate birth control measures, or who are lactating

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Chris Lee, BSc

Phone

(65)67726123

mdclywc@nus.edu.sg

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Seng Gee Lim, MBBS MD

Organizational Affiliation

National University Health System

Official's Role

Principal Investigator

Facility Information:

Facility Name

National University Hospital

City

Singapore

ZIP/Postal Code

119228

Country

Singapore

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Chris Lee, BSc

Phone

67726123

mdclywc@nus.edu.sg

12. IPD Sharing Statement

Plan to Share IPD

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Halting Nucleoside Analogues in Chronic Hepatitis B

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