E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
HBeAg negative chronic hepatitis B |
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E.1.1.1 | Medical condition in easily understood language |
HBeAg negative chronic hepatitis B |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052297 |
E.1.2 | Term | Hepatitis B e antigen negative |
E.1.2 | System Organ Class | 10022891 - Investigations |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Main objective:
To study whether stopping NA therapy – and delaying re-start - can trigger an immune response and set off a functional cure (i.e. HBsAg loss)
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E.2.2 | Secondary objectives of the trial |
Assess whether stopping NA therapy – and delaying re-start - leads to a longer time off treatment and shorter time to 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 effect of stopping NA therapy – and delaying start - on quality of life
-Assess the cost-effectiveness of stopping NA therapy – and delaying re-start
-Identify predictors of HBsAg loss
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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
- 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.
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E.4 | Principal 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 readings with concomitant ALT >200 U/L are not considered.
- Previous 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)
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E.5 End points |
E.5.1 | Primary end point(s) |
HBsAg loss within 3 years after stopping NA therapy |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
3 years after stopping NA therapy |
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E.5.2 | Secondary end point(s) |
- Time to HBsAg loss
-Time to restart of antiviral therapy
-Adverse events
-Changes in liver fibrosis measured by elastography
-Sustained off-therapy response viz HBV DNA <2000 IU/ml and ALT <40 U/L
-Changes in quality of life
-Cost-effectiveness
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Standard criteria for restart of therapy (different threshold values in the experimantal arm) |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |