E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hepatitis B viral infection |
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E.1.1.1 | Medical condition in easily understood language |
Hepatitis B viral infection |
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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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10008910 |
E.1.2 | Term | Chronic hepatitis B |
E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
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 |
The primary objective is to determine the rate of HBsAg loss three years after cessation of treatment with nucleos(t)ide analogues in patients with HBeAg-negative chronic HBV infection ie the amount of patients who have elimiated the virus. The rate of HBsAg loss will be compared in patients with simple treatment discontinuation against patients who are given a short course of interferon after nucleos(t)ide withdrawal. |
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E.2.2 | Secondary objectives of the trial |
1. To explore the safety of nucleoside withdrawal 2. To explore whether using interferon therapy in conjunction with treatment cessation is safe 3. To compare the number of patients in each treatment arm who become inactive HBV carriers. 4. Identification of virological and immunological biomarkers which predict a group of patients in which the loss of HBsAg is feasible 5. Correlate changes in HBsAg quantification and/or HBsAg status with innate and adaptive immune responses to HBV 6. To identify changes in immunological responses to HBV which occur after treatment withdrawal and after sequential NUC/IFN treatment |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age ≥ 18 • Chronic HBV infection • HBeAg negative • Nucleos(t)ide analogues treatment for ≥3 years • HBV DNA < 400 IU/ml ≥2 years • Informed consent |
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E.4 | Principal exclusion criteria |
• Cirrhosis at any time • HBeAg to anti-HBe seroconversion within the last 3 years • Interferon use in the last 3 years • Contraindications to interferon use • Participation in HBV-specific therapeutic vaccine studies within 12 months • HCV, HDV or HIV co-infection • Immunosuppressant use • Clinically significant comorbidities that, in the opinion of the investigator, render the patient unsuitable. |
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E.5 End points |
E.5.1 | Primary end point(s) |
HBsAg loss 3 years after randomisation
The primary endpoint will be the proportion of patients who lose HBsAg in each treatment arm 3 years after randomisation. Qualitative assays of HBsAg will be conducted on patients every 6 months using standard laboratory ELISA assays. Loss of HBsAg will be confirmed by repeating the test at least one month after the initial negative result. Patients in whom both tests are negative will be deemed to have lost HBsAg. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
3 years after randomisation |
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E.5.2 | Secondary end point(s) |
Efficacy endpoints • The proportion of patients who achieve HBsAg loss who also have undetectable HBV DNA • The proportion of patients in each group who become inactive HBV carriers; ie achieve a sustained virological response (HBV DNA < 2000 IU/ml & normal ALT values) at 3 years after randomisation • Magnitude of reduction in quantitative HBsAg levels at 1, 6, 12, 24 & 36 months after randomisation • Magnitude of changes in antiviral T cells response at 1, 5, 6, 12, 24 & 36 months after randomisation • Magnitude of changes in NK cells response at 1, 5, 6, 12, 24 & 36 months after randomisation Safety endpoints • Proportion of patients in each group with exaggerated hepatitis flares • Proportion of patients resuming nucleos(t)ide analogue therapy • Adherence to pegylated interferon therapy
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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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
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 |
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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 | 10 |
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 | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
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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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 | 5 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 30 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 30 |