| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic Hepatitis B Infection |
| Chronische hepatitis B infectie. |
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| E.1.1.1 | Medical condition in easily understood language |
| Chronic Hepatitis B Infection. |
| Chronische hepatitis B besmetting. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
| MedDRA Classification |
| 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 |
We will conduct the first prospective open-label clinical trial powered to examine the contribution of ethnicity to off-treatment viral outcomes, by controlled treatment interruption in an equal number of Caucasian and non-Caucasian patients with start of treatment HBeAg negative chronic hepatitis B infection. The off-treatment responses of the Caucasian participants will be compared versus the non-Caucasian participants.
We hypothesize that compared to non-Caucasian patients, a substantially higher proportion of Caucasian patients who stop treatment will reach the primary study endpoint (i.e. off-treatment HBV DNA ≤2000 IU/mL and ALT ≤2xULN 72 weeks after treatment cessation).
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| E.2.2 | Secondary objectives of the trial |
This study has two secondary objectives: first we will compare the occurrence of HBsAg-loss at week 72 after treatment stop and the time for reaching HBsAg-loss between the Caucasian patients and the non-Caucasian patients of the stop group.
We hypothesize that compared to non-Caucasian patients a higher fraction of the Caucasian patients will reach the secondary endpoint (i.e. HBsAg-loss) and they will also do this more quickly.
Another secondary objective is to estimate the cost-effectiveness of treatment cessation and long-term projections, based on data acquired during the clinical trial and in control patients who continue treatment as part of routine clinical practise. The HRQoL and health care expenditures of the stop group participants will be compared versus the control group participants.
We hypothesize that treatment cessation will result in a reduction in health care expenditures and an increase in HRQoL. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Stop group:
• ≥ 18 year old and ≤ 75 year old
• Chronic hepatitis B, defined as HBsAg positive or HBV DNA positive ≥6 months
• Start of treatment HBeAg negative
• Under continuous NA treatment (Lamivudin, Adefovir, Tenofovir or Entecavir)
• HBV DNA below the local limit of quantification for at least 36 months at cessation or ≤2log IU/mL for at least 48 months at cessation
• ALT ≤2x Upper Limit Normal (ULN) on 2 sequential measurements at least 6 months apart (one of which is at screening)
Control Group:
• ≥ 18 year old and ≤ 75 year old
• Chronic hepatitis B, defined as HBsAg positive or HBV DNA positive ≥6 months
• Start of treatment HBeAg negative
• Under continuous NA treatment (Lamivudin, Adefovir, Tenofovir or Entecavir) for at least 1 year
• HBV DNA below the local limit of quantification for at least 6 months at inclusion
• ALT ≤2xULN on 2 sequential measurements at least 6 months apart (one of which is at screening) |
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| E.4 | Principal exclusion criteria |
Stop group:
• INR >1.3xULN (unless caused by anticoagulation therapy or vitamin K deficiency) at any point prior to or at the time of screening
• Total bilirubin >1.2xULN (unless there is documentation of a benign cause such as Gilbert’s disease) at any point prior to or at the time of screening
• Fibrosis ≥F3 at pre-treatment start biopsy and/or ever a Fibroscan result >9 kPa and/or ever a ShearWave elastography (SWE) > 8.15 kPa (unless a recent (<6 months old) liver biopsy shows Metavir fibrosis ≤F2).
• Active confection: hepatitis C virus (HCV) RNA positive, hepatitis delta virus (HDV) RNA positive, human immunodeficiency virus (HIV) antigen (Ag)-Antibody (Ab) positive
• Immunocompromised individuals, defined as (in line with the National Health Service (NHS) criteria)
o Patients undergoing any radiotherapy or chemotherapy <1 year before study start
o Solid organ transplant recipients
o Bone marrow or stem cell transplant recipients
o Patients having multiple myeloma or genetic disorders affecting the immune system
o Individuals receiving immunosuppressive or immunomodulating biological therapy <6 months before study start
o Patients receiving protein kinase inhibitors or poly(ADP-ribose) polymerase (PARP) inhibitors
o Individuals treated with steroid sparing agents such as cyclophosphamide and mycophenolate mofetil
o Individuals treated with or likely to be treated with systemic steroids for more than a month at a dose equivalent to prednisolone at 20 mg or more per day for adults
o Patients with a history of haematological malignancy, including leukaemia, lymphoma, and myeloma
o Patients with systemic Lupus erythematosus, rheumatoid arthritis, or psoriasis who may require long term immunosuppressive treatments
• Patients that have either an antecedent of or ongoing HCC
• Patients with a family history of HCC despite compliance to standard of care follow-up
• Pregnancy or lactation
• Planned or recent (<6 months before inclusion) participation in other therapeutic interventional trials
• Ever participation in HBV small interfering RNA (siRNA) studies
Control group:
• INR >1.3xULN (unless caused by anticoagulation therapy or vitamin K deficiency) at any point prior to or at the time of screening
• Total bilirubin >1.2xULN (unless there is documentation of a benign cause such as Gilbert’s disease) at any point prior to or at the time of screening
• Fibrosis =F4 at pre-treatment start biopsy and/or ever a Fibroscan result ≥11.4 kPa and/or ever a SWE ≥11.5 kPa (unless a recent (<6 months old) liver biopsy shows Metavir fibrosis <F4).
• Active confection: HCV RNA positive, HDV RNA positive, HIV Ag-Ab positive
• Immunocompromised individuals, defined as (in line with the NHS criteria)
o Patients undergoing any radiotherapy or chemotherapy <1 year before study start
o Solid organ transplant recipients
o Bone marrow or stem cell transplant recipients
o Patients having multiple myeloma or genetic disorders affecting the immune system
o Individuals receiving immunosuppressive or immunomodulating biological therapy <6 months before study start
o Patients receiving protein kinase or PARP
o Individuals treated with steroid sparing agents such as cyclophosphamide and mycophenolate mofetil
o Individuals treated with or likely to be treated with systemic steroids for more than a month at a dose equivalent to prednisolone at 20 mg or more per day for adults
o Patients with a history of haematological malignancy, including leukaemia, lymphoma, and myeloma
o Patients with systemic Lupus erythematosus, rheumatoid arthritis, or psoriasis who may requires long term immunosuppressive treatments
• Patients that have an antecedent of or ongoing HCC
• Pregnancy or lactation
• Ongoing or planned participation in a therapeutic interventional trial during the full course of the COIN-B study
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is the occurrence of viral control defined as HBV DNA ≤2000 IU/mL and ALT ≤2xULN 72 weeks after treatment cessation. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
72 weeks after treatment cessation.
HBV DNA and ALT levels will be followed up every 2 to 6 weeks during the clinical trial. |
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| E.5.2 | Secondary end point(s) |
| The secondary endpoint of this study is HBsAg loss at week 72 after treatment cessation. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
72 weeks after treatment cessation.
HBsAg status will be followed up every 2 to 6 weeks during the trial. |
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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 | No |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| In this prospective, multicentre clinical trial an equal number of Caucasian and non-Caucasian start of treatment HBeAg negative CHB patients under long-term (>3 years) NA-induced viral suppression will stop NA treatment in a well-controlled setting to investigate 1) the influence of ethnicity on off-treatment response, 2) the cost-effectiveness of NA-treatment stop and 3) a set of both host and viral markers for their applicability to early discriminate between responders and non-responders. |
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| 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 | No |
| 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 | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 21 |
| 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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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
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