| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HBeAg negative chronic HBV |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 | 10008910 |
| E.1.2 | Term | Chronic hepatitis B |
| E.1.2 | System Organ Class | 10021881 - Infections and infestations |
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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 |
| To determine the safety and optimal dose of three doses of a novel therapeutic vaccine (ISA104) consisting of 12 synthetic long peptides, as well as an adjuvant agent (Amplivant), in patients with chronic hepatitis B (cHBV), receiving standard of care maintenance anti-viral therapy. |
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives
- To assess the immunogenicity of ISA104 with the use of standardized assays
- To assess the efficacy of ISA104 with the use of conventional viral parameters.
Exploratory objectives
- To assess the immunogenicity of ISA104 with the use of additional non-standardized assays.
- To determine the quality and define specificity of vaccine-induced HBV-specific T-cells in cHBV patients.
- To study novel HBV disease markers in the study patient population to assist with treatment decisions, and/or therapy response monitoring in general.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Chronic HBV.
• Receiving treatment at the time of study entry and for greater than or equal to 12 months prior to study entry with HBV-active nucleos(t)ides, with tenofovir- or entecavir-containing therapy: tenofovir disoproxil fumarate (TDF), tenofovir alafenamide (TAF), or entecavir.
• Positive HBsAg for more than 6 months before screening.
• Negative for HBeAg for more than 6 months before screening.
• HBV DNA < limit of quantification (20 IU/ml; CAP-CTM Roche Cobas).
• Available serum ALT values (within 1x ULN) for 2 different time points 14 days apart during the six months before the first dose of study drug with at least one of the determinations obtained during the screening period.
• Available liver biopsy or fibroscan within 12 months before inclusion indicating F0-F1 fibrosis.
• Willing to comply with effective contraception during the study if subject is male or woman of child bearing potential, up to 12 months after the vaccine administration.
• Patients must be ≥ 18 and ≤ 65 years of age and must be able to give written informed consent.
• Body mass index (BMI) ≥ 18.0 and < 32.0 kg/m2.
• Ability to return to the hospital for adequate follow-up as required by this protocol.
• The ability to communicate well with the Investigator in the Dutch or English language.
• Written informed consent according to ICH-GCP.
• Willing to comply with the study restrictions.
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| E.4 | Principal exclusion criteria |
• Co-infection with HCV, HIV, HDV, HEV.
• Immune-compromised.
• History or evidence of chronic airway or cardiac disease.
• History of severe seizure disorder or current anticonvulsant use and clinically unstable disease.
• Unstable ongoing severe psychiatric disease, especially depression (stable patients can be included).
• Evidence of active or suspected cancer or history of malignancy with recurrence risk >20% within 5 years.
• Current chronic, acute, or recurrent bacterial, fungal, or viral infection that is – in the opinion of the treating MD- serious and requires systemic therapy (within 30 days prior to screening).
• Major organ transplantation.
• Previously received any systemic anti-viral, anti-neoplastic, immunosuppressive or immuno-modulatory treatment other than Tamiflu, acyclovir for herpetic lesions or NUC (including supraphysiologic doses of steroids or radiation) within 3 months prior to inclusion or the expectation that such treatment will be needed at any time during the study.
• History of HDV, HAV, HIV. Determined as positive within 12 months before start of study for anti-HDV, anti-HAV IgM, anti-HIV.
• Patients who are expected to need systemic antiviral therapy other than that provided by the study or Tamiflu at any time during their participation in the study. Exception: patients who have had a limited (<7 day) course of acyclovir for herpetic lesions more than 1 month prior to inclusion are not excluded.
• Evidence of liver cirrhosis (Child Pugh A-B-C).
• Serum total bilirubin > 2xULN at screening.
• History or evidence of bleeding from oesophageal varices or other conditions consistent with decompensated liver disease.
• History or evidence of a medical condition associated with chronic liver disease other than HBV (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver diseases including Wilson's disease and alfa1-antitrypsin deficiency, alcoholic liver disease, toxin exposures, thalassemia).
• Hepatic steatosis on ultrasound in the absence of conditions mentioned above and in absence of liver fibrosis (histology or fibroscan F0-F1) and with elevated serum ALT.
• Women with ongoing pregnancy or who are breast feeding.
• Neutrophil count <1.500 cells/mm3 or platelet count <80.000 cells/mm3 at screening.
• Hemoglobin <7.1 mmol/L (<11.5 g/dL) for females and <7.8 mmol/L (<12.5 g/dL) for men at screening.
• Serum creatinine level >1.5xULN at screening.
• Patients with alfa-fetoprotein >2xULN, unless stability (less than 10% increase) has been documented over at least the previous 3 months.
• Evidence of current hard drug(s) use and/or alcohol abuse (>20g/day for women and >30g/day for men)
• Other routine vaccination within 14 days before any treatment day or 14 days after the last treatment day, nor booster vaccination during treatment days.
• Participation in an investigational drug, vaccine or device study* within 3 months prior to screening or more than 4 times a year.*Excluding donation of body materials for biobanking or research only.
• Documented allergy to the vaccine or one of its components.
• History or evidence of severe illness or any other conditions which would make the patient, in the opinion of the investigator, unsuitable for the study.
• Clinically significant abnormalities, as judged by the investigator, in laboratory test results (including blood chemistry, haematology and urinalysis). In the case of uncertain or questionable results, tests performed during screening may be repeated before randomization to confirm eligibility or judged to be clinically irrelevant for healthy subjects.
• Evidence of any other active or chronic disease (hematologic, renal, hepatic, cardiovascular, neurologic, endocrinal, gastrointestinal, oncologic, pulmonary, immunologic, or psychiatric disorders) or condition that could interfere with, or for which the treatment might interfere with, the conduct of the study, or that would pose an unacceptable risk to the subject in the opinion of the investigator (following a detailed medical history, physical examination, vital signs (systolic and diastolic blood pressure, and body temperature)). Minor deviations from the normal range may be accepted, if judged by the Investigator to have no clinical relevance.
• Asplenia.
• Loss or donation of blood over 500 mL within 1 month to screening or intention to donate blood or blood products during the study.
• Positive drug test or abuse at screening.
• Has body art (e.g. tattoos) or abnormalities that could interfere with the observation of injection site reactions.
• History of bleeding disorder (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions), significant bleeding or bruising following intramuscular injections or vena punctures, or currently receiving anticoagulants.
• Any known factor, condition, or disease that might interfere with treatment compliance, study conduct or interpretation of the results.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is to assess the safety and tolerability of ISA104 in cHBV patients receiving standard care anti-viral maintenance therapy. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
HBV specific Immunogenicity- following ISA104 vaccination
Efficacy of ISA104 vaccination
To assess the immunogenicity of ISA104 with the use of additional non-standardized assays
To determine the quality and define specificity of vaccine-induced HBV-specific T-cells in cHBV patients
To study novel HBV disease markers in the study patient population to assist with treatment decisions and/or therapy response monitoring in general |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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) | Yes |
| E.7.1.1 | First administration to humans | Yes |
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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