E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Adult subjects who received a primary vaccination course with Twinrix Adult following a two-dose schedule or Twinrix Junior following a three-dose schedule as adolescents (12-15 years) approximately 11 to 15 years ago.
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E.1.1.1 | Medical condition in easily understood language |
Long-term follow-up antibody persistence and immune memory study |
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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 |
For the long-term follow-up phase:
To evaluate anti-HAV and anti-HBs antibody persistence at Years 11, 12, 13, 14 and 15 after the first vaccine dose of a two-dose Twinrix Adult or a three-dose Twinrix Junior primary vaccination course.
For the Challenge dose phase:
To evaluate the immune memory 15 years after primary vaccination with a two-dose Twinrix Adult versus a three-dose Twinrix Junior vaccination course in subjects who became seronegative for anti-HAV antibodies (less than 15 mIU/ml) or whose anti-HBs antibody concentrations decreased below 10 mIU/ml during the long-term follow-up period.
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E.2.2 | Secondary objectives of the trial |
For the long-term follow-up phase:
To retrospectively record all SAEs causally related to study procedures or to hepatitis A or B infection.
For the Challenge dose phase:
To evaluate the immune memory 15 years after primary vaccination with a two-dose Twinrix Adult versus a three-dose Twinrix Junior vaccination course in subjects who became seronegative for anti-HAV antibodies (less than 15 mIU/ml) or whose anti-HBs antibody concentrations decreased below 10 mIU/ml during the long-term follow-up period.
To evaluate the safety and reactogenicity of a challenge dose of Engerix-B and/or Havrix in terms of solicited, unsolicited symptoms and serious adverse events (SAE). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
All subjects must satisfy the following criteria at entry into each of the time-points of the long-term follow-up phase:
• Subjects who the investigator believes that they can and will comply with the requirements of the protocol should be enrolled in the study.
• A male or female who received the complete primary vaccination course according to his/her group allocation in the primary study HAB-084.
• Written informed consent obtained from the subject.
All subjects must satisfy the following criteria at entry into the challenge dose phase:
• A male or female who received the complete primary vaccination course according to his/her group allocation in the primary study HAB-084.
• Subjects who participated in the long-term follow-up phase of the HAB-084 study and for whom the antibody concentrations were below 15 mIU/ml for anti-HAV antibodies and/ or 10 mIU/ml for anti-HBs antibodies at the last available follow-up time-points.
• Subjects who the investigator believes that they can and will comply with the requirements of the protocol should be enrolled in the study.
• Written informed consent obtained from the subject.
• Healthy subjects as established by medical history and clinical examination before entering into the challenge dose phase of this study.
• If the subject is female, she must be of non-childbearing potential, i.e. either surgically sterilized; or, if of childbearing potential, she must be abstinent or have used adequate contraceptive precautions (i.e. intrauterine contraceptive device; oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream or foam; Norplant® or DepoProvera®) for 30 days prior to vaccination, have a negative pregnancy test and must agree to continue such precautions for two months after the vaccination.
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E.4 | Principal exclusion criteria |
The following criteria should be checked at each follow-up visit. If any apply at study entry, the subject must not be included at that long-term follow-up visit.
• Use of any investigational or non-registered product (drug or vaccine) since the last blood sampling visit.
• Administration of a hepatitis A, hepatitis B or hepatitis combination vaccine since the primary vaccination course of the study HAB-084.
• History of hepatitis A or hepatitis B infection.
• Administration of hepatitis A or hepatitis B immunoglobulins and/or any blood products within 3 months prior to blood sampling.
The following criteria should be checked before the challenge dose phase. If any apply, the subject must not be included in the challenge dose phase:
• Use of any investigational or non-registered product (drug or vaccine) within 30 days before the administration of the challenge dose or planned use during the study period outside the context of the study.
• Administration of a hepatitis A, hepatitis B or hepatitis combination vaccine between the primary vaccination course of the study HAB-084 and the challenge dose visit.
• History of hepatitis A or hepatitis B infection.
• Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the challenge dose. (For corticosteroids, this will mean prednisone, or equivalent, 0.5 mg/kg/day. Inhaled and topical steroids are allowed).
• Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination (no laboratory testing required).
• History of allergic disease or reactions likely to be exacerbated by any component of the vaccines.
• Acute disease at the time of enrolment (Acute disease is defined as the presence of a moderate or severe illness with or without fever. All vaccines can be administered to persons with a minor illness such as diarrhoea, mild upper respiratory infection with or without low-grade febrile illness, i.e. Oral temperature <37.5°C/ Axillary temperature <37.5°C).
• Administration of immunoglobulins and/or any blood products within the three months preceding the administration of the challenge dose or planned administration before the final blood sampling point (one month after the challenge dose).
• Pregnant or lactating female.
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E.5 End points |
E.5.1 | Primary end point(s) |
For the long-term follow-up phase (at Years 11, 12, 13, 14 and 15):
• Anti-HAV: percentage of seropositive subjects and GMCs calculated on seropositive subjects.
• Anti-HBs: percentage of seropositive subjects and subjects with anti-HBs concentrations ≥10 mIU/ml as well as GMCs calculated on seropositive subjects.
For the challenge dose phase
• Anti-HAV anamnestic response to the challenge dose (for challenge dose with HAV vaccine).
Anamnestic response is defined as the following:
Anti-HAV antibody concentrations ≥ 15 mIU/ml at one month post-challenge dose in subjects, seronegative at the pre-challenge time-points.
At least a 2-fold increase in anti-HAV antibody concentrations one month after the challenge dose, in subjects having anti-HAV antibody concentrations ≥ 100 mIU/ml at the pre-challenge time-points.
or at least a 4-fold increase in anti-HAV antibody concentrations one month after the challenge dose, in seropositive subjects having anti-HAV antibody concentrations < 100 mIU/ml at the pre-challenge time-points.
• Anti-HBs anamnestic response to the challenge dose (for challenge dose with HBs vaccine).
Anamnestic response is defined as the following:
Anti-HBs antibody concentrations ≥ 10 mIU/ml at one month post-challenge dose in subjects seronegative at the pre-challenge time-points.
At least a 4-fold increase in anti-HBs antibody concentrations, at one month post-challenge dose in subjects seropositive at the pre-challenge time-points.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
at Years 11, 12, 13, 14 and 15 |
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E.5.2 | Secondary end point(s) |
For the long-term follow-up phase
• Occurrence of SAEs and/ or hepatitis A or B infection since the last long-term follow-up visit.
For the challenge dose phase
• Immunogenicity
Percentage of subjects with anti-HAV antibody concentrations 15 mIU/ml and GMCs calculated on seropositive subjects, before and one month after the challenge dose.
Percentage of subjects with anti-HBs antibody concentrations 3.3 mIU/ml, 10 mIU/ml, 100 mIU/ml and anti-HBs GMCs calculated on seropositive subjects, before and one month after the challenge dose.
• Reactogenicity
Occurrence and intensity of solicited local symptoms in the 4-day (Day 0 to
Day 3) follow-up period after the challenge dose.
Occurrence and intensity of solicited general symptoms in the 4-day (Day 0 to Day 3) follow-up period after the challenge dose.
• Safety
Occurrence, intensity and relationship to vaccination of unsolicited symptoms reported during the 31-day (Day 0 to 30) follow-up period after the challenge dose.
Occurrence, intensity and relationship to vaccination of all SAEs following the administration of the challenge dose. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For the long-term follow-up phase
• Occurrence of SAEs and/ or hepatitis A or B infection since the last long-term follow-up visit.
For the challenge dose phase
• Immunogenicity (before and one month after the challenge dose).
• Reactogenicity (Day 0 to Day 3).
• Safety (Day 0 to 30). |
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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 | Yes |
E.6.3 | Therapy | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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) | 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 | No |
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 | 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 | No |
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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 2 |
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 | Information not present in EudraCT |
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 | 6 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |