E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Influenza virus infection |
Influenza virus infectie |
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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] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 16.1 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10022005 |
E.1.2 | Term | Influenza viral infections |
E.1.2 | System Organ Class | 100000004862 |
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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 effects of BCG-vaccination on the immune response induced by subsequent influenza vaccination in healthy volunteers. This will be determined by measuring the Th1/Th2 response, and antibody titers induced by influenza vaccination in seronegative healthy volunteers who are, prior to influenza vaccination, vaccinated with either BCG or placebo in a double-blind randomized manner. |
Om de effecten van BCG vaccinatie op de door influenza vaccinatie uitgelokte immuunrespons te bepalen bij gezonde vrijwilligers. Dit zal worden bepaald door de Th1/Th2 respons en antistof vorming te meten veroorzaakt door influenza vaccinatie bij gezonde vrijwilligers die van tevoren gevaccineerd zijn met BCG. |
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E.2.2 | Secondary objectives of the trial |
There are 6 secondary objectives:
1. To determine the effects of BCG-vaccination on ex vivo responsiveness of leukocytes to inactivated influenza virus before and after influenza vaccination.
2. To determine the effects of BCG-vaccination on ex vivo responsiveness of leukocytes to various not related inflammatory stimuli following influenza vaccination.
3. To determine the effects of BCG-vaccination on the phenotype of circulating leukocytes following influenza vaccination (e.g. expression pattern of cell-surface receptors by use of flow cytometry).
4. To determine the effects of BCG-vaccination on inflammatory transcriptional pathways (determined by qPCR/microarrays) following influenza vaccination.
5. To determine the effects of BCG-vaccination on epigenetic changes, including H3K4 trimethylation, in circulating immune cells following influenza vaccination.
6. To determine whether age influences the immune modulating effects of BCG-vaccination.
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Er zijn 6 secundaire doelen:
1. Om de effecten van BCG vaccinatie op de ex vivo producticapaciteit van witte bloedcellen te meten die gestimuleerd werden met geinactiveerd influenza virus, voor en na influenza vaccinatie.
2. Om de effecten van BCG vaccinatie op de ex vivo producticapaciteit van witte bloedcellen te meten die gestimuleerd werden met verschillende niet gerelateerde inflammatoire stimuli, na influenza vaccinatie.
3. Om de effecten van BCG vaccinatie op het fenotype van circulerende witte bloedcellen te meten na influenza vaccinatie.
4. Om de effecten van BCG vaccinatie op inflammatoire transcriptionele pathways (bepaald middels qPCR/microarrays) te meten na influenza vaccinatie.
5. Om de effecten van BCG vaccinatie op epigenetische veranderingen van circulerende immuuncellen te meten, inclusief trimethylatie, na influenza vaccinatie.
6. Om te bepalen of leeftijd de immune modulerende effecten van BCG beinvloed. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age ≥18 and ≤35 yrs or ≥65 yrs
- Male
- Healthy
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- Leeftijd ≥18 and ≤35 jaar of ≥65 jaar
- Mannelijk geslacht
- Gezond
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E.4 | Principal exclusion criteria |
- Prior exposure to ‘Influvac’ influenza virus strains , measured by antibody titres. Previous exposure is defined by antibody titres ≥1:40.
- History of influenza vaccination within the year prior to study entry
- History of BCG vaccination within 5 years prior to study entry
- History of Mantoux testing within the year prior to study entry
- Vaccination other than BCG or influenza, within 3 months prior to study or within study period
- Medical history of any disease associated with immune deficiency
- Clinically significant acute illness, including infections, within 4 weeks before vaccination
- Participation in a drug trial or donation of blood 3 months prior to study entry
- Use of recreational drugs within 21 days prior to experiment day
- Recent hospital admission or surgery with general anaesthesia (<3 months)
- Known chronic kidney or liver disease
- Latent or active tuberculosis infection
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- Eerdere blootstelling aan ‘batrevac’ influenza virus stammen, gemeten middels antistof titers. Blootstelling wordt gedefinieerd als antibodie titers van ≥1:40.
- Voorgeschiedenis van influenza vaccinatie in het jaar voorafgaand aan studie deelname
- Voorgeschiedenis van iBCG vaccinatie in de vijf jaar voorafgaand aan studie deelname
- Een Mantoux test in het jaar voorafgaand aan studie deelname
- Andere dan BCG of influenza vaccinatie in de drie maanden voorafgaand aan studie deelname
- Voorgeschiedenis van ziekte of huidig medicijn gebruik geaccosieerd met een verminderd functioneren van het immuunsysteem
- Klinisch belangrijke acute ziekte in de vier weken voorafgaand aan studie deelname
- Deelname aan een medicijnen studie of bloeddonatie in de drie maanden voorafgaande aan studie deelname
- gebruik van drugs in de drie weken voorafgaand aan studie deelname
- Recente hospitalisatie of operatie met algehele narcose (<3 maanden)
- Bekende chronische nier of leverziekten
- Latente of actieve tuberculose infectie |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary study endpoint is the difference in influenza antibody titres 2 and 4 weeks (±2 days) after influenza vaccination between BCG-vaccinated subjects and subjects in the control group. |
Het primaire eindpunt is het verschil in influenza antistof titers 2 en 4 weken (±2 dagen) na influenza vaccinatie, tussen de BCG-gevaccineerde proefpersonen en de proefpersonen in de controle groep. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
2 and 4 weeks (±2 days) after influenza vaccination |
2 en 4 weken (±2 dagen) |
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E.5.2 | Secondary end point(s) |
- Proportion of participants in each group who achieved seroprotection (defined by antibody titre ≥1:40), 1, 2, 3 and 4 weeks (±2 days) after influenza vaccination.
- Proportion of participants in each group who achieved seroconversion (defined by a ≥4-fold rise in antibody titre), 1, 2, 3 and 4 weeks ((±2 days) after influenza vaccination.
- IFN-gamma/IL-10 production (reflecting the Th1/Th2 immune response) of leukocytes ex vivo stimulated with inactivated influenza virus (0.1ug HA/ml), before BCG vaccination, before influenza vaccination, and 2 and 4 weeks after influenza vaccination.
- Production of Type 1 IFNs, IL-17 and IL-22 by leukocytes ex vivo stimulated with inactivated influenza virus (0.1ug HA/ml), before BCG vaccination, before influenza vaccination, and 2 and 4 weeks after influenza vaccination.
- Production of other inflammatory mediators (including TNFα, IL-1β, IFN-gamma, IL-10, IL-17, IL-22) by leukocytes ex vivo stimulated with m. tuberculosis (1ug/ml end protein concentration), s. aureus (1x10e6 microorganisms/ml), C. albicans (1x10e6 microorgansims/ml strain UC820), and inactivated influenza ( 0.1ug HA/ml) , before BCG vaccination, before influenza vaccination, and 2 and 4 weeks after influenza vaccination.
- The phenotype of circulating leukocytes (expression of surface markers, including, but not limited to CD45, CD3, CD4, CD8, CD56, CD14, CD11b, TLR4, TLR2), before BCG vaccination, before influenza vaccination, and 2 and 4 weeks after influenza vaccination.
- Inflammatory transcriptional pathways (by use of qPCR/microarrays) , before BCG vaccination, before influenza vaccination, and 2 and 4 weeks after influenza vaccination.
- Epigenetic changes in leukocytes, including H3K4 trimethylation, before BCG vaccination, before influenza vaccination, and 4 weeks after influenza vaccination.
- Subanalyses will include differences in all these parameters between young and older subjects.
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- Proportie deelnemers in elke groep die seroprotectie bereiken 1, 2, 3 en 4 weken na influenza vaccinatie.
- Proportie deelnemers in elke groep die seroconversie bereiken 1, 2, 3 en 4 weken na influenza vaccinatie.
- IFN-gamma/IL-10 productie van witte bloedcellen die ex vivo gestimuleerd werden met geinactiveerd influenza virus (0.1ug HA/ml), voor BCG vaccinatie, voor influenza vaccinatie, en 2 en 4 weken na influenza vaccinatie.
- Type 1 IFNs, IL-17 en IL-22 productie van witte bloedcellen die ex vivo gestimuleerd werden met geinactiveerd influenza virus (0.1ug HA/ml), voor BCG vaccinatie, voor influenza vaccinatie, en 2 en 4 weken na influenza vaccinatie.
- Productie van andere inflammatoire stimuli (inclusief TNFα, IL-1β, IFN-gamma, IL-10, IL-17, IL-22) door witte bloedcellen die ex vivo gestimuleerd werden met m. tuberculosis (1ug/ml), s. aureus (1x10e6 microorganismen/ml), C. albicans (1x10e6 microorgansimen/ml stam UC820), en geinactiveer influenza virus ( 0.1ug HA/ml), voor BCG vaccinatie, voor influenza vaccinatie, en 2 en 4 weken na influenza vaccinatie
- Het fenotype van circulerende witte bloedcellenvoor BCG vaccinatie, voor influenza vaccinatie, en 2 en 4 weken na influenza vaccinatie
- Inflammatoire transcriptionele transcriptional pathways (middels qPCR/microarrays), voor BCG vaccinatie, voor influenza vaccinatie, en 2 en 4 weken na influenza vaccinatie.
- Epigenetische veranderingen in witte bloedcellen voor BCG vaccinatie, voor influenza vaccinatie, en 2 en 4 weken na influenza vaccinatie.
- Subanalyses zullen worden gedaan tussen oudere en jongere proefpersonene op al deze parameters. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
before BCG vaccination, before influenza vaccination, and 2, 3 and 4 weeks after influenza vaccination.
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voor BCG vaccinatie, voor influenza vaccinatie, en 2 en 4 weken na influenza vaccinatie |
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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 | Yes |
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 | 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 | 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 | No |
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 | 1 |
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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LVLS |
Laatste visite van de laatste proefpersoon |
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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 | 0 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |