E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
sepsis induced immunoparalysis |
sepsis geinduceerde immuunparalyse |
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E.1.1.1 | Medical condition in easily understood language |
subjects with impaired immune functions due to bacterial bloodstream infections |
personen met een verminderde afweer door bloedvergiftiging |
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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 | 16.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10040047 |
E.1.2 | Term | Sepsis |
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 |
1. Single endotoxemia
To determine the effects of γ-irradiated BCG-vaccination on the in vivo innate immune responses induced by human endotoxemia. This will be determined by measuring plasma levels of various pro- and anti-inflammatory cytokines and assessing the difference in the Lipopolysacharide (LPS)-induced cytokine response between γ-irradiated BCG-vaccined subjects and placebo-treated control subjects.
2. Repeated endotoxemia
To determine the effects of γ-irradiated BCG-vaccination on endotoxin tolerance induced by human endotoxemia. This will be determined by measuring plasma levels of various pro- and anti-inflammatory cytokines and assessing the difference in the LPS-induced cytokine response following the first and second endotoxemia, between γ-irradiated BCG-vaccined and placebo-treated control subjects.
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1. eenmalige LPS toediening
Om de effecten van γ-bestraalde BCG-vaccinatie te bepalen op de immuunrespons na LPS toediening in vivo bij gezonde vrijwilligers.
2. herhaalde LPS toediening
Om de effecten van-γ bestraald BCG-vaccinatie op endotoxine tolerantie veroorzaakt door menselijke endotoxinemie te bepalen. |
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E.2.2 | Secondary objectives of the trial |
1. To determine the effects of γ-irradiated BCG-vaccination on ex vivo responsiveness of leukocytes to various inflammatory stimuli.
2. To determine the effects of γ-irradiated BCG-vaccination on the phenotype of circulating monocytes (e.g. expression pattern of cell-surface receptors by use of flow cytometry).
3. To determine the effects of γ-irradiated BCG-vaccination on inflammatory transcriptional pathways (by use of qPCR/microarrays).
4. To determine the effects of γ-irradiated BCG-vaccination on epigenetic changes, including H3K4 trimethylation, in circulating immune cells.
5. To determine the effects of γ-irradiated BCG-vaccination on LPS-induced clinical symptoms (illness score) and hemodynamic/temperature changes.
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1. Om de effecten van γ-bestraalde BCG-vaccinatie op de ex vivo respons van leukocyten te bepalen op verschillende inflammatoire stimuli.
2. Om de effecten van γ-bestraalde BCG-vaccinatie op het fenotype van circulerende monocyten (bijv. expressiepatroon van celoppervlakte receptoren door gebruik van flowcytometrie) te bepalen.
3. Om de effecten van γ-bestraalde BCG-vaccinatie op de inflammatoire cascade (met behulp van qPCR / microarrays) te bepalen.
4. Om de effecten van γ-bestraalde BCG-vaccinatie op epigenetische veranderingen, waaronder H3K4 trimethylatie, van circulerende immuuncellen te bepalen
5. Om de effecten van-γ bestraald BCG-vaccinatie op LPS-geïnduceerde klinische symptomen (ziekte score) en hemodynamische / temperatuurveranderingen te bepalen. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Written informed consent
- Age ≥18 and ≤35 yrs
- Male
- Healthy
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- Schriftelijk informed consent
- Leeftijd ≥ 18 en ≤ 35 jaar
- Man
- Gezond |
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E.4 | Principal exclusion criteria |
- Use of any medication
- History of BCG-vaccination
- Vaccination other than BCG, within 3 months prior to study or within study period
- Smoking
- Previous spontaneous vagal collapse
- History of atrial or ventricular arrhythmia
- (Family) history of myocardial infarction or stroke under the age of 65 years
- Cardiac conduction abnormalities on the ECG consisting of a 2nd degree atrioventricular block or a complex bundle branch block
- Hypertension (defined as RR systolic > 160 or RR diastolic > 90)
- Hypotension (defined as RR systolic < 100 or RR diastolic < 50)
- Renal impairment (defined as plasma creatinin >120 μmol/l)
- Liver enzyme abnormalities or positive hepatitis serology
- Medical history of any disease associated with immune deficiency
- CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 4 weeks before endotoxin administration
- Participation in a drug trial or donation of blood 3 months prior to the LPS challenge
- Use of recreational drugs within 21 days prior to experiment day
- Recent hospital admission or surgery with general anaesthesia (<3 months) |
- Het gebruik van medicatie
- Vooreschiedenis van BCG - vaccinatie
- Vaccinatie anders dan BCG binnen 3 maanden voorafgaand aan de studie of binnen onderzoeksperiode
- Roken
- Voorgeschiedenis van spontane vagale collaps
- Voorgeschiedenis van atriale of ventriculaire aritmie
- ( Familiale ) voorgeschiedenis van myocardinfarct of beroerte onder de leeftijd van 65 jaar
- Hartgeleidingsstoornissen op het ECG bestaande uit een 2e graads AV- blok of een complex bundeltakblok
- Hypertensie ( gedefinieerd als systolische RR > 160 of diastolische RR > 90 )
- Hypotensie ( gedefinieerd als systolische RR < 100 of RR diastolische < 50 )
- Verminderde nierfunctie ( gedefinieerd als plasma creatinine > 120 micromol / l )
- Afwijkingen in de leverenzymen of positieve hepatitis serologie
- Medische voorgeschiedenis van een ziekte geassocieerd met immuundeficiëntie
- CRP > 20 mg / L , WBC > 12x109 / L of klinisch significante acute ziekte, waaronder infecties, binnen 4 weken voor endotoxine toediening
- Deelname aan een geneesmiddelenstudie of bloeddonatie 3 maanden voorafgaand aan de LPS toediening
- Het gebruik van recreatieve drugs binnen 21 dagen voorafgaand aan de dag van LPS toediening
- Recente ziekenhuisopname of operatie onder algehele anesthesie ( <3 maanden ) |
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E.5 End points |
E.5.1 | Primary end point(s) |
Single endotoxemia: the primary study endpoint is the differences in LPS-induced plasma concentration of TNF-α following endotoxemia, between γ-irradiated BCG-vaccined subjects and placebo-treated controls.
Repeated endotoxemia: the primary study endpoint is the difference in the LPS-induced TNF-α concentration following the first and second endotoxemia, between γ-irradiated BCG-vaccined and placebo-treated control subjects.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Single endotoxemia:
0, 60, 90, 120, 180, 240, 360 and 480 minutes after endotoxin administration
Repeated endotoxemia:
0, 60, 90, 120, 180, 240, 360 and 480 minutes after both endotoxin administrations |
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E.5.2 | Secondary end point(s) |
Secondary study parameters include various other inflammatory cytokines, including IL-6 and IL-10, the ex vivo production of inflammatory mediators by stimulated leukocytes, the phenotype of circulating monocytes, inflammatory transcriptional pathways (by use of qPCR/microarrays), epigenetic changes in leukocytes including H3K4 trimethylation, illness score, mean arterial pressure, heart rate and temperature |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Single endotoxemia:
0, 60, 90, 120, 180, 240, 360 and 480 minutes after endotoxin administration
Repeated endotoxemia:
0, 60, 90, 120, 180, 240, 360 and 480 minutes after both endotoxin administrations |
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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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 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 | 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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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 | 4 |
E.8.9.1 | In the Member State concerned days | 0 |