E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Inflammatory conditions in general and immunosuppressive conditions is particular |
immunoparalysis |
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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.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the study is to investigate the effects of an endotoxin challenge and subsequent development of endotoxin tolerance on the local immune response following Fluenz™ administration in vivo. The primary outcome measure is the difference in concentrations of CXCL-10 in nasal wash between subjects in the placebo-Fluenz™ group and the LPS-Fluenz™ group. |
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E.2.2 | Secondary objectives of the trial |
Secondary endpoints include other local inflammatory parameters, including antibodies, immune cells, cytokines and local symptoms. Also, systemic inflammatory effects will be assessed, including circulating antibodies, immune cells and cytokines, lower respiratory tract and systemic symptoms and peak expiratory flow. Furthermore, viral shedding of influenza will be measured in nasal wash. Finally, changes in the mucosal microbiome will be assessed. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Age ≥18 and ≤35 years of age
-Male
-Healthy
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E.4 | Principal exclusion criteria |
- Pre-existent lung disease, including asthma
- A history of allergic rhinitis
- Use of any medication
- Current smoker or more than 5 pack-year history
- Use of recreational drugs within 21 days prior to start of the study
- Use of caffeine or alcohol within 1 day prior to start of the study
- Surgery or trauma with significant blood loss or blood donation within 3 months prior to start of the study
- Participation in another clinical trial within 3 months prior to start of the study
- Frequent nosebleeds
- Recent nasal or otologic surgery
- Clinically significant acute (febrile) illness or a common cold within four weeks prior to start of the study
- History of frequent vaso-vagal collapse or of orthostatic hypotension History, signs or symptoms of cardiovascular disease.
- History of allergic reaction to Fluenz™, eggs / gelatin / gentamicin
- History of Guillain-Barré Syndrome
- 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 function abnormality: alkaline phosphatase>230 U/L and/or ALT>90 U/L
- CRP > 20 mg/L, WBC > 12x109/L
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E.5 End points |
E.5.1 | Primary end point(s) |
Our primary objective is to investigate the effects of endotoxin-induced systemic inflammation and subsequent development of endotoxin tolerance on the inflammatory response following Fluenz™ administration in vivo. To evaluate whether these effects involve local and/or systemic inflammation, symptoms, temperature and peak expiratory flow will be measured. Next, local inflammatory parameters are measured in nasal wash and systemic inflammatory parameters are measured in blood. Furthermore, we want to evaluate whether preceding endotoxemia influences the viral shedding of influenza in nasal wash. Finally, changes in the mucosal microbiome will be assessed. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoints in minutes relative to LPS administration: T= -90, -60, 0, 60, 90, 120, 180, 240, 360, 480
and in days post-LPS administration: D=7, 8,9, 10, 11, 14, 21, 35 |
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E.5.2 | Secondary end point(s) |
-Other cytokines / chemokines in nasal wash
-Influenza viral shedding in nasal wash
-Leukocyte numbers and differentiation in nasal wash
-Fluenz™ antibodies (IgA) in nasal wash (measured for all three subtypes H1N1, H3N2, B).
-Circulating leukocyte counts and differentiation
-Plasma cytokines
-Fluenz™ antibodies (IgG) in serum.
-Cytokine production by leukocytes ex vivo stimulated with various pathogens/stimuli.
-Body temperature.
-Hemodynamic parameters
-symptoms
Peak expiratory flow (PEF).
Mucosal microbiome.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Timepoints in minutes relative to LPS administration: T= -90, -60, 0, 60, 90, 120, 180, 240, 360, 480
and in days post-LPS administration: D=7, 8,9, 10, 11, 14, 21, 35 |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
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 | Yes |
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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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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 | 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 | 1 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |