E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Possible future indications: inflammatory conditions in general |
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E.1.1.1 | Medical condition in easily understood language |
The investigated therapy could prove to be beneficial in a variety of conditions associated with inflammation. |
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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 |
Determine the effect of transvenous vagus nerve stimulation (tVNS) on the innate immune response elicited by endotoxin administration in healthy volunteers up to 24 hours after stimulation. |
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E.2.2 | Secondary objectives of the trial |
• Determine effects of transvenous vagus nerve stimulation on autonomic nervous system activity up to 24 hours after stimulation
• Determine effects of transvenous vagus nerve stimulation on ethylene and NO concentration in exhaled breath up to 24 hours after stimulation
• Determine tolerability of acute side effects of transvenous vagus nerve stimulation
• Determine ease and safety of transvenous vagus nerve stimulation delivery
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Written informed consent to participate in this trial
2. Male subjects aged 18 to 35 years inclusive
3. Healthy as determined by medical history, physical examination, vital signs, 12 lead electrocardiogram, and clinical laboratory parameters
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E.4 | Principal exclusion criteria |
• Use of any medication(including herbal remedies and vitamin/mineral supplements) or recreational drugs within 7 days prior to profiling day
• Smoking
• Use of caffeine, or alcohol or within 1 day prior to profiling day
• Previous participation in a trial where LPS was administered
• Surgery or trauma with significant blood loss or blood donation within 3 months prior to profiling day
• Participation in another clinical trial within 3 months prior to profiling day.
• History, signs or symptoms of cardiovascular disease, in particular
• An implant that in the opinion of the investigator may make invasive proceedures risky for the subject due to the increased risks associated with a possible infection.
• Subject has an implanted active cardiac device (ICD, IPG and/or CRT)
• Implanted active neurostimulation device
• Subject has internal jugular vein that cannot be accessed
• History of frequent vaso-vagal collapse or of orthostatic hypotension
• History of atrial or ventricular arrhythmia
• Resting pulse rate ≤45 or ≥100 beats / min
• Hypertension (RR systolic >160 or RR diastolic >90)
• Hypotension (RR systolic <100 or RR diastolic <50)
• Conduction abnormalities on the ECG consisting of a 1st degree atrioventricular block or a complex bundle branch block
• Subject is diagnosed with epilepsy or history of seizures
• Renal impairment: plasma creatinine >120 µmol/L
• Liver function abnormality: alkaline phosphatase>230 U/L and/or ALT>90 U/L
• Coagulation abnormalities: APTT or PT > 1.5 times the reference range
• History of asthma
• Immuno-deficiency
• CRP > 20 mg/L, WBC > 12x109/L, or clinically significant acute illness, including infections, within 2 weeks before profiling day
• Known or suspected of not being able to comply with the trial protocol
• Inability to personally provide written informed consent (e.g. for linguistic or mental reasons) and/or take part in the study.
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E.5 End points |
E.5.1 | Primary end point(s) |
Plasma TNF-α concentration after LPS administration (Are Under Curve); comparison of subjects treated with tVNS versus sham tVNS. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
0, 30, 60, 90, 120, 180, 240, 360, 480 minutes and 24 hours after endotoxin administration |
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E.5.2 | Secondary end point(s) |
• Plasma concentrations of pro-inflammatory and anti-inflammatory cytokines (including TNF-α, IL 6, IL 1RA, IL 10) up to 24 h after LPS injection to document the immune response up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS.
• Leukocyte responses to ex vivo stimulation with inflammatory stimuli and leukocyte phagocytosis capacity up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS
• Endotoxemia-related clinical symptoms, hemodynamic parameters, and temperature up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS.
• Endotoxemia-induced circulating leukocyte changes up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS.
• Autonomic nervous system activity measured by heart rate variability up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS.
• Ethylene and NO concentration in exhaled breath up to 24 hrs; comparison of subjects treated with tVNS versus sham tVNS.
• Tolerability of acute side effects of tVNS
• Ease of tVNS delivery
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
at various time-points or continuous between -60 minutes and 24 hours after LPS administration. |
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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 | 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) | 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 | Yes |
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 | 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 | 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 | 1 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |