| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Analytical, Diagnostic and Therapeutic Techniques and Equipment [E] - Investigative Techniques [E05] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 |
Primary objectives:
• To identify whether EBC can be used as a non-invasive method to measure the PK of salbutamol and tobramycin.
• To determine whether the relationship in mild-moderate asthmatics between pulmonary lung function parameters and salbutamol concentrations can be better described by concentrations in the EBC compared to plasma.
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| E.2.2 | Secondary objectives of the trial |
Secondary objectives:
• To determine intra- and inter-subject variability of salbutamol and tobramycin concentrations in EBC after i.v. and inhaled administration.
• To determine the relationship between salbutamol and tobramycin concentrations in the EBC and plasma after i.v. and inhaled administration.
• Compare plasma/lung ratios between healthy volunteers and mild-moderate asthmatics with regard to the area under the curve (0-7h).
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
General inclusion criteria for all study subjects
• Healthy male subjects, 18 to 45 years of age, inclusive.
• Non-smokers or ex-smokers (stopped for at least 6 months before screening, and <10 pack-years).
• Body mass index (BMI) between 18 and 30 kg/m2.
• Able to participate and willing to give written informed consent and to comply with the study restrictions.
Specific inclusion criteria for asthmatic subjects
• History of mild to moderate persistent asthma, first diagnosed at least 6 months prior to the screening visit and currently controlled by β2-agonists on an “as needed” basis only.
• Clinically stable asthma, i.e. stable use of an “as needed” short-acting β2-agonist.
• Pre-bronchodilator FEV1 ≥ 70% of predicted.
• Demonstrate an increase in FEV1 of ≥ 12 % and 200 mL within 30 minutes after administration of 400 microgram inhaled salbutamol at screening.
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| E.4 | Principal exclusion criteria |
General exclusion criteria for all study subjects
• Known hypersensitivity to any excipients of the drug formulations; history of anaphylaxis or severe allergy for food or medication.
• Treatment with another investigational drug within 3 months prior to screening or more than 4 times a year.
• History or clinical evidence of any disease and/or existence of a surgical or medical condition which might interfere with the absorption, distribution, metabolism or excretion of the study drug.
• Clinically relevant history or evidence of cardiovascular disease (including angina pectoris and arrhythmias), hypertension, hyperthyroidism, renal disease, diabetes mellitus or glucose intolerance.
• Clinically relevant history of chronic or malignant diseases (except for basal cell carcinoma or squamous cell carcinoma of the skin).
• Clinically significant findings on physical examination.
• Clinically relevant abnormalities in 12-lead ECG.
• Any clinically significant abnormalities in blood (chemistry, hematology) or urine results.
• Renal clearance (MDRD formula) < 60 ml/min.
• Positive results for the HIV, HBV and HCV serology at screening.
• Excessive caffeine consumption, defined as > 8 cups/per day at screening – unable to discontinue caffeine consumption for at least 8 hours before and during the testing.
• History or clinical evidence of alcoholism within the 3-year period prior to screening (i.e. regular use of more than 21 units of alcohol/week).
• Positive results for urine drug and cotinine at screening.
• Recent respiratory tract infections (in 3 weeks before screening).
• Clinically meaningful blood loss (including blood donation), or a transfusion of any blood product within 12 week before screening.
Specific exclusion criteria for healthy volunteers
• A (family) history of hearing problems, clinical significant tinnitus or vestibular problems.
• History of hypersensitivity for sulphite or aminoglycosides.
• Clinically relevant pulmonary abnormalities.
Specific exclusion criteria for asthmatic subjects
• Clinically significant findings on physical examination other than allergy and mild to moderate persistent asthma.
• Controller therapy with anti-IgE (omalizumab) in the 6 months before screening.
• Systemic, inhaled or intranasal medication use of the following: corticosteroids in 4 weeks before screening (8 weeks for systemic use), leukotriene receptor antagonists (LTRA), cromones, theophyllines, long actin beta agonists (LABA) in the 2 weeks before screening.
• Desensitization therapy in the past.
• Severe exacerbation requiring hospital evaluation and/or admission in the past 2 years.
• Clinically relevant pulmonary comorbidity, other than asthma
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Pharmacokinetic endpoints
After study drug administration, PK in blood and EBC will be assessed by taking multiple paired blood and EBC samples at pre-specified time points.
Pharmacodynamic endpoints
Pulmonary function tests (Spirometry) will be performed only in asthma patients.
Tolerability / safety endpoints
Serious adverse events ((S)AEs) will be collected throughout the study.
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Healty volunteers: study day 1, 2, 3 and 4
Asthma patients: study day 1 and 2 |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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 | 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 | Yes |
| 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 | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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