| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic mild to moderate persistent asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic enduring asthma of mild to moderate severity |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 15.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003555 |
| E.1.2 | Term | Asthma bronchial |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 |
| This study aims to investigate anti-inflammatory effects of inhaled fluticasone in terms of reduction of fractional exhaled nitric oxide on patients with mild to moderate asthma. |
|
| E.2.2 | Secondary objectives of the trial |
| Following FDA recommendations, this pilot study aims to identify appropriate dose(s) for the subsequent pharmacodynamic bioequivalence study, optimal wash-out and dosing intervals, within subject variability, optimal population, pharmacodynamic parameter: dose-response for the pharmacodynamic marker, sample size estimation for the subsequent pharmacodynamic bioequivalence study, indicative of the dose level(s) of fluticasone propionate for this study, and last but not least, fractional exhaled nitric oxide apparatus/analyzer. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects must be 18 to 65 years (inclusive) of age at screening visit.
2. BMI between 18 and 35.
3. Willingness to give written informed consent and ability to adhere to dose and visit schedules.
4. Fractional exhaled nitric oxide (FeNO) ≥ 45 ppb at screening visit.
5. Forced expiratory volume in one second (FEV1) ≥ 60% predicted (NHANES III) at screening and baseline visits.
6. No tobacco within 6 months and does not have history of smoking > 10 pack years.
7. ≥ 6 months of chronic, persistent asthma (NAEPP 3). To document asthma diagnosis, historical reversibility defined as an increase in absolute forced expiratory volume (in liters) in 1 second (FEV1) of ≥ 12 % and ≥ 200 mL must have been performed within 12 months prior to screening visit. For subjects without historical reversibility, one of the following methods can be used at the screening visit or at any time before the baseline visit (for definition see below):
7a. Demonstration of an increase in absolute FEV1 of at least 12 % and a volume increase of at least 200 mL within 15-40 minutes after administration of 4 inhalations of salbutamol (total dose 360 to 400 mcg) or of nebulized short-acting beta-agonist (SABA) (2.5 mg), if confirmed as standard office practice, OR
7b. Demonstration of a peak expiratory flow (PEF) variability of more than 20 % expressed as a percentage of the mean highest and lowest morning pre-bronchodilator PEF over at least 1 week, OR
7c. Demonstration of a diurnal variation PEF of more than 20 % based on the difference between the pre-bronchodilator (before taking salbutamol) morning value and the post-bronchodilator value (after taking salbutamol) from the evening before, expressed as a percentage of the mean daily PEF value on any day during the open-label Run-in Period.
8. Clinical laboratory tests (complete blood count, blood chemistries, and urinalysis) conducted at the screening visit must be within normal limits or clinically acceptable to the investigator.
9. An electrocardiogram (ECG) performed at the screening visit or within 30 days prior to screening visit must be clinically acceptable to the investigator and have a QTc interval < 450 milliseconds (msec).
|
|
| E.4 | Principal exclusion criteria |
1. Use of systemic glucocorticosteroids within 3 months before screening visit.
2. Upper or lower respiratory tract infection within 6 weeks before screening visit.
3. Decrease in absolute forced expiratory volume in one second (FEV1) > 20 % between screening visit and baseline visits.
4. Requirement for > 8 inhalations per day of short-acting beta-agonist (SABA) metered dose inhaler, or 2 or more nebulized treatments of 2.5 mg SABA, on any 2 consecutive days between the screening visit and baseline visits.
5. A clinical asthma exacerbation defined as a clinical deterioration of asthma that results in emergency treatment, hospitalization for asthma, or treatment with additional, excluded asthma medication (including oral or other systemic corticosteroids but allowing SABA), as per investigator, between screening visit and baseline visits.
6.Clinically significant concomitant disease which may have an impact on the study participation.
7. Hyper-sensibility against fluticasone or study drug components.
8. Patients who have had treatment with live attenuated vaccinations within 14 days prior to screening visit (inactivated influenza vaccination is acceptable, provided that it is not administered within 7 days prior to screening visit).
9. The use of strong cytochrome P450 3A4 (CYP3A4) inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) within 6 weeks prior to screening.
10. The use of nitric oxide synthase inhibitors, leukotriene-axis modifiers (zileuton, zafirlukast, montelukast), nitric oxide donor drugs (nicorandil, furoxan) and L-arginine.
11. Other respiratory diseases (e.g. chronic obstructive pulmonary disease (COPD), cystic fibrosis, alpha-1-antitrypsin deficiency, sarcoidosis, bronchiectasis, allergic alveolitis, tuberculosis, etc.).
12. Other fungal, bacterial, viral or parasitic infections or ocular herpes simplex or chickenpox.
13. Drug or alcohol abuse which would interfere with the subject’s compliance.
14. For female subjects only: Has a positive urine pregnancy test at screening visit, is lactating, or is not practicing a medically acceptable form of contraception or abstinence. If abstinent, the subject must agree to use a double-barrier-method if she becomes sexually active during the study, If surgically sterilized (including hysterectomy) or postmenopausal, no contraceptive method is necessary.
15. Has participated in another study with an investigational drug within 1 month prior to screening visit. Observational studies are allowed if permission has been obtained from the sponsor.
16. Employee at study site, or spouse/partner or relative of the investigator or sub-investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean percent change from baseline after two weeks treatment in fractional exhaled nitric oxide (FeNO): compared to baseline (Day 1 of each treatment period). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Endpoint evaluated throughout each treatment period. |
|
| E.5.2 | Secondary end point(s) |
1. The appropriate dose(s) for the subsequent pharmacodynamic bioequivalence study.
2. The optimal wash-out and dosing intervals.
3. The within subject variability.
4. The optimal population.
5. Sample size estimation for the subsequent pharmacodynamic study.
6. Indicative of the dose level(s) of fluticasone for this study.
7. Appropriateness of the fractional exhaled nitric oxide (FeNO) apparatus/analyzer.
8. Changes in forced expiratory volume in one second (FEV1). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Endpoints evaluated throughout each treatment period. |
|
| 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 | No |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| 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 | No |
| E.8.2.3 | Other | No |
| 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
|
|
| 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 | 8 |
| E.8.9.1 | In the Member State concerned days | 0 |
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