| 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 | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003555 |
| E.1.2 | Term | Asthma bronchial |
| E.1.2 | System Organ Class | 100000004855 |
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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 |
| •To show non-inferiority of flutiform pMDI 50/5 µg (2 puffs bid) versus fluticasone pMDI 50 µg (2 puffs bid) based on the mean lower leg growth rates. |
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| E.2.2 | Secondary objectives of the trial |
Secondary Objectives:
•To compare the safety of flutiform pMDI 50/5 µg (2 puffs bid) versus fluticasone pMDI 50 µg (2 puffs bid) based on overnight urinary free cortisol (corrected for creatinine).
Exploratory Objectives:
•To compare mean lower leg growth rates with flutiform pMDI 50/5 µg and fluticasone pMDI 50 µg versus beclometasone Autohaler 50 µg.
•To compare the safety of flutiForm pMDI 50/5 µg and fluticasone pMDI 50 µg to beclometasone Autohaler 50 µg based on overnight urinary free cortisol (corrected for creatinine).
•To compare the efficacy of flutiForm pMDI 50/5 µg, fluticasone pMDI 50 µg and beclometasone Autohaler 50 µg by means of FEV1, PEFR, rescue medication use, asthma exacerbations asthma symptoms and activity limitations.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male and Female subjects 5 to <12 years old. Female subjects must be pre-menarche to be eligible.
2.Subjects must be pre-adolescent without any signs of puberty (acc. to Tanner scale).
3.Subjects are in normal range for their age in height and weight. Weight and height measurements should fall within the percentile range 3-97-% of normal values for age according to Danish growth charts.
4.Known history of mild intermittent or persistent reversible asthma for ≥ 3 months prior to the screening visit.
5.Require:
a.only inhaled SABA therapy (e.g. Bricanyl Turbuhaler) on an as required basis, and/or
b.Regular non-ICS controller medications for asthma (e.g., cromones or leukotriene receptor antagonists) at a stable dose for ≥ 3 months prior to the screening visit.
6.No ICS for >2 weeks prior to the screening visit.
7.Demonstrates adequate spirometry technique and able to use a home PEFR meter.
8.Demonstrated FEV1 of ≥ 80% predicted value at visit 1following appropriate withholding of asthma medications (if applicable) (no SABA use within 6 hours of the PFT).
9.Demonstrated satisfactory technique in the use of the pMDI plus spacer and Autohaler devices.
10.Must be continent of urine and willing to perform (with parental/guardian help) overnight urine collections.
11.Willing and able to complete morning and evening PEFR measures with the help of a parent or guardian, if necessary, and attend all study visits.
12.Willing and able to substitute pre-study prescribed inhaled asthma medication for the entire duration of the study with study medication.
13.Written informed consent obtained as per national laws.
Inclusion Criteria required following run-in:
14.FEV1 within ≤20% of the visit 1 value following appropriate withholding of rescue medication (no Airomir Autohaler use within 6 hours of the PFT).
15.Rescue medication use on ≤2 days during the last 7 days of the run in period.
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| E.4 | Principal exclusion criteria |
1.Require medications other than inhaled SABAs and/or regular non-ICS controller medications (e.g., cromones or leukotriene receptor antagonists) to maintain asthma control.
2.ICS use within ≤ 2 weeks prior to the screening visit.
3.Any asthma exacerbation of any severity for at least 3 months prior to the screening visit.
4.Any fracture in the leg to be measured by knemometry ≤6 months prior to the screening visit.
5.Any metabolic disorders or other diseases that may impact on normal growth patterns.
6.Near fatal or life-threatening asthma within the past year.
7.Hospitalisation or an emergency visit for asthma within the past 6 months.
8.History of oral or injectable corticosteroid medication ≤3 months prior to the screening visit.
9.Evidence of a clinically unstable disease, as determined by medical history, clinical laboratory tests, and physical examination that, in the Investigator’s opinion, preclude entry into the study. “Clinically significant” is defined as any disease that, in the opinion of the Investigator, would put the subject at risk through study participation, or which would affect the outcome of the study.
10.No major surgery requiring general anesthesia for at least 3 months prior to the screening visit.
11.No febrile illnesses with temperature > 39°C within a week of the screening visit.
12.In the Investigator’s opinion a clinically significant upper or lower respiratory infection within 4 weeks prior to the screening visit.
13.Significant, non-reversible active pulmonary disease (e.g. cystic fibrosis, bronchiectasis, tuberculosis).
14.Subjects who have taken β- blocking agents, tricyclic antidepressants, monoamine oxidase inhibitors, astemizole (Hismanal), quinidine type antiarrythmics, or potent CYP 3A4 inhibitors such as ketoconazole within 1 week prior to the screening visit.
15.Current use of medications, other than those allowed in the protocol.
16.Current evidence of hypersensitivity or idiosyncratic reaction to test medications or components.
17.Receipt of an Investigational medicinal product within 30 days of the screening visit.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Mean lower leg growth rate during each period |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Subjects randomised to receive one 1 of 3 possible treatment sequences outlined below:-
1)Treatment A:-Flutiform 50/5ug(2 puffs bid) pMDI
2)Treatment B:-Fluticasone 50ug(2 puffs bid) pMDI
3)Treatment C:-Beclometasone 50ug(2 puff bid)
Each Treatment Phase is 14 days, separated by 14 days for the wash-out period.
Measurement of lower leg growth using the knemometer will be taken at each visit by an assessor who is blinded to the study treatment. Knemometry measurements at visits 1 to 7 taken at the same time (+/-1hour) on the same day of the week wherever possible, corresponding to the beginning and the end of each treatment or wash-out period.
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| E.5.2 | Secondary end point(s) |
•Mean 12-hour urinary free cortisol (corrected for creatinine) during each period.
•Spontaneously reported adverse events.
•Mean FEV1 at clinic visits.
•Mean daily PEFR during each period.
•Days of rescue medication use during each period.
•Number (%) of asthma exacerbations during each period.
•Number (%) of asthma symptoms during each period.
•Number % of subjects who experienced any activity limitation due to asthma during each period.
•Study medication use (compliance) during treatment period.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
•12-hour urinary free cortisol (corrected for creatinine) during each period - overnight urine collections at end of each treatment phase.
•Spontaneously reported adverse events collected at during of study
•FEV1 at clinic visits.
•Daily PEFR during each period - morning & evening
•Days of rescue medication use during each period.
•Number (%) of asthma exacerbations during each period - day and evening
•Number (%) of asthma symptoms during each period.
•Number % of subjects who experienced any activity limitation due to asthma during each period.
•Study medication use (compliance) during treatment period.
Refer to protocol for full details |
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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 | Yes |
| E.6.6 | Pharmacokinetic | No |
| 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 | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | Yes |
| 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 | 3 |
| 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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| End of Trial is defined as the 'Last Visit Last Subject' - LVLS |
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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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
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