| 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 | 14.1 |
| 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 |
| The primary objective of the study is to show superiority in the efficacy of Flutiform pMDI 50/5μg (2 puffs bid) versus fluticasone pMDI 50 μg (2 puffs bid). |
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| E.2.2 | Secondary objectives of the trial |
The key secondary objective is to show non-inferiority in the efficacy of Flutiform 50/5 µg (2 puffs bid) to Seretide 50/25 µg (2 puffs bid)
Other secondary objectives of the study are to:
Compare the safety of Flutiform to fluticasone
Compare the safety of Flutiform to Seretide |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and Female subjects 5 to <12 years old.
2. Known history of moderate to severe persistent reversible asthma1 for ≥ 6 months prior to the screening visit.
3. Demonstrated FEV1 of ≥ 60% to ≤ 90% for predicted normal values (Polgar 1971) during the screening period following appropriate withholding of asthma medications (if applicable):
No LABA use within 12 hours and/or no SABA use within 6 hours of the PFT
No use of inhaled ICS-LABA asthma therapy within 12 hours of the PFT
Inhaled corticosteroids are allowed on the day of screening
4. Documented reversibility of ≥ 15% in FEV1 in the screening period
5. Current use of an inhaled corticosteroid for asthma at a stable dose for at least 4 weeks prior to the screening visit
6. Inadequate asthma control on an ICS alone at a dose of ≤ 500 μg fluticasone equivalents/day, OR controlled asthma on an ICS-LABA combination at a ICS dose of ≤ 200 μg fluticasone equivalents/day
7. Demonstrated satisfactory technique in the use of the pMDI and spacer device
8. Can perform spirometry adequately
9. Willing and able to enter information in the electronic diary with the help of a parent or guardian, if necessary and attend all study visits
10. Willing and able to substitute pre-study prescribed inhaled asthma medication for the entire duration of the study
11. If a female subject is post menarche a urine pregnancy test may be undertaken at the discretion of the investigator and the subjects‟ parent(s) /legal representative. This test must be negative.
12. Written informed consent and assent obtained as per national laws
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| E.4 | Principal exclusion criteria |
1. Near fatal or life-threatening (including intubation) asthma within the past year
2. Hospitalisation or an emergency visit for asthma within the past 6 months
3. History of systemic (injectable or oral) corticosteroid medication within 1 month of the screening visit
4. Current or prior non-response or partial response only to an ICS-LABA combination1
5. 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
6. In the Investigator‟s opinion a clinically significant upper or lower respiratory infection within 4 weeks prior to the screening visit
7. Significant, non-reversible active pulmonary disease (e.g. cystic fibrosis, bronchiecstasis, tuberculosis)
8. Known Human Immunodeficiency Virus (HIV)-positive status
9. Current smoking history within 12 months prior to the screening visit
10. Current evidence of alcohol or substance abuse within 12 months prior to the screening visit
11. 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
12. Current use of medications, other than those allowed in the protocol, that in the investigator‟s opinion will have an effect on bronchospasm and/or pulmonary function
13. Current evidence of hypersensitivity or idiosyncratic reaction to test medications or components
14. Receipt of an Investigational medicinal product within 30 days of the screening visit
15. Current participation in a clinical study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Primary endpoint is the change from pre-dose FEV1 at baseline to 2 hours post-dose FEV1 over the 12 week treatment period. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| End of the 12 week treatment period |
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| E.5.2 | Secondary end point(s) |
Key secondary endpoints which will be tested in a hierarchical (gate keeping manner) for the two study comparisons (Flutiform to Fluticasone, then Flutiform to Seretide):
• FEV1 AUC0-4 at Week 12
• Change in pre-dose FEV1 from baseline over the 12 week treatment period
Other exploratory secondary endpoints will include:
• Change from pre-dose FEV1 at baseline to 2-hours post-dose FEV1 at the end of the 12 week treatment period
• Change from pre-dose FEV1 at baseline to the end of the 12 week treatment period
• Change from pre-dose FEV1 at baseline to 2-hours post-dose FEV1 at Day 1
• FEV1 AUC0-4 at Day 1
• Change in morning and evening PEFR from baseline over the 12 week treatment period
• Change from baseline for other lung function parameters over the 12 week treatment period.
• Proportion of discontinuations due to lack of efficacy
• Change in amount of rescue medication use from baseline (end of run-in) over the 12 week treatment period
• Change in percentage of rescue medication free days from baseline (end of run-in) over the 12 week treatment period
• Change in asthma symptom scores from baseline (end of run-in) over the 12 week treatment period
• Change in percentage of asthma symptom free days from baseline (end of run-in) over the 12 week treatment period
• Change in sleep disturbance scores from baseline (end of run-in) over the 12 week treatment period
• Change in percentage of awakening free nights from baseline (end of run-in) over the 12 week treatment period
• Change in percentage of asthma control days from baseline (end of run-in) over the 12 week treatment period
• Incidence of treatment-emergent asthma exacerbations
• Annualised rate of treatment-emergent asthma exacerbations
• Amount of daily oral and parenteral corticosteroid use
• Compliance with study medication
• Mean change in paediatric asthma quality of life (PAQLQ-IA) from baseline to the end of the 12 week treatment period in all subjects
• Proportion of patients achieving a change from baseline to the end of the 12 week treatment period PAQLQ-IA ≥ 0.5 units.
• Mean change in Asthma Control Questionnaire-IA from baseline to end of the 12 week treatment period in all subjects
• Proportion of subjects achieving change in ACQ-IA score ≥0.5 units.
• Exhaled Nitric Oxide in a subgroup of approximately 30% of subjects in pre-selected centres
• Safety assessments will include incidence and type of spontaneously reported adverse events, vital signs and laboratory tests.
• HPA axis suppression via 12 hour overnight urinary cortisol profiles |
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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 | 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| fluticasone pMDI and Seretide pMDI |
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| 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
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 65 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Czech Republic |
| Hungary |
| India |
| Poland |
| Romania |
| Russian Federation |
| Ukraine |
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| 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 | 1 |
| E.8.9.1 | In the Member State concerned days | 3 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 1 |
| E.8.9.2 | In all countries concerned by the trial days | 3 |
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