| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| persistent moderate asthma |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003555 |
| E.1.2 | Term | Asthma bronchial |
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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 therapeutic equivalence (i.e. non-inferiority) of Salmeterol/Fluticasone DPI HEXAL (50 µg/100 µg of salmeterol/fluticasone per actuation, 2x1 actuation per day) to Seretide™ 100 Accuhaler™ (50 µg/100 µg of salmeterol/fluticasone per actuation, 2x1 actuation per day) in pediatric patients aged 6-11 years suffering from persistent moderate asthma. Conclusion of non-inferiority will be based on two primary efficacy variables since the treatment effects for fluticasone are different from salmeterol: absolute change in FEV1 and the area under the 4-hour serial FEV1 curve (AUC0-4) at the end of the double-blind treatment period relative to baseline FEV1 (Visit 0). |
|
| E.2.2 | Secondary objectives of the trial |
Efficacy:
Change in FEV1 from baseline (Visit 0) to Visit 3; Development of FEV1 and FEV1 % predicted over the course of the study; Development of FEV1 and FVC over the course of the study; Mean change in morning pre-dose FEV1; Time to onset of action; Mean change in morning pre-dose PEF; Development of PEF; Change in asthma symptoms scores and total asthma symptoms over time; Frequency of use of reliever medication; Incidence and severity of asthma exacerbations; Number of patients discontinuing due to asthma worsening; Overall assessment of efficacy.
Safety: Incidence and severity of AEs and drug-related AEs;
Clinically relevant changes in laboratory parameters, vital signs, ECG and physical examination parameters; Incidence of patients with oral candidiasis or voice hoarseness; Clinically relevant changes in morning serum cortisol levels; Serum cortisol concentration-time profiles at Visit 6; 16-hour urinary free cortisol levels; Overall assessment of tolerability of the IP. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Male or female children aged 4 to 11 years
2.Written informed consent signed according to local requirements by one or both of the patient’s parent(s) or the legal representative and by the patient, if applicable, prior to any protocol specific procedures
3.Medical history of persistent moderate asthma (according to GINA) of at least 6 months duration
4.Regular use of ICS or ICS plus LABA over the 6 months preceding Visit -1
5.Regular treatment with medium- to high-dose ICS or medium-dose ICS plus LABA for children <5 years, high-dose ICS or low- to medium-dose ICS plus LABA for children >5 years within the 4 weeks preceding Visit -1
6.Ability to perform spirometric maneuvers with a forced expiratory time of at least 1 second
7.FEV1 > 60% of the predicted value by the European Community for Coal and Steel (ECCS) after a washout period of at least 6 hours for rapid-acting beta 2-agonists (RABA) and at least 12 hours for LABA
8.Reversible and variable airflow limitation: at least 12% increase of FEV1 compared to baseline after the stepwise reversibility test
9.Ability to read and write and to fill in the patient diary by the patient or by patient’s parent(s) or legal representative
10.Ability to handle correctly the peak flow meter
11.Capable to handle and inhale from the investigational devices.
12.FEV1 greater than 60% and less than 80% of the predicted value by the European Community for Coal and Steel (ECCS) after a washout period of at least 6 hours for RABA (reliever medication)
13.FEV1 within +/- 15% of the value obtained at Visit -1
14.At least 2 of the following criteria fulfilled during the last 7 days of the run-in period:
14.1.Nighttime symptom score (diary card rating of asthma symptoms) is at least 1 on at least 1 day
14.2.Daytime symptom score (diary card rating of asthma symptoms) is at least 1 on at least 3 days
14.3. Use of RABA for symptomatic relief (not prophylaxis) on at least 4 days
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| E.4 | Principal exclusion criteria |
1.Intermittent or persistent mild or severe asthma as defined by GINA
2.Evidence of any active concomitant pulmonary disease other than asthma, i.e. chronic bronchitis, COPD
3.Respiratory tract infection (including sinusitis) and middle ear infection within 4 weeks prior to Visit -1
4.Acute asthma exacerbation within 4 weeks preceding Visit -1
5.Acute asthma exacerbation requiring hospitalization or emergency room visit within 12 weeks preceding Visit -1
6.History of life-threatening acute attacks or intubation for asthma
7.History of seasonal asthma exacerbation
8.History of paradoxical bronchospasm after inhaled asthma therapy
9. Active or inactive lung tuberculosis
10.Smoking habits: current smokers or smokers who stopped smoking less than 6 months before Visit -1
11.Overdependence on RABA, i.e. frequency of RABA inhalation not consistent with persistent moderate asthma
12.Patients naive for inhaled corticosteroids
13.Change in asthma medication or regimen (other than inhalation of RABA) within 4 weeks preceding Visit -1
14.Administration of cromones within 4 weeks preceding Visit -1
15.Administration of oral, nasal, rectal, parenteral or depot corticosteroids within 4 weeks preceding Visit -1
16.More than 2 courses of oral corticosteroids within the last 12 weeks
17.Theophylline, leukotriene modifiers and anticholinergics within 4 weeks preceding Visit -1
18.Long-acting antihistamines within 1 week preceding Visit -1 (astemizole within 12 weeks)
19.Use of beta-blockers, non-potassium sparing diuretics or potent inhibitors of the cytochrome P450-3A4 system like ketoconazole, itraconazole, ritonavir within 4 weeks preceding Visit -1
20.Vaccination with live-attenuated virus within 2 weeks preceding Visit -1
21.Impaired adrenal cortex function
22.Severe renal or hepatic disease
23.Hypokalaemia uncorrected and/or serum potassium value on Visit -1 less than 3.5 mmol/L
24.Acute or history of severe cardiovascular disorders (New York Heart Association class II-IV heart failure, heart rhythm abnormalities)
25.Untreated or unstable hypertension
26.Known diabetes
27.Hyperthyroidism not adequately controlled
28.Glaucoma
29.History of hypersensitivity to at least one of the active ingredients of the investigational products or the reliever medication
30.History of allergy to lactose or milk protein or – as judged by the investigator - of intolerance to small amounts of lactose
31.Presence of any other severe decompensated concomitant disease (endocrine, hematological, neurological, immunological)
32.Known active and significant pulmonary abnormalities as detected on available chest radiographs
33.Other relevant medical condition, ECG abnormality, or laboratory profile that might compromise the patient’s safety, compliance, or interfere with the evaluation or preclude completion as judged by the investigator or other contraindication to the investigational drug or the reliever medication
34.Girls of childbearing potential, not willing to abstain from sexual activities throughout complete duration of participation in the study, pregnancy or nursing
35.History of non-compliance with asthma management plan
36.Suspected alcohol or drug abuse
37.Current participation in another investigational drug study, or previous participation within 1 month prior to Visit -1 in the HEXAL study with protocol no. 2007-41-DOS-3 or participation in any other clinical study involving an investigational drug within 3 months prior to Visit -1. For screening failures of the present study 2006-57-DPI-2 a one-time re-screening is allowed.
38.Lack of sufficient co-operation or compliance or existing psychosocial problems of the patient or the patient’s parent(s) or legal representative
39.Legal incapacity of the patient’s parent(s) or legal representative or other circumstances rendering the patient’s parent(s) or legal representative unable to understand the nature, scope and possible consequences of the study
40.Acute respiratory tract infection during run-in period
41.Severe asthma exacerbation during run-in period
42.Any intake of asthma medication other than the inhalation of the supplied reliever medication during run-in period
43.Use of more than 8 actuations of reliever medication on any single day during the run-in period
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|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary aim of this study is to show therapeutic equivalence (i.e. non-inferiority) of Salmeterol/Fluticasone DPI HEXAL (50 µg/100 µg of salmeterol/fluticasone per actuation, 2x1 actuation per day) to Seretide™ 100 Accuhaler™ (50 µg/100 µg of salmeterol/fluticasone per actuation, 2x1 actuation per day) in pediatric patients aged 6-11 years suffering from persistent moderate asthma. Conclusion of non-inferiority will be based on two primary efficacy variables since the treatment effects for fluticasone are different from salmeterol: absolute change in FEV1 and the area under the 4-hour serial FEV1 curve (AUC0-4) at the end of the double-blind treatment period relative to baseline FEV1 (Visit 0).
Non-inferiority based on change in FEV1 will be concluded if the resulting one-sided 97.5% confidence interval for the difference between LSMEANs of the two treatment groups with respect to the absolute change in FEV1 (Visit 6 minus Visit 0) lies entirely within the pre-specified interval [-12%; inifinte].
Non-inferiority with respect to FEV1 AUC0-4 after 12 weeks of treatment relative to baseline FEV1 will be concluded if the resulting one-sided 97.5% confidence interval for the ratio of the LSMEANs of the two treatment groups, µtest / µref, lies entirely within the pre-specified interval [80%; infinite]
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | Information not present in EudraCT |
| E.6.2 | Prophylaxis | Information not present in EudraCT |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | Information not present in EudraCT |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Information not present in EudraCT |
| E.6.11 | Pharmacogenomic | Information not present in EudraCT |
| E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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.8.3 |
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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 19 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 8 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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