| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| moderate-to-severe persistent 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 |
|
| 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 MDI HEXAL (25 µg/50 µg of salmeterol/fluticasone per actuation, 2x2 actuations per day) to SeretideTM 50 EvohalerTM (25 µg/50 µg of salmeterol/fluticasone per actuation, 2x2 actuations per day) in adolescent and adult patients with moderate-to-severe persistent asthma. Conclusion of non-inferiority will be based on two primary efficacy variables since the treatment effects for fluticasone-17-propionate are different from salmeterol: Absolute change in FEV1 and the area under the 12-hour serial FEV1 curve (AUC0-12) 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 to Visit 3; Development of FEV1, FEV1 % predicted and FVC; Change in morning pre-dose PEF; Development of morning and evening PEF; Change in daytime and nighttime symptoms score and in total asthma symptoms score; Use of reliever medication; Incidence and severity of asthma exacerbations; Number of patients discontinuing the study due to asthma worsening; Assessment of efficacy by patient, patient’s parent(s) and investigator.
Safety: Incidence and severity of AEs and drug-related AEs; Clinically relevant changes in laboratory parameters, vital signs, ECG, physical examination parameters and in morning serum cortisol levels; Serum cortisol concentration-time profiles, 24-hr urinary free cortisol levels and pre- and post-inhalation plasma levels of fluticasone and salmeterol at Visit 6; Incidence of oral candidiasis or voice hoarseness; Assessment of tolerability of the investigational product by patient, patient’s parent(s) and investigator.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
At Visit -1:
1. Male or female patients aged 12 to 65 years
2. Written informed consent signed by the patient or for patients younger than 18 years (adolescents) signed also by the parent(s) or by the legal guardian prior to any protocol specific procedures
3. Medical history of moderate-to-severe persistent asthma (according to GINA) of at least 6 months duration
4. Regular use of ICS or ICS plus LABA over the 6 months immediately prior to Visit -1
5. Regular treatment with high-dose ICS alone or low- to high-dose ICS plus LABA within the 4 weeks immediately prior to Visit -1 (see Appendix V for daily dosages of ICS according to GINA)
6. FEV1 ≥50% 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
7. Reversible and variable airflow limitation: at least 15% increase of FEV1 15-20 min after RABA inhalation (200 µg salbutamol). Reversibility has to be demonstrated at Visit -1 or needs to be documented by valid spirometric results, obtained with 200-400µg of salbutamol, within 6 months prior to Visit -1
8. Ability to read and write and to fill in the patient diary
9. Ability to handle correctly the metered-dose inhalers and the peak flow meter
At Visit 0:
1. FEV1 ≥ 50% and < 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)
2. FEV1 pre-inhalation within ±15% of the value obtained at Visit -1
3. At least 2 of the following criteria fulfilled during the last 7 days of the run-in period:
3.1. Nighttime symptom score (diary card rating of asthma symptoms) is at least 1 on at least 1 day
3.2. Daytime symptom score (diary card rating of asthma symptoms) is at least 1 on at least 3 days
3.3. Use of RABA for symptomatic relief (not prophylaxis) on at least 4 days |
|
| E.4 | Principal exclusion criteria |
At Visit -1:
1. Intermittent or persistent mild 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) 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, smokers who stopped smoking less than 6 months before Visit -1 or former smokers with a history of ≥10 pack-years.
11. Overdependence on RABA, i.e. frequency of RABA inhalation not consistent with controlled moderate-to-severe persistent 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, 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
21. Impaired adrenal cortex function
22. Severe renal or hepatic disease
23. Hypokalemia 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 of all types
27. Hyperthyroidism not adequately controlled
28. Glaucoma
29. History of hypersensitivity to one or both of the active ingredients or to any other component of the preparations or reliever medication
30. Presence of any other severe decompensated concomitant disease (endocrine, hematological, neurological, immunological)
31. Known active and significant pulmonary abnormalities as detected on available chest radiographs
32. 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 test drug
33. Pregnant or nursing women
34. Females of childbearing potential (not surgically sterilized / hysterectomized or postmenopausal for at least 1 year), who are not using and not willing to use medically reliable methods of contraception for the entire study duration (such as oral, injectable, or implantable contraceptives, or intrauterine contraceptive devices)
35. Necessity to use a spacer device for inhalation
36. History of non-compliance with asthma management plan
37. Suspected alcohol or drug abuse
38. Current participation in another investigational drug study, or participation in any clinical study involving an investigational drug within 3 months prior to Visit -1 (except patients previously participating in HEXAL protocol No. 2006-03-DOS-1)
39. Lack of sufficient co-operation or compliance or existing psychosocial problems
40. Legal incapacity or other circumstances rendering the patient, patient’s parent(s) or legal representative unable to understand the nature, scope and possible consequences of the study
At Visit 0:
1. Acute respiratory tract infection during run-in period
2. Severe asthma exacerbation during run-in period
3. Any intake of asthma medication other than the inhalation of the supplied reliever medication during run-in period
4. Use of more than 12 actuations of reliever medication on any single day during the run-in period
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
1. FEV1 at the end of the 12-week study period (Visit 6) compared with baseline (Visit 0)
2. Area under the 12-hour serial FEV1 curve (AUC0-12) at the end of the 12-week study period (Visit 6) relative to baseline FEV1 (Visit 0)
|
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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) | 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 | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 | 9 |
| 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 | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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