| 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] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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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 demonstrate equivalence of the test IMP, ComboFS 250 mcg/25 mcg and 125 mcg/25 mcg of fluticasone propionate and salmeterol to the reference IMP, Seretide® Diskus® 500 mcg/50 mcg and 250 mcg/50 mcg of fluticasone propionate and salmeterol, regarding the change from baseline in forced expiratory volume in 1 second (FEV1) at day 56 and day 112 as well as baseline adjusted area under the serial FEV1 from 0 to 12 hours (AUC0-12 hours) on the first day of treatment. Primary objective will be assessed in the first 40 subjects enrolled, while primary objective of the study for the change from baseline in FEV1 at the end of each 8-week treatment period will be assessed in other patients enrolled. The limitation of the size of population is motivated by technical difficulties in performing serial spirometry in COVID pandemic, while the size of the subpopulation under this analysis should be sufficient to provide required testing power. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objectives will include the evaluation of the change from baseline in forced expiratory volume in 1 second (FEV1) at day 56 and day 112 as well as changes in morning peak expiratory flow (PEF) rate, analysis of FEV1 measurements performed on each visit, as well as the assessment of Asthma Control Questionnaire results. Moreover, safety of the IMPs, in particular changes in morning serum and serial blood collection samples cortisol levels will be evaluated. Secondary objective of the study for baseline adjusted under the serial FEV1 from time 0 to 12 hours (AUC0-12 hours) at the end of each study period and serial serum cortisol levels will be assessed in the first 40 subjects enrolled to the study, while other secondary objectives of the study will be assessed in the relevant population from the whole group of subjects enrolled to the study. Safety parameters will include, among others, the assessment of serum potassium levels and results of ECG examinations. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and female patients aged 18 years and older
2. Patient/Subject or legal representative has signed the ICF prior to any protocol specific procedure
3. Symptomatic patients suffering from unstable asthma partly controlled according to international recommendations provided by GINA 2019:
a. with 60% <FEV1 <95% of the normal value predicted by the European Community for Coal and Steel (ECCS) formulae. This criterion has to be demonstrated at Visit 1 after a sufficient washout period (at least 6 hours for short-acting β 2-agonist inhalation and at least 12 hours for long-acting β 2-agonist inhalation).
b. which fulfill at least 2 of the following criteria during the last 7 days of the run-in period:
i. symptom score (diary card rating of asthma symptoms) ≥2 on any 2 days
ii. use of short acting beta2-agoinst (rescue medication) more than twice daily on any 2 days
iii. night-time diary card symptom score of ≥1 on one occasion
iv. diurnal variation in PEF of more than 30% on at least 1 day
c. which have been stable for 6 months prior to visit 2 (Baseline)
4. Patients with at least 12% increase of FEV1 and a minimum of 200 ml of due value approx. 15-20 min after a short acting β2-agonist inhalation (400 µg salbutamol). Reversibility test has to be demonstrated at Visit 1 (week -2) (the test can be repeated during seven following days) or at Visit 2 or has to be documented within 12 months prior to Visit 1by using spirometry.
5. 5. Patients who have been treated before the study with fluticasone propionate + salmeterol combination in the dose of 500 mcg + 50 mcg twice a day will be randomized to receive either ComboFS 250 mcg/25 mcg or Seretide® Diskus® 500/50 mcg/dose.
Patients who have been treated before the study with fluticasone propionate + salmeterol combination in the dose of 250 mcg + 25 mcg or 250 mcg + 50 mcg twice a day will be randomized to receive either ComboFS 125 mcg/25 mcg vs. Seretide® Diskus® 250/50 mcg/dose.
6. Patients must be able to read and write and to fill in the patient’s diary.
7. Patients must be able to handle the metered dose inhalers and a mini-Wright peak flow meter.
8. Patients have to be in a stable general condition.
ECG safety criteria:
The subject must have no ECG abnormalities that would, in the opinion of investigator, compromise subject safety, or significantly affect subject’s ability to complete the trial. As such, the investigator will determine the clinical significance of any ECG abnormality and determine if a subject is precluded from entering the study. At Visit 1 (Screening and Run-in Visit), ECG safety criteria must be:
• QT interval corrected for heart rate (QTc) or QT interval corrected for heart rate according to Fridericia formula (QTcF) <450 msec or
• QTc <480 msec for subjects with bundle branch block
Investigators will be responsible for ensuring appropriate clinical interpretation of ECGs.
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| E.4 | Principal exclusion criteria |
Disease specific criteria
1. Acute upper respiratory infection within 4 weeks prior to Visit 2 (Baseline)or during screening/run-in period.
2. Acute lower respiratory infection within 12 weeks prior to Visit 2 (Baseline) or during screening/run-in period.
3. Unstable asthma as evidenced by
a. any deterioration of asthma / acute asthma exacerbation requiring hospitalization or emergency room visit or
b. any change in asthma therapy (other than inhalation of short-acting ß2 agonists) within 6 months preceding Visit 2 (Baseline)
4. Previous history of life-threatening acute attacks or intubation for asthma
5. History of seasonal asthma exacerbation,
6. Active or inactive lung tuberculosis or evidence of any active concomitant pulmonary disease other than asthma, i.e. chronic bronchitis, COPD,
7. Smoking within 6 months prior to visit 2 or during the study; for ex-smokers a smoking history of more than 10 pack-years (the equivalent of one pack per day for 10 years)
Previous / Concomitant medication
8. Patients naive for inhaled corticosteroids
9. More than 4 short courses of oral corticosteroids within the last year before visit 2 or any oral steroids within 6 months prior to visit 2.
10. Allergen immunotherapy in escalation dose regime within 3 months preceding visit 2
11. Within 3 days preceding to visit 1 or planned to be applied during the trial (after Visit2) use of:
a. leukotriene antagonists, inhaled cromolyn sodium; oral or parenteral corticosteroids (oral steroids are permitted for one period of maximal 14 days during the trial), long acting β2-agonists (other than study medication), theophylline, inhaled anti-cholinergics,
b. ß-blockers or potent inhibitors of the cytochrome P450-3A4 system e.g. ketoconazole, itroconazole (Selective β-blockers i.e. Nebivolol or Bisoprolol can be taken),
c. Vaccination with live-attenuated virus; exception: oral polio vaccine (Sabin) is allowed
12. Use of short-acting ß2 agonists within 6 hours preceding Visit 2 or planned to be applied during the trial except to rescue medication;
Other diseases and conditions
13. Impairment of adrenal cortex function, severe renal or hepatic disease.
14. Acute or history of severe cardiovascular disorders including cardiac arrhythmia, tachycardia (more than 120), idiopathic subvalvular coarctation of the aorta.
15. Serum potassium value on screening visit ˂ 3,5 mmol/L
16. Not controlled diabetes mellitus.
17. Not controlled hyperthyroidism.
18. History of paradoxical bronchospasm after inhalative asthma therapy.
19. History of hypersensibility to one or both of the active ingredient or to any other component of the IMP,Seretide® Diskus®, or rescue medication.
20. Presence of any other severe decompensated concomitant systemic disease (cardiovascular, endocrine, hematological, neurological, immunological) as judged by the investigator.
21. Other significant 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
Special restrictions for females
22. Pregnant or nursing women
23. Females of childbearing potential, 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, unless they are surgically sterilized / hysterectomized or any other criteria considered sufficiently reliable by the investigator in individual cases.
Others
24. Investigator’s suspicion of alcohol, drug or chemical abuse
25. Treatment with any investigational drug (i.e. drug not yet approved) within the last 3 months prior to Visit 2.
26. Previous or simultaneous participation in any other clinical study within 8 weeks preceding visit 1
27. Lack of sufficient co-operation / compliance or psychosocial problems.
28. Legal incapacity and/or other circumstances rendering the patient unable to understand the nature, scope and possible consequences of the study.
29. Positive SARS-CoV-2 Antigen test obtained at visit 1.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
To demonstrate equivalence of the test Investigational Medicinal Product (IMP), ComboFS, in the strengths 250 mcg/25 mcg and 125 mcg/25 mcg of fluticasone propionate and salmeterol to the reference IMP, Seretide® Diskus®, in the strengths 500 mcg/50 mcg and 250 mcg/50 mcg of fluticasone propionate and salmeterol, regarding the change from baseline in forced expiratory volume in 1 second (FEV1) at day 56 (end of first 8-week treatment period) and at day 112 (end of second 8-week treatment period) as well as baseline adjusted area under the serial FEV1 from time 0 to 12 hours (AUC0-12 hours) on the first day of treatment.
Primary endpoint of the study for baseline adjusted under the serial FEV1 from time 0 to 12 hours (AUC0-12 hours) on the first day of treatment will be assessed in the relevant subpopulation of the first 40 subjects enrolled to the study, while primary endpoint of the study for the change from baseline in FEV1 at the end of each 8-week treatment period will be assessed in the relevant population from the whole group of subjects enrolled to the study. The limitation of the size of population on which the objective for baseline adjusted FEV1 AUC0-12 hours will be assessed is motivated by technical difficulties in performing serial measurements of spirometry in pandemic conditions, while the size of the subpopulation under this analysis should be sufficient to provide the required testing power. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The secondary objectives will include the evaluation of baseline adjusted FEV1 AUC 0-12 hours at the end of each study periods, which will be evaluated on day 56, and day 112, as well as the evaluation of changes in morning peak expiratory flow (PEF) rate, analysis of FEV1 measurements performed each visit, as well as the assessment of Asthma Control Questionnaire (ACQ) results. Moreover, safety of the IMPs, in particular changes in morning serum and serial blood collection samples cortisol levels will be evaluated.
Secondary endpoint of the study for baseline adjusted under the serial FEV1 from time 0 to 12 hours (AUC0-12 hours) at the end of each study period and serial serum cortisol levels will be assessed in the relevant subpopulation of the first 40 subjects enrolled to the study, while other secondary endpoints will be assessed in the relevant population from the whole group of subjects enrolled to the study.
Safety
The following safety parameters will be assessed:
1. Safety laboratory examination: haematology, clinical chemistry (serum potassium levels in particular) and cortisol levels;
2. Vital signs (blood pressure, heart rate, body temperature);
3. Results of ECG examination;
4. Results of physical examination;
5. Adverse events.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Day 0, 14,4 2, 56, 70, 98, 112. |
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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 | 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) | 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 | Yes |
| 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 | 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 | 4 |
| 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 | 15 |
| 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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| 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 | 5 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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