| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ASTHMA UNCONTROLLED ON MEDIUM DOSES OF INHALED CORTICOSTEROIDS IN COMBINATION WITH LONG-ACTING ß2- AGONISTS |
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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 | 22.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003555 |
| E.1.2 | Term | Asthma bronchial |
| 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 the superiority of medium-dose BDP/FF/GB pMDI (100/6/12.5 µg, 2 puffs bid) compared to high-dose BDP/FF pMDI (200/6 pMDI µg, 2 puffs bid) in terms of the proportion of subjects exhibiting on average no Persistent Airflow Limitation (NPAL) over 26 weeks of treatment in the study sub-population with Persistent Airflow Limitation (PAL) at screening.
•A subject is defined as having PAL at screening if their post-bronchodilator (salbutamol) FEV1/FVC ratio is < 0.7.
•A subject is defined as having NPAL during the treatment period if the mean of their 2h post-dose FEV1/FVC ratios collected during the 26-week treatment period (i.e. from Week 0 to Week 26) is ≥ 0.7.
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| E.2.2 | Secondary objectives of the trial |
| To demonstrate the superiority of medium-dose BDP/FF/GB pMDI (100/6/12.5 µg, 2 puffs bid) compared to high dose BDP/FF pMDI (200/6 µg, 2 puffs bid) in terms of change from baseline in pre-dose FEV1 at Week 26 in the study sub-population meeting PAL criterion at screening. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed consent: Subject’s written informed consent obtained prior to any study related procedures;
2. Sex and age: Male or female subjects aged ≥ 18 and ≤ 75 years;
3. Diagnosis of asthma: A documented diagnosis of persistent asthma for at least 1 year according to GINA recommendations (Box 1-2, GINA report 2021), and with diagnosis before the subject’s age of 40 years;
4. Stable asthma therapy: a stable treatment with medium dose of inhaled corticosteroids (ICS) (extrafine BDP daily dose > 200 and ≤400 μg or estimated clinically comparable dose, as described in GINA 2021 box 3-6) plus a long-acting ß2-agonist (LABA) (formoterol 24 μg or salmeterol 100 μg or vilanterol 25 μg or other approved dose of LABA as clinically comparable to the others) for at least
4 weeks prior to screening;
5. Lung function: A prebronchodilator FEV1 < 80% of the predicted normal value, after appropriate washout from bronchodilators, at the screening and randomisation visits;
6. Bronchodilator responsiveness: A demonstrated increase in FEV1 > 12% and > 200 mL over baseline within 30 minutes after inhaling 400 μg of salbutamol pMDI (based on ATS/ERS guidelines);
7. A Post-bronchodilator FEV1/FVC ratio ≥ 0.5 within 30 minutes after inhaling 400 μg of salbutamol pMDI at screening (based on ATS/ERS guidelines);
8. Poor Asthma control: Evidence of poorly controlled or uncontrolled asthma as based on an Asthma Control Questionnaire© (ACQ-7) score ≥ 1.5 at screening and at randomisation;
9. History of asthma exacerbations: A documented history of one or more asthma exacerbations requiring treatment with systemic corticosteroids or emergency department visit or inpatient hospitalisation in the last 3 years prior to screening;
10. A willingness and ability:
- to correctly use the pMDI inhalers;
- to perform all trial related procedures including technically acceptable pulmonary function tests;
- to correctly use the e-Diary/e-Peak flow meter
11. Female subjects:
Woman of Childbearing Potential (WOCBP) fulfilling one of the following criteria: i. WOCBP with fertile male partners: they and/or their partner must be willing to use a highly effective birth control method from the signature of the informed consent and until the follow-up call or ii. WOCBP with non-fertile male partners (contraception is not required in this case).
For the definition of WOCBP and of fertile men and the list of highly effective birth control methods, refer to Appendix 4.
or
Female patient of non-childbearing potential defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile, as per definitions given in Appendix 4). Tubal ligation or partial surgical interventions are not acceptable. If indicated, as per investigator’s request, post-menopausal status may be confirmed by follicle-stimulating hormone levels (according to local laboratory ranges).
In case one of the inclusion criteria #5, #6, or #7 (#5: Pre-bronchodilator FEV1 value,
#6: Reversibility threshold, #7: Post-bronchodilator FEV1/FVC ratio) is not met at screening, they can be repeated together with ACQ-7 (inclusion criterion #8) once, no later than 5 days before randomisation.
Inclusion criteria #5 (Lung function), #8 (Poor Asthma control) and #10 (Co-operative attitude and ability) should be re-checked at the randomisation visit. |
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| E.4 | Principal exclusion criteria |
1. Pregnant or lactating woman where pregnancy is defined as the state of a female after conception and until termination of the gestation, confirmed by a positive pregnancy test (serum pregnancy test to be performed at screening visit and urine pregnancy test to be performed prior to randomisation);
2. Run-in compliance to study drug and e-Diary completion < 50% at randomisation;
3. History of “high risk” asthma: History of near fatal asthma or hospitalisation for asthma in an intensive care unit which, in the judgement of the Investigator, may place the subject at undue risk if enrolled in this study;
4. Recent asthma exacerbation: hospitalisation, emergency room admission or use of systemic corticosteroids for an asthma exacerbation in the 4 weeks prior to screening visit or during the run-in period;
Note: Subjects experiencing an exacerbation during the run-in period may be rescreened once, at least 4 weeks after recovery.
5. Non-persistent asthma: exercise-induced, seasonal asthma (as the only asthmarelated diagnosis) not requiring daily asthma control medicine;
6. Subjects using systemic corticosteroid medication in the 4 weeks or slow release corticosteroids in the 12 weeks, prior to screening;
7. Asthma requiring use of biologics: Subjects receiving asthma treatment with an injectable biologic drug such as monoclonal antibodies;
8. Respiratory disorders other than asthma: Subjects with known respiratory disorders other than asthma. This can include but is not limited to: diagnosis of COPD as defined by the current guidelines (e.g. GOLD Report), known alpha1-antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, interstitial lung diseases, idiopathic pulmonary fibrosis, and pulmonary hypertension;
Note: Diagnostic testing for tuberculosis is fully at the discretion of the investigator who should follow local disease diagnosis and reporting guidelines to confirm/exclude cases with suspicion of active or latent respiratory tuberculosis.
Appropriate testing may include a chest X-ray, sputum culture, histological investigations, and/or further imaging assessment, etc.
9. Lung cancer or history of lung cancer: Subjects with an active diagnosis of lung cancer or a history of lung cancer;
10. Lung resection: Subjects with a history of lung volume resection;
11. Respiratory tract infection: Subjects with respiratory tract infection within 4 weeks prior to screening or during the run-in period;
Note: Subjects experiencing a respiratory tract infection during the run-in period may be re-screened once, at least 4 weeks after recovery.
12. Smoking status: Current smoker or ex-smoker with a smoking history of ≥10 packyears (pack-years = the number of cigarette packs per day times the number of years).
Ex-smokers must have stopped smoking for ≥1 year (≥ 6 months for e-cigarettes).
13. Cancer or history of cancer (other than lung): Subjects with active cancer or a history of cancer with less than 5 years disease free survival time (whether or not there is evidence of local recurrence or metastases). Localised carcinoma (e.g. basal cell carcinoma, in situ carcinoma of the cervix adequately treated, …) is acceptable
For full list please refer to the Protocol
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of subjects exhibiting on average NPAL - status over 26 weeks of treatment in the study sub-population meeting PAL criterion at
screening. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Over 26 weeks of treatment |
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| E.5.2 | Secondary end point(s) |
| Change from baseline in pre-dose morning FEV1 at Week 26 in the study sub-population meeting PAL criterion at screening. |
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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 | No |
| E.6.4 | Safety | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
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| 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) | No |
| E.7.4 | Therapeutic use (Phase IV) | Yes |
| 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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 201 |
| 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 |
| United Kingdom |
| Belgium |
| Bulgaria |
| Czechia |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Latvia |
| Netherlands |
| Poland |
| Slovakia |
| Spain |
| Sweden |
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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 | 3 |
| E.8.9.1 | In the Member State concerned days | 16 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 25 |
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