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 | 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 |
To demonstrate the superiority of BDP/FF/GB 100/6/12.5 pMDI compared to BDP/FF 200/6 pMDI in terms of the proportion of subjects exhibiting on average no Airflow Obstruction (AO-) over 26 weeks of treatment in the study sub-population with airflow obstruction (AO+) at screening. •A subject is defined as AO+ at screening if their post-bronchodilator (salbutamol) FEV1/FVC ratio is < 0.7. •A subject is defined as AO- during the treatment period if the mean of their 3h 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 BDP/FF/GB 100/6/12.5 pMDI compared to BDP/FF 200/6 pMDI in terms of change from baseline in pre-dose FEV1 at Week 26 in the study sub-population meeting AO+ 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.Gender and age: Male or female subjects aged ≥ 18 and ≤ 75 years; 3.Diagnosis of asthma: A documented diagnosis of permanent 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 pre bronchodilator FEV1 < 80% of the predicted normal value, after appropriate washout from bronchodilators, at the screening and randomisation visits; 6.Reversibility of bronchoconstriction: 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 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 cooperative attitude 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 and home-spirometry device. 11.Female subjects: a.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). or b.Female patient of non-childbearing potential defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile). 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).
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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 “at risk” asthma: History of near fatal asthma or of a past hospitalisation for asthma in intensive care unit which, in the judgement of the Investigator, may place the subject at undue risk; 4.Recent 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 re-screened once, at least 4 weeks after recovery. 5.Non-permanent asthma: exercise-induced, seasonal asthma (as the only asthma-related 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 α1-antitrypsine deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension and interstitial lung disease; 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 pack-years (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; 14.Cardiovascular diseases: Subjects who have clinically significant (CS) cardiovascular condition according to Investigator’s judgement, such as but not limited to: congestive heart failure (NYHA class IV), unstable or acute ischaemic heart disease in the last year prior to screening, history of sustained and non-sustained cardiac arrhythmias diagnosed in the last 6 months prior to screening (sustained meant lasting more than 30 seconds or ending only with external action, or led to haemodynamic collapse; non-sustained meant > 3 beats < 30 seconds, and or ending spontaneously, and or asymptomatic), high degree impulse conduction blocks (> 2nd degree atrioventricular block type 2),persistent, long standing or paroxysmal atrial fibrillation (AF); Note: Subjects with permanent AF (for at least 6 months prior screening) with a resting ventricular rate < 100/min, controlled with a rate control strategy (i.e. selective β blocker, calcium channel blocker, pacemaker placement, digoxin or ablation therapy) can be considered for enrolment; 15.ECG criteria: Any abnormal and clinically significant 12-lead ECG that in the investigator's opinion would affect efficacy or safety evaluation or place the subjects at risk. 16.ECG QTcF: Male subjects with a Fridericia’s corrected QT interval (QTcF) >450 msec and female subjects with a QTcF >470 msec at screening are not eligible (not applicable for subjects with permanent atrial fibrillation and for subjects with pacemaker); 17.Subjects with a medical history or current diagnosis of narrow angle glaucoma, symptomatic prostatic hypertrophy, urinary retention bladder neck obstruction that, in the opinion of the Investigator, would prevent use of anticholinergic agents; Note: Benign prostatic hyperplasia subjects who are stable under treatment can be considered for inclusion. 18.CNS disorders: Subjects with a history of symptoms or significant neurological disease such as but not limited to transient ischemic attack (TIA), stroke, seizure disorder or behavioural disturbances according to the investigator’s opinion;
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 Airflow Obstruction- status over 26 weeks of treatment in the study sub-population meeting AO+ 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 Airflow Obstruction+ 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 | 10 |
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 |
Belgium |
Bulgaria |
Finland |
France |
Germany |
Hungary |
Italy |
Latvia |
Netherlands |
Poland |
Slovakia |
Spain |
Sweden |
United Kingdom |
Czechia |
Greece |
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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 | 4 |
E.8.9.1 | In the Member State concerned days | 5 |
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 |