E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic or heritable patients with pulmonary arterial hypertension (PAH). |
Idiopathic or heritable patients with pulmonary arterial hypertension (PAH). |
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E.1.1.1 | Medical condition in easily understood language |
Lung arterial hypertension |
Hyper tension artérielle pulmonaire |
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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 | 18.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
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 test the hypothesis that administration of inhaled BDs (?2-agonist and/or anticholinergic), as add-ons to vasodilators, would be beneficial to PAH patients by reducing and/or delaying the rate of onset of DH-induced critical ventilatory constraints, thus ameliorating the exertional symptoms in patients with stable PAH undergoing high-intensity constant work-rate (CWR) cycle endurance test. |
To test the hypothesis that administration of inhaled BDs (?2-agonist and/or anticholinergic), as add-ons to vasodilators, would be beneficial to PAH patients by reducing and/or delaying the rate of onset of DH-induced critical ventilatory constraints, thus ameliorating the exertional symptoms in patients with stable PAH undergoing high-intensity constant work-rate (CWR) cycle endurance test. |
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E.2.2 | Secondary objectives of the trial |
Difference (BD versus placebo) in CWR endurance time (60 seconds difference) will be also evaluated as potential index of improved exercise tolerance (secondary evaluation criterion). |
Difference (BD versus placebo) in CWR endurance time (60 seconds difference) will be also evaluated as potential index of improved exercise tolerance (secondary evaluation criterion). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Idiopathic or heritable PAH patients, clinically stable during the 3 preceding months, non/never smokers, with normal FEV1/VC ratio but FEF75% ? 60% predicted. |
Idiopathic or heritable PAH patients, clinically stable during the 3 preceding months, non/never smokers, with normal FEV1/VC ratio but FEF75% ? 60% predicted. |
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E.4 | Principal exclusion criteria |
1. Pregnant women 2. Past or current tobacco-smoking history, 3. A spirometric evidence of an obstructive ventilatory defect as defined by a reduced FEV1/VC ratio below the 5th percentile of the predicted value [43], 4. A FEF75% >60% of predicted normal values at spirometry, 5. A TLC below the 5th percentile of the predicted value [43], 6. A body mass index >30 kg.m-2, 7. Use of supplemental oxygen, 8. PAH induced by drugs and toxins, 9. PAH associated with other conditions, including connective tissue diseases, congenital heart diseases, portal hypertension, and HIV infection [42], 10. Chronic thromboembolic pulmonary hypertension [42], 11. Other respiratory, cardiac and other diseases that could contribute to dyspnoea or exercise limitation, 12. Contraindications to clinical exercise testing, such as NYHA functional class IV, syncope and others, as detailed page 28 elsewhere [26, 44]. 1. NYHA functional class IV 2. Syncope 3. Acute myocardial infarction (3-5 days) 4. Unstable angina 5. Uncontrolled arrhythmias causing symptoms or hemodynamic compromise 6. Uncontrolled heart failure 7. Active endocarditis 8. Acute myocarditis or pericarditis 9. Symptomatic severe aortic stenosis 10. Suspected dissecting aneurysm 11. Acute pulmonary embolus or pulmonary infarction 12. Thrombosis of lower extremities 13. Uncontrolled asthma 14. Pulmonary edema 15. Room air desaturation at rest <85% 16. Respiratory failure 17. Acute non-cardiopulmonary disorder that may affect exercise performance or be aggravated by exercise (i.e. infection, renal failure, thyrotoxicosis) 18. Mental impairment leading to inability to cooperate
Relative Contraindications to clinical exercise testing: Specific precision for exclusion criteria n°12: Absolute Contraindications to clinical exercise testing: 1. Left main coronary stenosis or its equivalent 2. Moderate stenotic valvular heart disease 3. Severe untreated arterial hypertension at rest (>200 mm Hg systolic, >120 mm Hg diastolic) 4. Tachyarrhythmias or bradyarrhythmias 5. High-degree atrioventricular block 6. Hypertrophic cardiomyopathy 7. Electrolyte abnormalities 8. Orthopedic impairment that compromises exercise performance 13. Specific contraindications (precautions and drug interactions) to the administration of IB or IB+SALB (please refer to section 7).
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1. Pregnant women 2. Past or current tobacco-smoking history, 3. A spirometric evidence of an obstructive ventilatory defect as defined by a reduced FEV1/VC ratio below the 5th percentile of the predicted value [43], 4. A FEF75% >60% of predicted normal values at spirometry, 5. A TLC below the 5th percentile of the predicted value [43], 6. A body mass index >30 kg.m-2, 7. Use of supplemental oxygen, 8. PAH induced by drugs and toxins, 9. PAH associated with other conditions, including connective tissue diseases, congenital heart diseases, portal hypertension, and HIV infection [42], 10. Chronic thromboembolic pulmonary hypertension [42], 11. Other respiratory, cardiac and other diseases that could contribute to dyspnoea or exercise limitation, 12. Contraindications to clinical exercise testing, such as NYHA functional class IV, syncope and others, as detailed page 28 elsewhere [26, 44]. 1. NYHA functional class IV 2. Syncope 3. Acute myocardial infarction (3-5 days) 4. Unstable angina 5. Uncontrolled arrhythmias causing symptoms or hemodynamic compromise 6. Uncontrolled heart failure 7. Active endocarditis 8. Acute myocarditis or pericarditis 9. Symptomatic severe aortic stenosis 10. Suspected dissecting aneurysm 11. Acute pulmonary embolus or pulmonary infarction 12. Thrombosis of lower extremities 13. Uncontrolled asthma 14. Pulmonary edema 15. Room air desaturation at rest <85% 16. Respiratory failure 17. Acute non-cardiopulmonary disorder that may affect exercise performance or be aggravated by exercise (i.e. infection, renal failure, thyrotoxicosis) 18. Mental impairment leading to inability to cooperate
Relative Contraindications to clinical exercise testing: Specific precision for exclusion criteria n°12: Absolute Contraindications to clinical exercise testing: 1. Left main coronary stenosis or its equivalent 2. Moderate stenotic valvular heart disease 3. Severe untreated arterial hypertension at rest (>200 mm Hg systolic, >120 mm Hg diastolic) 4. Tachyarrhythmias or bradyarrhythmias 5. High-degree atrioventricular block 6. Hypertrophic cardiomyopathy 7. Electrolyte abnormalities 8. Orthopedic impairment that compromises exercise performance 13. Specific contraindications (precautions and drug interactions) to the administration of IB or IB+SALB (please refer to section 7).
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E.5 End points |
E.5.1 | Primary end point(s) |
primary endpoint: ameliorating the exertional symptoms in patients with stable PAH undergoing high-intensity constant work-rate (CWR) cycle endurance test.
secondary endpoint: potential index of improved exercise tolerance (secondary evaluation criterion). |
primary endpoint: ameliorating the exertional symptoms in patients with stable PAH undergoing high-intensity constant work-rate (CWR) cycle endurance test.
secondary endpoint: potential index of improved exercise tolerance (secondary evaluation criterion). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
LSLV |
dernier visite du dernier patient |
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E.5.2 | Secondary end point(s) |
Change (increase) of at least 60 seconds in CWR-CPET endurance time between pre-dose and post-dose BD measured at the end of CWR bouts. This criterion will be used to evaluate the potential improvement in exercise tolerance. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
LSLV |
dernière visite du dernier patient |
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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 | No |
E.6.5 | Efficacy | No |
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 | No |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
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 | 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) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
sérum physiologique |
Physiological serum |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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 | Information not present in EudraCT |
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 | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |