E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Idiopathic pulmonal arterial hypertension |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 12.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10020787 |
E.1.2 | Term | Hypertension pulmonary |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The main question of this study is: ‘Is selective beta-blocker treatment safe and effective in reducing sympathetic overdrive, thereby improving RV function and remodeling in patients with iPAH?‘ Safety of Bisoprolol treatment in iPAH patients is not taken as a primary endpoint but seen as a precondition for this study and will be closely monitored. Dose titration will be guided by possible side effects. Furthermore, although beta-blocker are considered contraindicated in PAH patients, a considerable number of patients frequently receives beta-blocker therapy in an uncontrolled way (3), without any side effects being reported until now. Our primary efficacy endpoint is improvement in RV function as reflected by RVEF determined by means of cardiac MRI.
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E.2.2 | Secondary objectives of the trial |
In addition to the determination of RVEF, we will explore how beta-blocker therapy affects sympathetic overdrive, remodeling of the RV, single beat elastance, exercise capacity and mechanical efficiency. This will provide us with useful information with regards to the mode of action of beta-blocker therapy in iPAH, or alternatively, why beta-blocker may be ineffective in these patients. Therefore we have the following additional study questions: * Is Bisoprolol treatment effective in reducing sympathetic overdrive? * Is Bisoprolol effective in reversing maladaptive remodeling of the right ventricular wall, and does Bisoprolol thereby improve the diastolic properties of the right ventricle? * Is Bisoprolol treatment effective in improving the perfusion and mechanical efficiency (oxygen consumption per joule) of the heart? * Is Bisoprolol effective in improving exercise capacity? |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Population: The VUMC serves as a national tertiary referral centre for the diagnosis and treatment of PAH and had 1500 referrals in 10 years. Currently more than 100 idiopathic PAH patients are treated in the VUMC, which make it possible to select our study population with care from this large cohort. We choose to limit our study to idiopathic PAH patients, since this is a well-characterized homogenous group with little or no co-morbidities. It is estimated that the current prevalence of iPAH in the Netherlands is about 200 patients. However, if our results turn out to be positive this might have an important impact on the management of other more common types of pulmonary hypertension.
Inclusion criteria From our database containing currently 156 PAH patients we will carefully select patients who meet the following inclusion criteria: • Idiopathic PAH patients • Stable on PAH specific treatment defined o No change in PAH specific treatment in the past 6 months o No change in functional class in the past 6 months o <10 % change in 6 minute walk distance in the past 6 months • Functional class 2 or 3 • In sinus rhythm
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E.4 | Principal exclusion criteria |
Exclusion criteria are • History of systemic hypertension, ischaemic heart disease, valvular disease or cardiomyopathy. • Asthma • Use of concomitant medication other than diuretics, Acenocoumarol and PAH targeted therapy • History of cardiac arrhythmias or the use of anti-arrhythmic drugs • Sick sinus syndrome • systolic hypotension < 90 mmHg • AV-block • Clinically relevant sinus-bradycardia.
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E.5 End points |
E.5.1 | Primary end point(s) |
Safety of Bisoprolol treatment in iPAH patients is not taken as a primary endpoint but seen as a precondition for this study and will be closely monitored. Dose titration will be guided by possible side effects. Furthermore, although beta-blocker are considered contraindicated in PAH patients, a considerable number of patients frequently receives beta-blocker therapy in an uncontrolled way (3), without any side effects being reported until now. Our primary efficacy endpoint is improvement in RV function as reflected by RVEF determined by means of cardiac MRI.
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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 | 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.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 | 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 | Yes |
E.8.2.3 | Other | No |
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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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 | 6 |
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 |