E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Symptomatic Pulmonary Arterial Hypertension (WHO functional class II-III) of the following types: - Idiopathic - Familial - Associated with: Corrected congenital systemic-to-pulmonary shunts Drugs and toxins Patients are already on prescribed bosentan therapy for at least 12 weeks. |
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MedDRA Classification |
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 |
To demonstrate that a single dose of sildenafil 25 mg reduces pulmonary vascular resistance (PVR) in symptomatic stable patients with pulmonary arterial hypertension (PAH) already treated with bosentan 125 mg b.i.d. for at least 12 weeks. |
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E.2.2 | Secondary objectives of the trial |
To assess the effect of a single dose of sildenafil 25 mg on
1) total pulmonary resistance (TPR) and on
2) N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) in symptomatic stable patients with PAH already treated with bosentan 125 mg b.i.d. for at least 12 weeks.
3) To explore whether previous treatment with bosentan 125 mg b.i.d. for at least 12 weeks promotes vasoreactivity in patients who had been non-responders in a previous acute vasoreactivity test. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1) Signed informed consent
2) Men or women >= 18 years of age
3) Symptomatic PAH (WHO functional class II-III) of the following types: - Idiopathic - Familial - Associated with: Corrected congenital systemic-to-pulmonary shunts Drugs and toxins
4) PAH diagnosed by right heart catheter within 24 months before enrollment, showing: - Mean pulmonary arterial pressure (mPAP) >= 25 mmHg - Pulmonary capillary wedge pressure (PCWP) <= 15 mmHg
5) Documented non-responsiveness to acute vasoreactivity testing done within 24 months before enrollment but before start of bosentan therapy
6) Treated with bosentan 125 mg b.i.d. as monotherapy for PAH for at least 12 weeks before enrollment
7) Patient stable for at least 12 weeks before enrollment
8) Right heart catheterization for 2-3 hours medically acceptable
9) Pulmonary vascular resistance (PVR) at baseline 1 on the day of study performance >= 320 dyn.sec/cm5
10) Women of childbearing potential must have a negative pre-treatment urine pregnancy test and use a reliable method of contraception during bosentan treatment and for at least 3 months after bosentan treatment termination. |
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E.4 | Principal exclusion criteria |
1) Other types of PAH than listed above
2) Epoprostenol treatment planned
3) Suspected pulmonary veno-occlusive disease based on pulmonary edema during a previous vasoreactivity test or on abnormal findings compatible with that diagnosis (septal lines or pulmonary edema at high resolution computer tomography)
4) Systolic blood pressure < 85 mmHg
5) Body weight < 40 kg
6) Hemoglobin <75% of the lower limit of the normal range
7) AST and/or ALT > 3 times the upper limit of normal ranges
8) Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C
9) Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements
10) Conditions that prevent compliance with the protocol or adherence to therapy
11) Pregnancy or breast-feeding
12) Hypersensitivity to bosentan, sildenafil, or any of the excipients of their formulations
13) Use of an investigational drug within 3 months before enrollment
14) Treatment with PAH drugs, including endothelin receptor antagonists other than bosentan, PDE-5 inhibitors incl sildenafil, parenteral treatment (e.g., epoprostenol), other prostanoids, NO, or L-arginine within 3 months before enrollment
15) Treatment with calcineurin inhibitors (e.g., cyclosporine A, tacrolimus, everolimus, sirolimus), fluconazole, ketoconazole, miconazole, amiodarone, ritonavir, glibenclamide (glyburide), alpha-blockers, nitrates, or calcium antagonists within 3 months before enrollment |
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E.5 End points |
E.5.1 | Primary end point(s) |
PVR reduction from baseline 2 to 60 min after sildenafil administration expressed as percent change. This parameter is expected to be normally distributed with an SD of 20%. The reduction to be detected is 10%. |
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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 | 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 | Information not present in EudraCT |
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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Information not present in EudraCT |
E.8.1.3 | Single blind | Information not present in EudraCT |
E.8.1.4 | Double blind | Information not present in EudraCT |
E.8.1.5 | Parallel group | Information not present in EudraCT |
E.8.1.6 | Cross over | Information not present in EudraCT |
E.8.1.7 | Other | Information not present in EudraCT |
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 | No |
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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 |
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E.8.7 | Trial has a data monitoring committee | Information not present in EudraCT |
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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The end of trial is the last visit of the patient (28 days follow-up) |
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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 | |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 9 |