E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
severe pulmonary hypertension |
ipertensione polmonare severa |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | HLT |
E.1.2 | Classification code | 10037401 |
E.1.2 | Term | Pulmonary hypertensions |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
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 purpose of this study is to evaluate the tolerability and clinical efficacy of an oral combination therapy Bosentan-Sildenafil, in patients with severe pulmonary hypertension due to PAH or distal chronic thromboembolic pulmonary hypertension. |
Scopo primario dello studio e' la valutazione dell'efficacia e della tollerabilita' dell�+associazione terapeutica Bosentan-Sildenafil nel trattamento dell�ipertensione polmonare severa dovuta o ad ipertensione arteriosa polmonare primitiva o ad ipertensione polmonare secondaria a malattia tromboembolica distale cronica. |
|
E.2.2 | Secondary objectives of the trial |
The study will be extended also to patients with distal CTEPH because: - These patients present, beside proximal vessels obstruction, with distal lesion involving small and medium size pulmonary arteries similar to other form of severe pulmonary hypertension. - Furthermore an open uncontrolled study suggest beneficial hemodynamic effect after epoprostenol , sildenafil and bosentan therapy. |
Lo studio verra' esteso anche a pazienti con ipertensione polmonare da malattia tromboembolica distale cronica perche': questi pazienti presentano ostruzione vascolare prossimale con lesioni distali che coinvolgono arterie polmonari di piccolo e medio calibro come in altre forme di ipertensione polmonare severa uno studio �aperto� ha suggerito un benefico effetto sull�emodinamica polmonare dopo l�assunzione di terapia combinata con prostanoidi, IPDE-5 e antagonisti del recettore per endotelina. Lo studio confrontera' l�efficacia della terapia combinata Bosentan-Sildenafil rispetto alla monoterapia con Bosentan o Sildenafil nei pazienti con ipertensione polmonare severa. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria 1) Patients with idiopathic or familial pulmonary arterial hypertension (PAH) 2) Patients with distal Chronic Thromboembolic Pulmonary Hypertension 3) PAH associated to connective tissue disease, anorexigen, congenital heart disease. 4) Age > 18 years 5) Mean pulmonary pressure > 25 mmHg, mean pulmonary capillary ''wedge'' pressure <15 mm Hg at right catheterization evaluation 6) No vasodilating response to inhaled nitric oxide, or ''vasoreactive'' patients in chronic calcium channel blockers 7) WHO functional class 2-3 |
Criteri di inclusione: 1) Pazienti con ipertensione arteriosa polmonare Idiopatica o Familiare 2) Pazienti con ipertensione polmonare da malattia tromboembolica distale cronica 3) Ipertensione arteriosa polmonare associata a malattie del connettivo, assunzione di farmaci anoressizzanti e cardiopatie congenite 4) Eta' >18 anni 5) Pressione arteriosa polmonare media >25 mmHg, (pressione capillare polmonare media �wedge� pressure >15 mmHg stimata con cateterismo cardiaco) 6) Pazienti non responders a terapia inalatoria con ossido nitrico o pazienti �vasoreattivi� in terapia cronica con calcio-antagonisti 7) II o III classe funzionale WHO |
|
E.4 | Principal exclusion criteria |
Exclusion criteria: 1) Significant reduction in pulmonary function test (FVC, FEV1 < 70 % normal predicted value) 2) Treatment with other drug for PAH (endothelin receptor antagonist, prostanoids, PDE-5 inhibitors 3) Previous combination therapy with current drugs 4) Systemic hypotension (systolic blood pressure < 90 mmHg) 5) Chronic liver disease (Child-Pugh class B o C) or transaminases increased > 3 fold upper normal limits 6) Pshyschiatric disease or other condition that will be an impediment to the protocol 7) Pregnancy or lactation 8) Known hypersensitivity to bosentan or sildenafil 9) Treatment with other drugs that could have significant interaction with bosentan or sildenafil: calcineurine inhibitors (ciclosporine tacrolimus…), antimycotics (fluconazole, chetoconazole…), amiodarone, antiretroviral drug, glibencamide, nitrates, alfa-blockers. |
Criteri di esclusione: 1) Significativa riduzione nelle prove di funzionalita' respiratoria (FVC, FEV1<70% valori normali) 2) Trattamento con altri farmaci per ipertensione arteriosa polmonare (antagonisti dei recettori per l�endotelina, prostanoidi, IPDE-5) 3) Precedente assunzione di terapia combinata con farmaci in uso 4) Ipotensione sistemica (pressione arteriosa sistolica < 90 mmHg) 5) Malattie croniche epatiche (classe B o C Child-Pugh) o incremento delle transaminasi >3 FOLD (volte) oltre i limiti normali 6) Malattie psichiatriche o patologie che impediscono la realizzazione del protocollo 7) Gravidanza o allattamento 8) Ipersensibilita' nota ad uno dei farmaci in studio 9) Trattamento con altri farmaci che potrebbero avere interazioni significative con il bosentan o l�udenafil: inibitori della calcineurina (ciclosporina o tacrolimus), antimicotici (fluconazolo, ketoconazolo), amiodarone, farmaci antiretrovirali, glibenclamide, nitrati, alfa litici. |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary endpoints will be: - Improvement of functional capacity compared to the basal conditions and to the period of monotherapy evaluated through distance 6 minutes walking test. - Improvement of the quality of life (WHOQOL-BRIEF questionnaire) |
I principali risultati attesi saranno: - miglioramento della capacita' funzionale dopo terapia combinata confrontata con le condizioni basali e in seguito ai tre mesi di monoterapia valutata attraverso il test di 6 minuti del cammino - miglioramento della qualita' di vita valutato attraverso un questionario (WHOQOL-BRIEF questionnaire) |
|
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 | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | 11 |
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 | No |
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
|
arruolamento di tutti i pazienti |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 24 |
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 | 24 |
E.8.9.2 | In all countries concerned by the trial days | 0 |