| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Pulmonary Arterial Hypertension (PAH) |
| Ipertensione Arteriosa Polmonare |
|
| E.1.1.1 | Medical condition in easily understood language |
| Pulmonary Arterial Hypertension |
| Ipertensione Arteriosa Polmonare |
|
| 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 | 14.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10037400 |
| E.1.2 | Term | Pulmonary hypertension |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
|
| 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 |
| Primary objective • To evaluate the effect of nilotinib on pulmonary vascular resistance (PVR) compared to placebo after 24 weeks of therapy |
| Obiettivo Primario o Valutare l’effetto di nilotinib sulle resistenze vascolari polmonari (RVP) confrontato verso placebo dopo 24 settimane di terapia |
|
| E.2.2 | Secondary objectives of the trial |
| Secondary objectives Key • To test the effect of nilotinib on 6 min walk distance (6MWD) relative to baseline and compared to placebo after 24 weeks of therapy. Other • Establish the safety and tolerability of nilotinib in patients with PAH including effects on QTc and platelet activation • To test the effect of nilotinib on pulmonary vascular resistance relative to baseline after 24 weeks of therapy • To test the effect of nilotinib on other hemodynamic parameters, including cardiac output/index (CO/CI), pulmonary artery pressure (PaP), pulmonary capillary wedge pressure (PCWP), systemic pressure (SAP) and resistance (SVR) • To test the effect of nilotinib on time to clinical worsening (TTCW) compared to placebo • To assess change in Borg dyspnea score during 6-min walk testing, with nilotinib as compared to placebo • To assess the pharmacokinetics of nilotinib in this patient population. |
| Obiettivi Secondari Chiave o Testare l’effetto di nilotinib sulla 6 min walk distance (6MWD) rispetto al basale e confrontato verso placebo dopo 24 settimane di terapia Altri o Stabilire la sicurezza e la tollerabilita` di nilotinib in pazienti con PAH inclusi gli effetti sul QTc e l’attivazione piastrinica o Testare l’efficacia di nilotinib sulle resistenze vascolari polmonari rispetto al basale dopo 24 settimane di trattamento o Testare l’effetto di nilotinib su altri parametri emodinamici,inclusi l’outout/indice cardiaco,la pressione dell’arteria polmonare,la pressione di incuneamento capillare polmonare,la pressione arteriosa e le resistenze periferiche o Valutare modifiche nella scala di Borg della dispnea durante 6MWD con nilotinib confrontato verso placebo o Valutare la farmacocinetica di nilotinib in questa popolazione di pazienti |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| Inclusion criteria Patients eligible for inclusion in this study have to fulfill all of the following criteria: 1. Written informed consent must be obtained before any assessment is performed 2. Male or female 18 years of age or older who are unable to bear children and females of child bearing potential not disqualified as per Exclusion Criterion 1 (below) 3. WHO Functional Class II or III 4. 6MWD ≥ 150 m and ≤ 450 m at screening. Distances of two consecutive 6MWTs should be within 15% of one another 5. A current diagnosis of Pulmonary Arterial Hypertension according to the Dana Point 2008 Meeting: WHO Diagnostic Group I, idiopathic or heritable (familial or sporadic) PAH, PAH associated with collagen vascular disease including systemic sclerosis, rheumatoid arthritis, mixed connective tissue diseases, and overlap syndrome. PAH following one year repair of congenital heart defect (ASD, VSD or PDA), or PAH associated with diet therapies or other drugs 6. Inadequate clinical response despite stabilization on one or more class(es) of PAH drug [e.g., PDE5 inhibitor, endothelin receptor blocker, vasodilator prostaglandin (systemic, inhaled or oral)] 7. Stabilization of pulmonary hypertension medications defined as observed for ≥ 2 months on approved therapeutic dose of at least one PAH drug and still symptomatic with WHO functional Class II or III performance. |
| Inclusione • Pazienti che hanno fornito consenso informato scritto • Maschi o femmine di eta` maggiore o uguale a 18 anni • Classe funzionale II o III secondo la classificazione della WHO • Distanza >150 m e <450 m al 6MWD al basale • Diagnosi di Ipertensione Arteriosa Polmonare in accordo alla definizione del Meeting Dana Point 2008: Gruppo Diagnostico I secondo la classificazione WHO, PAH idiopatica o ereditaria (familiare o sporadica), PAH associata a collagenopatie incluse la sclerodermia, l’artrite reumatoide, patologie del tessuto connettivo, e sindrome da overlap. PAH conseguente a correzione di difetti cardiaci congeniti (difetto del setto interatriale, difetto del setto interventricolare o dell’arteria discendente posteriore) o PAH associata ad assunzione prolungata di farmaci inibitori del senso della fame o di altri farmaci • Inadeguata risposta clinica nonostante terapia stabile da almeno un anno con una classe di farmaci specifici per la PAH |
|
| E.4 | Principal exclusion criteria |
| Exclusion criteria Patients fulfilling any of the following criteria are not eligible for inclusion in this study: 1. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. UNLESS they are: women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner women whose partners have been sterilized by vasectomy or other means using two birth control methods. The two methods can be a double barrier method or a barrier method plus a hormonal method. Adequate barrier methods of contraception include: diaphragm, condom (by the partner), intrauterine device (copper or hormonal), sponge or spermicide. Hormonal contraceptives include any marketed contraceptive agent that includes an estrogen and/or a progestational agent 2. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 10 mIU/mL) 3. History of ventricular tachycardia, ventricular fibrillation or ventricular flutter 4. Use of drugs known to prolong the QT interval or known to be strong CYP3A4 inhibitors (refer to Appendix 6) 5. Untreated or inadequately controlled hypokalemia (<3.5 mmol/L) or hypomagnesemia (<0.65 mmol/L) at the screening visit (Visit 1) 6. Evidence of clinically significant left ventricular dysfunction. 7. Evidence of clinically significant hepatic impairment, including AST or ALT > 3 times the upper limit of normal (if due to bosentan therapy subject is excluded unless bosentan is discontinued and the above LFTs return to < 2 times the upper limit of normal; Subject must still be on a stable regimen including at least one approved PAH therapy at time of study drug randomization). Bilirubin > 2 times the upper limit of normal. [Canada only: AST or ALT > 1.5 times the upper limit of normal] 8. Atrial fibrillation or history of atrial fibrillation in the previous 3 months 9. Having syncope in the 3 months prior to the screening visit 10. History of previous myocardial infarction, unstable angina, or clinically significant bradycardia (<60 bpm and accompanied by clinical symptoms) 11. QRS > 120 ms or > 140 ms in the presence of bundle branch block 12. Current or history of consistently prolonged QTcF (2 or more ECGs in the prior 12 months in the absence of a right bundle branch block or QTcF>450 ms for males and > 470 ms for females at screening); family history of long QT syndrome 13. WHO Class IV 14. History of Torsades de Pointes 15. In treatment with chronic nitric oxide therapy 16. Pre-existing lung disease including parasitic diseases affecting lungs, congenital abnormalities of the lungs, COPD, thorax or diaphragm or bronchial asthma, associated with chronic hypoxia that may contribute to severity of PAH 17. With a pulmonary capillary wedge pressure > 15 mm Hg to rule out PAH secondary to left ventricular dysfunction 18. Diagnosis of pulmonary artery or vein stenosis 19. With other diagnosis of PAH in WHO Diagnostic Group 1 are excluded including congenital systemic to pulmonary shunts (large, small that are not surgically repaired), portal hypertension, HIV infection, glycogen storage disease, Gaucher’s disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders) 20. With a diagnosis of PAH associated with: venous hypertension (WHO Diagnostic Group II), hypoxia (WHO Diagnostic Group III), chronic pulmonary thromboembolic disease (WHO Diagnostic Group IV) or other miscellaneous causes (WHO Diagnostic Class V, which includes sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels) 21.PLS SEE PROTOCOL |
| Esclusione • QTc >450 ms nei maschi e >470 ms nelle femmine al basale • Storia di sincope nei tre mesi precedenti la visita di screening • Storia di malattie ematologiche o di sanguinamento Per maggiori dettagli consultare il capitolo 4 del protocollo originale. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Pulmonary Vascular Resistance (PVR) |
| Resistenza Vascolare Polmonare |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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 | Yes |
| 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) | 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 | 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| - Stesso farmaco ad altro dosaggio |
| - same IMP used at different dosage |
|
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Canada |
| Korea, Republic of |
| Singapore |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| LVLS : 14/OCT/2013 |
| LVLS : 14/10/2013 |
|
| 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 | 17 |
| 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 | 27 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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