E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial hypertension (PAH) patients who have a PVR≥800 dynes.sec.cm-5 despite treatment with two or more specific PAH therapies |
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MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 9.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10064911 |
E.1.2 | Term | Pulmonary arterial hypertension |
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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 |
• To evaluate the efficacy of QTI571 compared to placebo as measured by the change in 6-minute walk distance (6MWD) from baseline to 24-weeks |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the time to clinical worsening (TTCW), defined as all cause mortality, overnight hospitalization for worsening PAH (established by external adjudication committee), worsening of WHO functional class or a drop in 6MWD by 15% during 24 weeks of treatment with QTI571 as compared to placebo • To assess changes in health-related quality of life after 24 weeks of treatment (using CAMPHOR) with QTI571 compared with placebo • To assess the safety and tolerability of QTI571 • To evaluate change in pulmonary hemodynamics from baseline in patients after 24 weeks of treatment with QTI571 as compared to placebo • To assess change in Borg dyspnea score during 6MWT, monthly, with QTI571 as compared to placebo. • To assess the pharmacokinetics of QTI571 and the potential for interaction of QTI571 on sildenafil and bosentan • To assess the pharmacogenetics of QTI571 • To assess the use of different possible definitions of time TTCW as a measure of efficacy in treatment of PAH |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1) Male or female 18 years of age or older 2) 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 associated systemic sclerosis, PAH following one year repair of congenital heart defect (ASD, VSD or PDA), or PAH associated with diet therapies or other drugs 3) A PVR≥800 dynes.sec.cm-5 despite treatment with two or more specific PAH therapies, including endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5), or subcutaneous, inhaled, intravenous or oral prostacyclin analogues for ≥3 months. Background therapy doses must be stable for ≥30 days except for warfarin and prostacyclin analogues (≥30 days but doses can vary even within the month before enrollment) 4) WHO Functional Class II-IV. For WHO Functional Class IV, one of the 2 or more specific PAH therapies must be an inhaled, subcutaneous, intravenous or oral prostacyclin analogue, unless the subject has been shown to be intolerant of prostacyclin analogues. 5) 6MWD ≥ 150 meters and ≤ 450 meters at screening. Distances of two consecutive 6MWTs should be within 15% of one another. 6) Ability to provide written informed consent by the patient or a legal guardian
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E.4 | Principal exclusion criteria |
1. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. UNLESS they are a. women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner b. women whose partners have been sterilized by vasectomy or other means c. two birth control methods. 2. pregnant or nursing (lactating) women 3. have previously received treatment with imatinib 4. in treatment with chronic nitric oxide therapy 5. with a diagnosis of pre-existing severe lung disease including parasitic diseases affecting lungs, congenital abnormalities of the lungs, thorax or diaphragm or bronchial asthma that may significantly contribute to severity of PAH in the opinion of the investigator 6. with a pulmonary capillary wedge pressure > 15 mm Hg to rule out PAH secondary to left ventricular dysfunction If pulmonary capillary wedge pressure is not attainable, then a left atrial pressure measurement may be used in its place 7. with a diagnosis of pulmonary artery or vein stenosis 8. with other diagnosis of PAH in WHO Diagnostic Group 1 or 1' are excluded including congenital systemic to pulmonary shunts (large, small that are not surgically repaired), portal hypertension, HIV infection, hereditary hemorrhagic telangiectasia, hemoglobinopathies, veno-occlusive disease) 9. With a diagnosis of PAH associated with: venous hypertension (WHO Diagnostic Group II, including LVEF < 45%), 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, glycogen storage disease, Gaucher’s disease, myeloproliferative disorders). 9. with thrombocytopenia <50 x109/L 10. with a history of left heart failure in the past 3 months 11. with uncontrolled systemic arterial hypertension, systolic > 160 mmHg or diastolic >90 mmHg 12. with hemoglobin <100 g/L 13. with deficiencies of blood coagulation [for details, please report to the protocol] 14. with disseminated intravascular coagulation 15. with evidence of major bleeding or intracranial hemorrhage 16. with a history of elevated intracranial pressure 17. with a history of latent bleeding risk [for details, please report to the protocol] 18. with a history of moderate or greater hepatic insufficiency transaminase levels for details, please report to the protocol] 19. with a history of renal insufficiency 20. previous therapeutic radiation of lungs or mediastinum 21. with a history of sickle cell anemia 22. with a QTcF >450 msec for males and >470 msec for females at screening and baseline in the absence of right bundle branch block. 23. with a history of ventricular tachycardia, ventricular fibrillation or ventricular flutter 24. having a syncope in the 3 months prior to the screening visit 25. with a history of Torsades de Pointes 26. with a history of long QT syndrome 27. having undergone atrial septostomy in the 3 months prior to the screening visit 28. having undergone radiofrequency catheter ablation for atrial or sinus arrhythmias in the 3 months prior to screening visit 29. with an advanced, severe, or unstable disease of any type that may interfere with the primary and secondary endpoint evaluations 30. with a history of immunodeficiency diseases, including HIV 31. with a known hypersensitivity to QTI571 or drugs similar to the study drug 32. with a disability that may prevent the patient from completing all study requirements 33. with a life expectancy of 6 months or less 34. having used other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer 35. with a history of malignancy of any organ system, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases 36. With a diagnosis of Hepatitis B or C 37. With a history of alcohol abuse within 6 months of screening 38. With a history of illicit drug abuse within 6 months of screening 39. Male subjects must be using two acceptable methods of contraception, (e.g spermicidal gel plus condom) for the entire duration of the study, up to the Study Completion visit, and refrain from fathering a child in the three months following the last study drug administration. Periodic abstinence and withdrawal are not acceptable methods of contraception. 40. Patients with a diagnosis of systemic sclerosis, with the exception of those who can provide results from a pulmonary function test conducted within the 6 months preceding enrollment, showing total lung capacity(TLC)>70% If TLC ≤70%, a chest CT showing minimal lung parenchymal involvement must be produced Patients who fail to meet all inclusion/exclusion criteria may be re-screened. All re-screened patients must be assigned a new subject number. |
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E.5 End points |
E.5.1 | Primary end point(s) |
• 6MWD – a marker of exercise tolerance (the distance walked in 6 minutes during a 6-minute walk test according to ATS guidelines) |
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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 | 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 | 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 | 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 | 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.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 29 |
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 | 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
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
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 |