E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial hypertension (PAH) |
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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 |
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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 investigate the effect of two dose levels of QTI571 on the pharmacokinetics of the coadministered drugs sildenafil and bosentan at steady-state in patients with pulmonary arterial hypertension. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the safety and tolerability of QTI571 and the co-administered drugs sildenafil and bosentan at pharmacokinetic steady state in patients with pulmonary arterial hypertension - To evaluate the pharmacokinetics of QTI571 and its active metabolite at steady-state in patients with pulmonary arterial hypertension |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Male or female patients aged 18 years or older. 2.A current diagnosis of Pulmonary Arterial Hypertension (PAH) 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 post 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 as assessed by right heart catheterization (RHC) at screening or within 6 months preceding screening, despite treatment with two specific PAH therapies such as endothelin receptor antagonists, phosphodiesterase 5 inhibitor or prostacyclin analogues. 4.WHO Functional Class II-III. 5.Ability to provide written informed consent. 6.Patients must be on a stable dose of bosentan (125 mg b.i.d) and a stable dose of sildenafil(as prescribed by their physician) for at least 4 weeks prior to randomization, and are expected to remain on these doses throughout the duration of the study. |
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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 use two birth control methods.2. Pregnant or nursing (lactating) women 3.Have previously received treatment with QTI571 (imatinib).4.Have shown intolerance to sildenafil or bosentan.5. With other diagnosis of PAH in WHO Diagnostic Group 1.6.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).7.Significant lung disease not related to PAH such as parasitic diseases affecting lungs, congenital abnormalities of the lungs,thorax or diaphragm or bronchial asthma associated with chronic hypoxia that may contribute to severity of PAH, diagnosis of pulmonary artery or vein stenosis, a diagnosis of chronic pulmonary thromboembolic disease(WHO Diagnostic Group IV).8.Patients with systemic sclerosis may participate only if a pulmonary function test result within the last 6 months is available at screening visit, that shows a total lung capacity of >70% of predicted,or if the TLC≤70% of the predicted,a chest CT (within last 6 months)must be available that shows minimal lung parenchyma involvement.9. Significant hematological disorders including: thrombocyte dysfunction, thrombocytopenia with platelet < 50 x 103/μL, neutropenia with WBC < 0.5 of the lower limit of normal range, or hemoglobin < 10 g/dL 10.Cardiovascular disorders (for more details, see the protocol).11.With deficiencies of blood coagulation, inherited or acquired blood coagulation disorders (for more details, see the protocol).12.With evidence of major bleeding or intracranial hemorrhage and a history of latent bleeding risk such as diabetic retinopathy,gastrointestinal bleeding due to gastric or duodenal ulcers, or colitis ulcerosa.13. With a history of elevated intracranial pressure.14. With a history of moderate or greater hepatic insufficiency or transaminase levels > 3 times the upper limit of normal or bilirubin > 2 times ULN. 15. With a history of renal insufficiency (serum creatinine > 200 μmol/L or 2.6 mg/dL).16.Previous therapeutic radiation of lungs or mediastinum.17.With a history of sickle cell anemia.18.With an advanced, severe, or unstable disease of any type that may interfere with the primary and secondary endpoint evaluations.19.With a history of immunodeficiency diseases, including HIV,a history of Hepatitis B or C.20. Alcohol or drug abuse within last 6 months before screening visit.21.With a known hypersensitivity to QTI571 (imatinib) or drugs similar to the study drug.22.With absolute contraindications to sildenafil (concomitant use of organic nitrates,hypersensitivity ractions to sildenafil, intake of other PDE-5 inhibitors).23.With absolute contraindications to bosentan (pregnancy, concomitant intake of cyclosporine A or glyburide, hypersensitivity reactions).24.Body weight below 40 kg.25.Need for concomitant treatment with the compounds known to be strong inhibitors or inducers of CYP3A, CYP2C9.26.Having used other investigational drugs at the time of enrollment, or within 30 days or 5 elimination half-lives of the drug at enrollment, whichever is longer.27. Fertile males UNLESS the subject agrees to comply with two highly effective contraceptive methods comprising a barrier method for the entire duration of the study, up to the Study Completion visit, and refrain from fathering a child for at least three (3) months following the last study drug administration Periodic abstinence and withdrawal are not acceptable methods of contraception.28.In treatment with chronic nitric oxide therapy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pharmacokinetics analysis |
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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 | No |
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 | 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) | 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 | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
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 | Yes |
E.8.2.3.1 | Comparator description |
- same IMP used at different dosage |
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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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 | 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
| |
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 | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |