E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
pulmonary arterial hypertension |
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MedDRA Classification |
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 |
• To assess the safety and tolerability of oral STI571 compared with placebo in patients with pulmonary arterial hypertension. • To evaluate efficacy of oral STI571 as measured by improvement in 6-minute walk test.
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E.2.2 | Secondary objectives of the trial |
•To evaluate the efficacy of oral STI571 as measured by improvement Borg dyspoena scale, clinical status (WHO/NYHA class and dyspoena score), and changes in pulmonary haemodynamic parameters (including mean pulmonary arterial pressure, cardiac output and pulmonary vascular resistance) time to clinical worsening, changes in plasma biomarker levels. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Male and female patients equal to or greater than 18 years of age. 2. Diagnosis of pulmonary arterial hypertension (PAH) according to the Venice classification system (2003), of either primary (idiopathic), familial or secondary to systemic sclerosis (excluding those with marked pulmonary fibrosis). 3. Patients must have symptoms with a WHO class of II-IV (maximum of 50% of patients WHO Class IV will be included in the study). 4.Patients must have pulmonary vascular resistance (PVR) > 300 dyn sec-1 cm-5. 5. PAH medication must have been stable for at least 3 months prior to inclusion in the study (Baseline visit). 6. Female patients of child bearing potential must be using a double-barrier local contraception, i.e. intra-uterine device plus condom, or spermicidal gel plus condom up to completion of the Study Completion visit. 7. Able to communicate well with the investigator, to understand and comply with the requirements of the study. Understand and sign the written informed consent.
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E.4 | Principal exclusion criteria |
1. Use of unspecific phosphodiesterase inhibitors e.g. pentoxyfillin, enoximon, milrinone or pimobendan for the duration of the trial (screening visit to last measurement performed/ Study close-out visit). 2.Chronic inhaled Nitric oxide therapy from baseline to study completion visit (screening visit to last measurement performed/ Study completion visit). 3. Treatment with catecholamines (e.g. adrenalin > 500 ng/kg x min, noradrenalin > 500ng/kg x min, dopamine >5 ng/kg x min.), from screening visit to last measurement performed/ Study close-out visit. 4. Grapefruit juice should not be drunk whilst patients participate in the study. Special attention should be given to the co prescription of CYP3A4 inhibitors e.g. Amiodarone, Diltiazem, Verapamil, macrolide antibiotics, Itraconazole and Ketoconazole (For guidance on drug-drug interactions see section on concomitant medication) 5. Patient who have taken over-the-counter (OTC) medication (vitamins, herbal supplements and dietary supplements) within four (4) weeks prior to dosing. Paracetamol is acceptable, but must be documented in the Concomitant medications / Significant non-drug therapies page of the CRF. 6.Participation in any treatment studies within 3 months prior to dosing or longer if required by local regulations, and for any other limitation of participation based on local regulations. 7. Donation or loss of 400 ml or more of blood within 8 weeks prior to first dosing, or longer if required by local regulation. 8. History of other significant illness within four weeks prior to dosing. 9. Pre-exisiting lung disease including parasitic diseases affecting lungs, bronchial asthma congenital abnormalities of the lungs, thorax and diaphragm. 10. Pulmonary artery or valve stenosis (documented by corresponding pressure gradients detected at right heart catheterization), 11. Pulmonary venous hypertension with pulmonary capillary wedge pressure (PCWP) in excess of 12 mmHg 12. Chronic thromboembolic pulmonary hypertension 13. Acute heart failure or chronic left sided heart failure 14. Severe (systemic) arterial hypertension (> 200 mmHg (systolic) or > 120 mmHg (diastolic)) 15. Congenital or acquired valvular or myocardial disease 16. Deficiencies of blood coagulation (i.e. based on relevant changes in coagulation parameters), inherited or acquired blood coagulation disorders e.g. defects in factor VIII (Haemophilia A, v. Willebrand syndrome), factor XII, factor XIII; decreased generation of coagulation factors due to acute or chronic liver diseases, deficient coagulation due to auto-antibodies against coagulation factors such as in lupus anticoagulant 17. Disseminated intravascular coagulation (DIC) 18. Deficient thrombocyte function, thrombocytopenia < 40000/µl 19. Evidence of major bleeding or intracranial hemorrhage 20. Latent bleeding risk such as diabetic retinopathy, history of gastrointestinal bleeding (due to gastric or duodenal ulcers), colitis ulcerosa. 21. Moderate hepatic insufficiency Transaminase levels >4 fold the upper limit of normal or a bilirubin > 2 fold the upper limit of normal 22. Renal insufficiency (serum creatinine > 200 µmol/l) 23. Previous therapeutic radiation of lungs or mediastinum 24. History of elevated intracranial pressure (ICP 20 mmHg). 25. Pregnancy, breast feeding or lack of safe contraception (hormonal contraception, IUD, bilateral tubal ligation, hysterectomy) in premenopausal women. 26. Patients whose underlying disease is not likely to permit them to survive the study 27. Sickle cell anemia 28. History of clinically significant drug allergy or history of atopic allergy (asthma, urticaria, eczematous dermatitis). A known hypersensitivity to the study drug or drugs similar to the study drug. 29. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism or excretion of drugs or which may jeopardize the patient in case of participation in the study. The investigator should be guided by evidence of any of the following: •history of inflammatory bowel syndrome, gastritis, ulcers, gastrointestinal or rectal bleeding; •history of major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel resection; 30. History of immunodeficiency diseases, including a positive HIV (ELISA and Western blot) test result. 31. A positive Hepatitis B surface antigen (HBsAg) or Hepatitis C test result. 32. History of drug or alcohol abuse within the 12 months prior to dosing or evidence of such abuse as indicated by the laboratory assays conducted during the screening or baseline evaluations.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary efficacy analysis, will be on the difference between six minute walk tests at Week 24 between the two treatment groups, appropriate statistical testing will be performed on an intention to treat basis. A secondary analysis on the per protocol population will also be performed. Further analysis will be performed on all other secondary variables, where the mean and confidence interval for each variable will be listed and appropriate statistical comparisons made.
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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 | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
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 | 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) | 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
| No |
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 | 4 |
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 | Information not present in EudraCT |
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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Last visit of last subject |
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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 | 0 |
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 years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 9 |