A randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of six months treatment with the tyrosine kinase inhibitor of STI571 for the treatment of pulmonary arterial hypertension.

• Register: EUCTR
• Last refreshed on: 10 July 2015
• Main ID: EUCTR2005-005569-12-GB
• Date of registration: 02/12/2005
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public title: A randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of six months treatment with the tyrosine kinase inhibitor of STI571 for the treatment of pulmonary arterial hypertension.
• Scientific title: A randomized, double-blind, placebo-controlled study to evaluate the safety and efficacy of six months treatment with the tyrosine kinase inhibitor of STI571 for the treatment of pulmonary arterial hypertension.
• Date of first enrolment: 26/01/2006
• Target sample size: 60
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2005-005569-12
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: no Cross over: no Other: yes Other trial design description: open label phase after 6 months. If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: yes Other specify the comparator: Open label phase after 6 months

Countries of recruitment

Austria, Germany, United Kingdom

Key inclusion & exclusion criteria

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 or oral contraceptive 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.
OPEN LABEL PHASE:
1. Males and Females 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. Female patients of child bearing potential must be using a double-barrier contraception, i.e. intra-uterine device plus condom, or spermicidal gel plus condom or oral contraceptive plus condom up to completion of the Study Completion visit.
4. Able to communicate well with the investigator, to understand and comply with the requirements of the study. Understand and sign the written informed consent.
5. Subjects who are presently receiving imatinib following participation in teh randomised STI571E2203 study or subjects who will complete participation in the six month randomised STI571E2203 study.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

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.
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. Although patients on open long term extensions from other trials can participate in this study providing that the formal study period is over.
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, congenital abnormalities of the lungs, thorax or diaphragm or bronchial asthma
associated with chronic hypoxia that may contribute to the severity of Pulmonary Arterial Hypertension
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. History of latent bleeding risk such as diabetic retinopathy, gastrointestinal bleeding (due to gastric or duodenal ulcers) or 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. Elevated transaminase level should be carefully monitored because of known liver toxicity of STI571.
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
26. Patients whose underlying disease is not likely to permit them to survive

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

pulmonary arterial hypertension

Intervention(s)

Trade Name: Glivec
Product Name: Glivec
Product Code: STI571
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Imatinib
Current Sponsor code: STI571
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Capsule, hard
Route of administration of the placebo: Oral use

Product Code: STI571
Pharmaceutical Form: Coated tablet
INN or Proposed INN: Imatinib
Current Sponsor code: STI571
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-

Primary Outcome(s)

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.

Main Objective: • 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.

Secondary Objective: •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.
•To collect and monitor safety data of imatinib, provided as open-label medication to patients with pulmonary arterial hypertension (PAH) who were enrolled in the six month randomised, placebo controlled STI571E2203.

Secondary ID(s)

CSTI571E2203