Safety and Efficacy of Imatinib Mesylate in Patients With Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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This study will evaluate the safety, tolerability, and efficacy of imatinib mesylate in patients with pulmonary arterial hypertension

Official Title
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A Randomised, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of the Six Months Treatment With the Tyrosine Kinase Inhibitor STI571 for the Treatment of Pulmonary Arterial Hypertension (PAH)

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Imatinib mesylate
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of PAH of either primary (idiopathic), familial or secondary to systemic sclerosis (excluding those with marked pulmonary fibrosis) according to World Conference on Pulmonary Hypertension classification (Venice, 2003). Symptoms with a WHO class of II-IV Exclusion Criteria: Use of unspecific phosphodiesterase inhibitors (for example, pentoxyfillin, enoximon, milrinone or pimobendan) during the study Chronic inhaled nitric oxide therapy from start to study completion Treatment with catecholamines (for example, adrenalin, noradrenalin, dopamine), Pre-existing lung diseases, including parasitic diseases affecting lungs, asthma, congenital abnormalities of the lungs, chest, and diaphragm. Pulmonary artery or valve stenosis; pulmonary venous hypertension; chronic thromboembolic pulmonary hypertension Acute heart failure or chronic left sided heart failure; congenital or acquired valvular or myocardial disease Severe (systemic) arterial hypertension (> 200 mmHg (systolic) or > 120 mmHg (diastolic)) Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: STI571<br>STI571 | Drug: Imatinib mesylate<br> <br> * Other names: Imatinib, Glivec, Gleevec, STI571, QTI571;|
| Placebo Comparator: Placebo<br>Placebo | Drug: Placebo<br> <br> |
| Experimental: All Patients<br>Open label extension | Drug: Imatinib mesylate<br> <br> * Other names: Imatinib, Glivec, Gleevec, STI571, QTI571;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Death During the Core | In this analysis patients with all (serious and non -serious) adverse events, and death were reported. See Safety Section. | 6 months | 
| Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Death During the Extension | In this analysis patients with all (serious and non -serious) adverse events, and death were reported. See Safety Section. | 72 months | 
| Change From Baseline of Six Minute Walk Test - Total Distance Walked at Different Time Periods | The Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Distance <500 meters suggests considerable exercise limitation; Distance 500-800 meters suggests moderate limitation; Distance >800 meters (with no rests) suggests mild or no limitation. | Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) | 
| Change From Baseline of Six Minute Walk Test - Number of Stops at Different Time Periods | The Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Number of stops were recorded for each patient. | Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) | 
| Change From Baseline of Six Minute Walk Test - Total Duration of Stops at Different Time Periods | The Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. If the patient stopped the duration of each stop was recorded. | Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients With Pulmonary Hypertension (PAH) Assessd by World Health Organization (WHO) Classification on Physical Activity | PAH assessed according to the WHO classification: Class I Patients with PAH but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain or near syncope. Class II Patients with PAH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III Patients with PAH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope. Class IV Patients with PAH with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. | Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion | 
| Borg Score-Oxygen Saturation(SaO2) During the Six Minutes Walk Test at Different Time Periods | Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. During the walk the patient was connected to a portable pulse oximeter via a finger probe. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. The test was terminated if the patient became too distressed or if their SaO2% fell below 60%. | Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) | 
| Borg Score-Systolic Blood Pressure During the Six Minutes Walk Test at Different Time Periods | Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. During the walk the patient was connected to a portable pulse oximeter via a finger probe. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Systolic blood pressure (mmHg) were recorded before the test at resting, at the end of the test and two minutes after the end of the test | Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) | 
| Borg Score-Diastolic Blood Pressure During the Six Minutes Walk Test at Different Time Periods | Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. During the walk the patient was connected to a portable pulse oximeter via a finger probe. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Diastolic blood pressure (mmHg) were recorded before the test at resting, at the end of the test and two minutes after the end of the test | Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) | 
| Borg Score-Heart Rate (HR) During the Six Minutes Walk Test at Different Time Periods | Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. During the walk the patient was connected to a portable pulse oximeter via a finger probe. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Heart Rate (bpm) were recorded before the test at resting, at the end of the test and two minutes after the end of the test | Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) | 
| Borg Score During the Six Minutes Walk Test at Different Time Periods | Borg Score during Six Minute Walk test was carried out along a course, such as a hospital corridor, measuring at least 20 meters delineated by markers. During the walk the patient was connected to a portable pulse oximeter via a finger probe. Patients were instructed to walk at a comfortable speed as far as they could manage in six minutes, resting whenever they needed to. Borg Score of Breathlessness was recorded using the following score of 0 to 10, how breathless do you feel? 0 is nothing at all and 10 is maximal breathlessness | Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) | 
| Mean Pulmonary Artery Pressure (PAP) at Baseline and Study Completion | The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including right Pulmonary Arterial Pressure (PAP). Were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. | Baseline, and Study completion (Week 24) | 
| Mean Pulmonary Artery Wedge Pressure (PAWP) at Baseline and Study Completion | The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including Pulmonary Arterial Wedge Pressure (PAWP). Were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. | Baseline, and Study completion (Week 24) | 
| Mean Systolic Arterial Pressure (SAP) at Baseline and Study Completion | The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including Systolic Arterial Pressure (SAP). Were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. | Baseline, and Study completion (Week 24) | 
| Mean Heart Rate (HR) at Baseline and Study Completion | The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including Heart Rate (HR). Were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. | Baseline, and Study completion (Week 24) | 
| Mean Cardiac Output (CO) at Baseline and Study Completion | The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including Cardiac Output (CO). Were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. | Baseline, and Study completion (Week 24) | 
| Mean Pulmonary Vascular Resistance (PVR) at Baseline and Study Completion | The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including Pulmonary Vascular Resistance (PVR). Were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. PVR calculated according to the equation:PVR = (PAP - PCWP)/CO | Baseline, and Study completion (Week 24) | 
| Mean Systemic Vascular Resistance (SVR) at Baseline and Study Completion | The right heart catheter assessment was performed to assess several prognostic hemodynamic variables in pulmonary hypertension, including Systemic Vascular Resistance (SVR). Were assessed when the patient was in a stable hemodynamic rest state (as demonstrated by three consecutive Mean PAP and CO measurements within 10% of each other). PAP was assessed when the patient was breathing ambient air, every 2 minutes whilst breathing Nitric Oxide(NO) (1st and 2nd), 5 min after the end of NO administration, and 15 mins after the end of NO administration. SVR was calculated according to the equation: SVR = (Paorta - Pright atrium)/CO | Baseline, and Study completion (Week 24) | 
| Blood Gas Measurement - PaO2 at Baseline and Study Completion | The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including PaO2 levels at baseline and Study completion Week 24. | Baseline, and Study completion (Week 24) | 
| Blood Gas Measurement - PaCO2 at Baseline and Study Completion | The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including PaCO2 levels at baseline and Study completion Week 24. | Baseline, and Study completion (Week 24) | 
| Blood Gas Measurement - PvO2 at Baseline and Study Completion | The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including PvO2 levels at baseline and Study completion Week 24. | Baseline, and Study completion (Week 24) | 
| Blood Gas Measurement - Arterial Saturation at Baseline and Study Completion | The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including Arterial Saturation levels at baseline and Study completion Week 24. | Baseline, and Study completion (Week 24) | 
| Blood Gas Measurement - Venous Saturation at Baseline and Study Completion | The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including Venous Saturation levels at baseline and Study completion Week 24. | Baseline, and Study completion (Week 24) | 
| Blood Gas Measurement - pH at Baseline and Study Completion | The right heart catheter assessment was performed to assess Blood Gas Measurements in pulmonary hypertension, including pH levels at baseline and Study completion Week 24. The pH scale measures how acidic or basic a substance is. It ranges from 0 to 14. A pH of 7 is neutral. A pH less than 7 is acidic, and a pH greater than 7 is basic. | Baseline, and Study completion (Week 24) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Arterial Hypertension, tyrosine kinase inhibitor, STI571