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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00477269
First received: May 22, 2007
Last updated: March 10, 2015
Last verified: March 2015
  Purpose

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


Condition Intervention Phase
Pulmonary Arterial Hypertension
Drug: Imatinib mesylate
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: 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)

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Death During the Core [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
    In this analysis patients with all (serious and non -serious) adverse events, and death were reported. See Safety Section.

  • Number of Patients With Adverse Events (AEs), Serious Adverse Events (SAEs) and Death During the Extension [ Time Frame: 72 months ] [ Designated as safety issue: Yes ]
    In this analysis patients with all (serious and non -serious) adverse events, and death were reported. See Safety Section.

  • Change From Baseline of Six Minute Walk Test - Total Distance Walked at Different Time Periods [ Time Frame: Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline of Six Minute Walk Test - Number of Stops at Different Time Periods [ Time Frame: Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Change From Baseline of Six Minute Walk Test - Total Duration of Stops at Different Time Periods [ Time Frame: Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Number of Patients With Pulmonary Hypertension (PAH) Assessd by World Health Organization (WHO) Classification on Physical Activity [ Time Frame: Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion ] [ Designated as safety issue: No ]
    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.

  • Borg Score-Oxygen Saturation(SaO2) During the Six Minutes Walk Test at Different Time Periods [ Time Frame: Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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%.

  • Borg Score-Systolic Blood Pressure During the Six Minutes Walk Test at Different Time Periods [ Time Frame: Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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

  • Borg Score-Diastolic Blood Pressure During the Six Minutes Walk Test at Different Time Periods [ Time Frame: Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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

  • Borg Score-Heart Rate (HR) During the Six Minutes Walk Test at Different Time Periods [ Time Frame: Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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

  • Borg Score During the Six Minutes Walk Test at Different Time Periods [ Time Frame: Baseline, Day 32, Week 8, Week 12, Week 16, Week 20 and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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

  • Mean Pulmonary Artery Pressure (PAP) at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Mean Pulmonary Artery Wedge Pressure (PAWP) at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Mean Systolic Arterial Pressure (SAP) at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Mean Heart Rate (HR) at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Mean Cardiac Output (CO) at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Mean Pulmonary Vascular Resistance (PVR) at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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

  • Mean Systemic Vascular Resistance (SVR) at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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

  • Blood Gas Measurement - PaO2 at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Blood Gas Measurement - PaCO2 at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Blood Gas Measurement - PvO2 at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Blood Gas Measurement - Arterial Saturation at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Blood Gas Measurement - Venous Saturation at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.

  • Blood Gas Measurement - pH at Baseline and Study Completion [ Time Frame: Baseline, and Study completion (Week 24) ] [ Designated as safety issue: No ]
    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.


Enrollment: 59
Study Start Date: April 2006
Study Completion Date: January 2014
Primary Completion Date: January 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: STI571
STI571
Drug: Imatinib mesylate
Other Name: Imatinib, Glivec, Gleevec, STI571, QTI571
Placebo Comparator: Placebo
Placebo
Drug: Placebo
Experimental: All Patients
Open label extension
Drug: Imatinib mesylate
Other Name: Imatinib, Glivec, Gleevec, STI571, QTI571

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00477269

Locations
United States, California
Novartis Investigative Site
Los Angeles, California, United States, 90073
United States, New Jersey
Novartis investigative site
Newark, New Jersey, United States, 07112
United States, New York
Novartis Investigative Site
New York, New York, United States, 10032
Austria
Novartis Investigative Site
Graz, Austria, A-8036
Novartis Investigative site
Graz, Austria
Germany
Novartis Investigative Site
Giessen, Germany, 35385
Novartis Investigative site
Giessen, Germany
Novartis Investigative site
Hannover, Germany
Novartis Investigative Site
Hannover, Germany, 30625
United Kingdom
Novartis Investigative Site
Cambridge, Cambridgeshire, United Kingdom, CB23 3RE
Novartis Investigative Site
Glasgow, United Kingdom, G11 6NT
Novartis Investigative site
Glasgow, United Kingdom
Novartis Investigative site
Papworth, United Kingdom
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
Principal Investigator: Novartis Investigative site
  More Information

No publications provided by Novartis

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier: NCT00477269     History of Changes
Other Study ID Numbers: CSTI571E2203, 2005-005569-12
Study First Received: May 22, 2007
Results First Received: January 26, 2015
Last Updated: March 10, 2015
Health Authority: United States: Food and Drug Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Germany: Federal Institute for Drugs and Medical Devices
Austria: Agency for Health and Food Safety

Keywords provided by Novartis:
Pulmonary Arterial Hypertension, tyrosine kinase inhibitor, STI571

Additional relevant MeSH terms:
Hypertension
Cardiovascular Diseases
Vascular Diseases
Imatinib
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses

ClinicalTrials.gov processed this record on March 26, 2015