Trial record 3 of 5 for:    QTI571

Imatinib (QTI571) in Pulmonary Arterial Hypertension (IMPRES)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:
NCT00902174
First received: May 13, 2009
Last updated: June 12, 2013
Last verified: June 2013
  Purpose

A multinational, multicenter, double blind, placebo-controlled study evaluating the efficacy and safety of imatinib as an add-on therapy in the treatment of patients with severe pulmonary arterial hypertension (PAH).


Condition Intervention Phase
Pulmonary Arterial Hypertension
Drug: imatinib mesylate
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A 24-week Randomized Placebo-controlled, Double-blind Multi-center Clinical Trial Evaluating the Efficacy and Safety of Oral QTI571 as an add-on Therapy in the Treatment of Severe Pulmonary Arterial Hypertension: Imatinib in Pulmonary Arterial Hypertension, a Randomized, Efficacy Study (IMPRES)

Resource links provided by NLM:


Further study details as provided by Novartis:

Primary Outcome Measures:
  • Difference in Six-minute Walk Distance Test (6MWD) Between Imatinib and Placebo at 24 Weeks [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    This standardized walk course was 30 meters in length. During the walk the participant was connected to a portable pulse oximeter via a finger probe. Participants were instructed to walk at a comfortable speed for as far as they could manage in 6 minutes. The total distance walked (in meters) was recorded. Results were compared between the 2 groups.


Secondary Outcome Measures:
  • Clinical Worsening Comparing Imatinib Versus Placebo for Adjudicated Cases [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Clinical worsening per participant was measured by the onset of any adjudicated event (all cause mortality; overnight hospitalization for worsening of Pulmonary Arterial Hypertension (PAH); worsening of WHO functional class by one level; 15% decline in Six Minute Walk Distance (6MWD) measured on two consecutive occasions) at 24 weeks treatment, comparing imatinib to placebo groups. A cox regression analysis model was used.

  • Change From Baseline in Right Atrial Pressure [ Time Frame: baseline and week 24 ] [ Designated as safety issue: No ]
    Change from baseline in right atrial pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The right atrial pressure was assessed when the participant was in a stable hemodynamic rest state. A higher right atrial pressure number indicates worsening.

  • Change From Baseline in Mean Pulmonary Arterial Pressure [ Time Frame: baseline and week 24 ] [ Designated as safety issue: No ]
    Change from baseline in mean pulmonary arterial pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The mean pulmonary arterial pressure was assessed when the participant was in a stable hemodynamic rest state. A higher mean pulmonary arterial pressure number indicates worsening.

  • Change From Baseline in Mean Pulmonary Capillary Wedge Pressure [ Time Frame: baseline and week 24 ] [ Designated as safety issue: No ]
    Change from baseline in mean pulmonary capillary wedge pressure (mmHg)was measured via right heart catheterization according to the local hospital procedures. The right atrial mean pulmonary capillary wedge pressure was assessed when the participant was in a stable hemodynamic rest state.

  • Change From Baseline in Systemic Vascular Resistance [ Time Frame: baseline and week 24 ] [ Designated as safety issue: No ]
    Change from baseline in systemic vascular resistance (dynes*sec*cm^-5) was measured via right heart catheterization according to the local hospital procedures. The systemic vascular resistance was assessed when the participant was in a stable hemodynamic rest state. Reduction from baseline in mean systemic vascular resistance indicates improvement.

  • Change From Baseline in Pulmonary Vascular Resistance [ Time Frame: baseline and week 24 ] [ Designated as safety issue: No ]
    Change from baseline in pulmonary vascular resistance (dynes*sec*cm^-5) was measured via right heart catheterization according to the local hospital procedures. The pulmonary vascular resistance was assessed when the participant was in a stable hemodynamic rest state. Reduction from baseline in pulmonary vascular resistance indicates improvement.

  • Change From Baseline in Pulmonary Resistance Index [ Time Frame: baseline and week 24 ] [ Designated as safety issue: No ]
    Change from baseline in pulmonary resistance index (dynes*sec*cm^-5/m2) was measured via right heart catheterization according to the local hospital procedures. The pulmonary resistance index was assessed when the participant was in a stable hemodynamic rest state. A reduction from baseline in pulmonary resistance index indicates improvement.

  • Change From Baseline in Cardiac Output [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Change from baseline in cardiac output (L/min) was measured via right heart catheterization according to the local hospital procedures. The cardiac output was assessed when the participant was in a stable hemodynamic rest state. An increase from baseline (higher number) in cardiac output indicates improvement.

  • Change From Baseline in Systolic Arterial Blood Pressure [ Time Frame: baseline and week 24 ] [ Designated as safety issue: No ]
    Change from baseline in systolic arterial blood pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The systolic arterial blood was assessed when the participant was in a stable hemodynamic rest state.

  • Change From Baseline in Diastolic Arterial Blood Pressure [ Time Frame: baseline and week 24 ] [ Designated as safety issue: No ]
    Change from baseline in diastolic arterial blood pressure (mmHg) was measured via right heart catheterization according to the local hospital procedures. The diastolic arterial blood pressure was assessed when the participant was in a stable hemodynamic rest state.

  • Change From Baseline in Heart Rate [ Time Frame: 24 weeks ] [ Designated as safety issue: No ]
    Change from baseline in heart rate (bpm) was measured via right heart catheterization according to the local hospital procedures. The heart rate was assessed when the participant was in a stable hemodynamic rest state.

  • Change in Borg Dyspnea Score During 6-minute Walk Test [ Time Frame: week 24 ] [ Designated as safety issue: No ]
    Change in Borg scale was measured at different time points at week 24. The Borg Scale consists of scale range of 0 to 10. Participants pointed to indicate their level of dyspnea before and at the end of exercise testing (where 0 indicates no breathlessness at all and 10 indicates maximum breathlessness). A reduction in this score indicates an improvement.

  • Covariance of End of Study CAMPHOR Score [ Time Frame: Week 24 ] [ Designated as safety issue: No ]
    The CAMPHOR test consists of 65 items and 3 scales. Two scales measure Health Related Quality of Life. 1) Symptoms: consists of 25 items measuring loss or abnormality of psychological, physiological or anatomical structure or function; further sub-divided into 3 subscales (energy, breathlessness and mood), 2) Disability: consists of 15 items measuring any restriction or lack of ability to perform an activity. 3) Quality of Life (QOL): consists of 25 items defining how individuals perceived ability and capacity to satisfy their needs. The 25-item symptom and QOL scales score from 0-25 where a higher score indicates the presence of more symptoms and poor QOL, respectively. The 15-item functioning scale scores 0-30; a higher score indicates poor functioning.

  • Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant [ Time Frame: predose and between 0 hour to 3 hour post dose at day 1, day 14, day 28 and day 168 ] [ Designated as safety issue: No ]

    Blood samples were taken from each subject participating in the study (placebo group and active treatment group) once predose and once between 0 hour to 3 hour post dose at day 1 (baseline), day 14, day 28 and day 168.

    The parent compound QTI571 and its active metabolite, GCP74588, were measured in plasma by validated liquid chromatography-mass spectrometry (HPLC-MS/MS) assay.


  • Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant [ Time Frame: predose and between 0 hour to 3 hour post dose at day 1, day 14, day 28 and day 168 ] [ Designated as safety issue: No ]

    Blood samples were taken from each subject participating in the study (placebo group and active treatment group) once predose and once between 0 hour to 3 hour post dose at day 1 (baseline), day 14, day 28 and day 168.

    The parent compound QTI571 and its active metabolite, GCP74588, were measured in plasma by validated liquid chromatography-mass spectrometry (HPLC-MS/MS) assay.



Enrollment: 202
Study Start Date: September 2009
Study Completion Date: May 2011
Primary Completion Date: May 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: imatinib mesylate
Imatinib mesylate (QTI571) 200 mg once daily for two weeks, increased to 400 mg once daily if well tolerated. If 400 mg dose was not well tolerated, a down titration to 200 mg once daily was permitted.
Drug: imatinib mesylate
Two or 4 imatinib mesylate (QTI571) 100 mg film coated tablets once daily.
Placebo Comparator: Placebo
Placebo to imatinib mesylate taken once daily. Participants receiving placebo were allowed to receive already approved PAH treatments.
Drug: Placebo
Placebo to imatinib 100 mg film coated tablets

  Eligibility

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

Key Inclusion criteria

  • Male or female patients ≥18 years of age with a current diagnosis of pulmonary arterial hypertension (PAH) according to the Dana Point 2008 Meeting: World Health Organization (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 repair of congenital heart defect [Atrial Septal Defect (ASD), Ventricular Septal Defect (VSD) or Posterior Descending Artery (PDA)], or PAH associated with diet therapies or other drugs
  • A Pulmonary Vascular Resistance (PVR) ≥ 800 dynes.sec.cm-5 (as assessed by Right Heart Catheterization (RHC) at screening or in the 3 months preceding the screening visit) despite treatment with two or more specific PAH therapies, including Endothelin Receptor Antagonists (ERAs), phosphodiesterase 5 inhibitors (PDE5), or subcutaneous, inhaled, intravenous or oral prostacyclin analogues for ≥ 3 months. Background therapy doses were to be stable for ≥ 30 days except for warfarin and prostacyclin analogues ( ≥ 30 days but doses could vary even within the month before enrollment).
  • World Health Organization functional Class II-IV. For WHO Functional Class IV, one of the 2 or more specific PAH therapies were to be an inhaled, subcutaneous, intravenous or oral prostacyclin analogue, unless the subject showed intolerance of prostacyclin analogues.
  • 6MWD ≥ 150 meters and ≤ 450 meters at screening. Distances of two consecutive 6MWTs were to be within 15% of one another.

Key Exclusion criteria

  • With a pulmonary capillary wedge pressure > 15 mm Hg to rule out PAH secondary to left ventricular dysfunction.
  • With a diagnosis of pulmonary artery or vein stenosis
  • Left ventricular ejection fraction (LVEF) < 45%
  • With Disseminated Intravascular Coagulation (DIC)
  • With evidence of major bleeding or intracranial hemorrhage
  • With a history of elevated intracranial pressure
  • With a history of latent bleeding risk such as diabetic retinopathy, gastrointestinal bleeding due to gastric or duodenal ulcers, or colitis ulcerosa
  • With a QTcF > 450 msec for males and > 470 msec for females at screening and baseline in the absence of right bundle branch block.
  • With a history of ventricular tachycardia, ventricular fibrillation or ventricular flutter
  • With a history of Torsades de Pointes
  • With a history of long QT syndrome
  • Having undergone atrial septostomy in the 3 months prior to the screening visit
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00902174

  Show 95 Study Locations
Sponsors and Collaborators
Novartis Pharmaceuticals
Investigators
Study Director: Novartis Pharmaceuticals Novartis Pharmaceuticals
  More Information

Additional 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: NCT00902174     History of Changes
Other Study ID Numbers: CQTI571A2301
Study First Received: May 13, 2009
Results First Received: April 16, 2013
Last Updated: June 12, 2013
Health Authority: United States: Food and Drug Administration
Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicinal Products and Health Products
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Germany: Federal Institute for Drugs and Medical Devices
Italy: The Italian Medicines Agency
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Spain: Spanish Agency of Medicines
Sweden: Medical Products Agency
United Kingdom: Medicines and Healthcare Products Regulatory Agency
Switzerland: Swissmedic
Korea: Food and Drug Administration
Japan: Pharmaceuticals and Medical Devices Agency
Canada: Health Canada

Keywords provided by Novartis:
Pulmonary arterial hypertension
Imatinib
6MWD
Borg scale
Pulmonary hypertension

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

ClinicalTrials.gov processed this record on April 17, 2014