Imatinib (QTI571) in Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension Clinical Trial

— IMPRES  

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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00902174
• Other study ID #: CQTI571A2301
• Status: Completed
• Phase: Phase 3
• First received: May 13, 2009
• Last updated: February 16, 2016
• Start date: September 2009
• Est. completion date: May 2011

Study information

• Verified date: June 2013
• Source: Novartis
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationAustria: Federal Office for Safety in Health CareBelgium: Federal Agency for Medicinal Products and Health ProductsFrance: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)Germany: Federal Institute for Drugs and Medical DevicesItaly: The Italian Medicines AgencyNetherlands: The Central Committee on Research Involving Human Subjects (CCMO)Spain: Spanish Agency of MedicinesSweden: Medical Products AgencyUnited Kingdom: Medicines and Healthcare Products Regulatory AgencySwitzerland: SwissmedicKorea: Food and Drug AdministrationJapan: Pharmaceuticals and Medical Devices AgencyCanada: Health Canada
• Study type: Interventional

Clinical Trial Summary

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 202
• Est. completion date: May 2011
• Est. primary completion date: May 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• imatinib mesylate
Two or 4 imatinib mesylate (QTI571) 100 mg film coated tablets once daily.
• Placebo
Placebo to imatinib 100 mg film coated tablets

Locations

Country	Name	City	State
Austria	Novartis investigative site	Innsbruck
Austria	Novartis Investigative Site	Vienna
Belgium	Novartis Investigative Site	Bruxelles
Belgium	Novartis Investigative Site	Leuven
Canada	Novartis Investigative Site	Calgary
Canada	Novartis Investigative Site	Edmonton
Canada	Novartis Investigative Site	London
Canada	Novartis Investigative Site	Montreal
Canada	Novartis Investigative Site	Ottawa
Canada	Novartis investigative site	Toronto
Canada	Novartis Investigative Site	Vancouver
France	Novartis Investigative Site	Clamart Cedex
Germany	Novartis Investigative Site	Berlin
Germany	Novartis Investigative Site	Dresden
Germany	Novartis Investigative Site	Giessen
Germany	Novartis Investigative Site	Greifswald
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Homburg
Germany	Novartis Investigative Site	Koln
Germany	Novartis investigative site	Lowenstein
Germany	Novartis Investigative Site	Munchen
Germany	Novartis Investigative Site	Regensberg
Germany	Novartis Investigative Site	Wurzberg
Italy	Novartis Investigative Site	Bologna
Italy	Novartis Investigative Site	Pavia
Italy	Novartis Investigative Site	Pisa
Italy	Novartis Investigative Site	Roma
Japan	Novartis Investigative Site	Bunkyo-ku
Japan	Novartis Investigative Site	Hamamatsu
Japan	Novartis Investigative Site	Mitaka
Japan	Novartis Investigative Site	Okayama
Japan	Novartis Investigative Site	Sendai
Japan	Novartis Investigative Site	Suita
Korea, Republic of	Novartis Investigative Site	Seoul
Netherlands	Novartis Investigative Site	Amsterdam
Spain	Novartis Investigative Site	Barcelona
Spain	Novartis Investigative Site	Caceras
Spain	Novartis Investigative Site	La Coruna
Spain	Novartis investigative site	La Laguna
Spain	Novartis Investigative Site	Las Palmas de Gran Canarias
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga
Spain	Novartis Investigative Site	Santa Cruz de Tenerife
Spain	Novartis Investigative Site	Santander
Spain	Novartis Investigative Site	Sevilla
Spain	Novartis investigative site	Valencia
Spain	Novartis Investigative Site	Valladolid
Sweden	Novartis Investigative Site	Lund
Sweden	Novartis Investigative Site	Stockholm
Sweden	Novartis Investigative Site	Umea
Sweden	Novartis Investigative Site	Uppsala
Switzerland	University Hospital Basel	Basel
Switzerland	Novartis Investigative Site	Bern
Switzerland	Novartis Investigative Site	Lausanne
Switzerland	Novartis Investigative Site	St. Gallen
United Kingdom	Novartis Investigative Site	Cambridge
United Kingdom	Novartis Investigative Site	Clydebank
United Kingdom	Novartis Investigative Site	London
United Kingdom	Novartis Investigative Site	Newcastle Upon Tyne
United Kingdom	Novartis Investigative Site	Sheffield
United States	Novartis Investigative Site	Atlanta	Georgia
United States	Novartis Investigative Site	Aurora	Colorado
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Birmingham	Alabama
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Boston	Massachusetts
United States	Novartis Investigative Site	Chicago	Illinois
United States	Novartis Investigative Site	Cincinnati	Ohio
United States	Novartis Investigative Site	Clearwater	Florida
United States	Novartis Investigative Site	Cleveland	Ohio
United States	Novartis Investigative Site	Cleveland	Ohio
United States	Novartis Investigative Site	Dallas	Texas
United States	Novartis Investigative Site	Durham	North Carolina
United States	Novartis Investigative Site	Houston	Texas
United States	Novartis Investigative Site	Knoxville	Tennessee
United States	Novartis Investigative Site	Los Angeles	California
United States	Novartis Investigative Site	Miami Beach	Florida
United States	Novartis Investigative Site	Milwaukee	Wisconsin
United States	Novartis Investigative Site	Minneola	New York
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	New York	New York
United States	Novartis Investigative Site	Oklahoma City	Oklahoma
United States	Novartis Investigative Site	Omaha	Nebraska
United States	Novartis Investigative Site	Philadelphia	Pennsylvania
United States	Novartis Investigative Site	Phoenix	Arizona
United States	Novartis Investigative Site	Pittsburgh	Pennsylvania
United States	Novartis Investigative Site	Pittsburgh	Pennsylvania
United States	Novartis Investigative Site	Portland	Oregon
United States	Novartis Investigative Site	Rochester	Minnesota
United States	Novartis Investigative Site	San Francisco	California
United States	Novartis Investigative Site	St. Louis	Missouri
United States	Novartis Investigative Site	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Austria,  Belgium,  Canada,  France,  Germany,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Spain,  Sweden,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Difference in Six-minute Walk Distance Test (6MWD) Between Imatinib and Placebo at 24 Weeks	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.	24 weeks	No
Secondary	Clinical Worsening Comparing Imatinib Versus Placebo for Adjudicated Cases	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.	24 weeks	No
Secondary	Change From Baseline in Right Atrial Pressure	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.	baseline and week 24	No
Secondary	Change From Baseline in Mean Pulmonary Arterial Pressure	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.	baseline and week 24	No
Secondary	Change From Baseline in Mean Pulmonary Capillary Wedge Pressure	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.	baseline and week 24	No
Secondary	Change From Baseline in Systemic Vascular Resistance	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.	baseline and week 24	No
Secondary	Change From Baseline in Pulmonary Vascular Resistance	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.	baseline and week 24	No
Secondary	Change From Baseline in Pulmonary Resistance Index	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.	baseline and week 24	No
Secondary	Change From Baseline in Cardiac Output	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.	24 weeks	No
Secondary	Change From Baseline in Systolic Arterial Blood Pressure	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.	baseline and week 24	No
Secondary	Change From Baseline in Diastolic Arterial Blood Pressure	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.	baseline and week 24	No
Secondary	Change From Baseline in Heart Rate	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.	24 weeks	No
Secondary	Change in Borg Dyspnea Score During 6-minute Walk Test	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.	week 24	No
Secondary	Covariance of End of Study CAMPHOR Score	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.	Week 24	No
Secondary	Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant	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.	predose and between 0 hour to 3 hour post dose at day 1, day 14, day 28 and day 168	No
Secondary	Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant	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.	predose and between 0 hour to 3 hour post dose at day 1, day 14, day 28 and day 168	No

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