Clinical trial NCT00902174: Imatinib (QTI571) in Pulmonary Arterial Hypertension
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary arterial hypertension
Imatinib
6MWD
Borg scale
Pulmonary hypertension
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2009-05-15
Enrollment: 202
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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).


Eligibility 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

Primary outcomes:
measure: Difference in Six-minute Walk Distance Test (6MWD) Between Imatinib and Placebo at 24 Weeks
timeFrame: 24 weeks
Secondary outcomes:
measure: Clinical Worsening Comparing Imatinib Versus Placebo for Adjudicated Cases
timeFrame: 24 weeks
measure: Change From Baseline in Right Atrial Pressure
timeFrame: baseline and week 24
measure: Change From Baseline in Mean Pulmonary Arterial Pressure
timeFrame: baseline and week 24
measure: Change From Baseline in Mean Pulmonary Capillary Wedge Pressure
timeFrame: baseline and week 24
measure: Change From Baseline in Systemic Vascular Resistance
timeFrame: baseline and week 24
measure: Change From Baseline in Pulmonary Vascular Resistance
timeFrame: baseline and week 24
measure: Change From Baseline in Pulmonary Resistance Index
timeFrame: baseline and week 24
measure: Change From Baseline in Cardiac Output
timeFrame: 24 weeks
measure: Change From Baseline in Systolic Arterial Blood Pressure
timeFrame: baseline and week 24
measure: Change From Baseline in Diastolic Arterial Blood Pressure
timeFrame: baseline and week 24
measure: Change From Baseline in Heart Rate
timeFrame: 24 weeks
measure: Change in Borg Dyspnea Score During 6-minute Walk Test
timeFrame: week 24
measure: Covariance of End of Study CAMPHOR Score
timeFrame: Week 24
measure: Plasma Concentration of QTI571 200 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant
timeFrame: predose and between 0 hour to 3 hour post dose at day 1, day 14, day 28 and day 168
measure: Plasma Concentration of QTI571 400 mg and Its Metabolite (GCP74588) Pre-dose and Between 0 Hour to 3 Hour Post-dose Per Participant
timeFrame: predose and between 0 hour to 3 hour post dose at day 1, day 14, day 28 and day 168
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Novartis Investigative Site
state: Alabama
city: Phoenix
country: United States
facility: Novartis Investigative Site
state: Arizona
city: Los Angeles
country: United States
facility: Novartis Investigative Site
state: California
city: San Francisco
country: United States
facility: Novartis Investigative Site
state: California
city: Aurora
country: United States
facility: Novartis Investigative Site
state: Colorado
city: Clearwater
country: United States
facility: Novartis Investigative Site
state: Florida
city: Miami Beach
country: United States
facility: Novartis Investigative Site
state: Florida
city: Weston
country: United States
facility: Novartis Investigative Site
state: Florida
city: Atlanta
country: United States
facility: Novartis Investigative Site
state: Georgia
city: Chicago
country: United States
facility: Novartis Investigative Site
state: Illinois
city: Baltimore
country: United States
facility: Novartis Investigative Site
state: Maryland
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Boston
country: United States
facility: Novartis Investigative Site
state: Massachusetts
city: Rochester
country: United States
facility: Novartis Investigative Site
state: Minnesota
city: St. Louis
country: United States
facility: Novartis Investigative Site
state: Missouri
city: Omaha
country: United States
facility: Novartis Investigative Site
state: Nebraska
city: Minneola
country: United States
facility: Novartis Investigative Site
state: New York
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: New York
country: United States
facility: Novartis Investigative Site
state: New York
city: Durham
country: United States
facility: Novartis Investigative Site
state: North Carolina
city: Cincinnati
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Cleveland
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Cleveland
country: United States
facility: Novartis Investigative Site
state: Ohio
city: Oklahoma City
country: United States
facility: Novartis Investigative Site
state: Oklahoma
city: Portland
country: United States
facility: Novartis Investigative Site
state: Oregon
city: Philadelphia
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Novartis Investigative Site
state: Pennsylvania
city: Knoxville
country: United States
facility: Novartis Investigative Site
state: Tennessee
city: Dallas
country: United States
facility: Novartis Investigative Site
state: Texas
city: Houston
country: United States
facility: Novartis Investigative Site
state: Texas
city: Milwaukee
country: United States
facility: Novartis Investigative Site
state: Wisconsin
city: Innsbruck
country: Austria
facility: Novartis investigative site
city: Vienna
country: Austria
facility: Novartis Investigative Site
city: Bruxelles
country: Belgium
facility: Novartis Investigative Site
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Calgary
country: Canada
facility: Novartis Investigative Site
city: Edmonton
country: Canada
facility: Novartis Investigative Site
city: London
country: Canada
facility: Novartis Investigative Site
city: Montreal
country: Canada
facility: Novartis Investigative Site
city: Ottawa
country: Canada
facility: Novartis Investigative Site
city: Toronto
country: Canada
facility: Novartis investigative site
city: Vancouver
country: Canada
facility: Novartis Investigative Site
city: Clamart Cedex
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Dresden
country: Germany
facility: Novartis Investigative Site
city: Giessen
country: Germany
facility: Novartis Investigative Site
city: Greifswald
country: Germany
facility: Novartis Investigative Site
city: Hamburg
country: Germany
facility: Novartis Investigative Site
city: Hannover
country: Germany
facility: Novartis Investigative Site
city: Heidelberg
country: Germany
facility: Novartis Investigative Site
city: Homburg
country: Germany
facility: Novartis Investigative Site
city: Koln
country: Germany
facility: Novartis Investigative Site
city: Lowenstein
country: Germany
facility: Novartis investigative site
city: Munchen
country: Germany
facility: Novartis Investigative Site
city: Regensberg
country: Germany
facility: Novartis Investigative Site
city: Wurzberg
country: Germany
facility: Novartis Investigative Site
city: Bologna
country: Italy
facility: Novartis Investigative Site
city: Pavia
country: Italy
facility: Novartis Investigative Site
city: Pisa
country: Italy
facility: Novartis Investigative Site
city: Roma
country: Italy
facility: Novartis Investigative Site
city: Bunkyo-ku
country: Japan
facility: Novartis Investigative Site
city: Hamamatsu
country: Japan
facility: Novartis Investigative Site
city: Mitaka
country: Japan
facility: Novartis Investigative Site
city: Okayama
country: Japan
facility: Novartis Investigative Site
city: Sendai
country: Japan
facility: Novartis Investigative Site
city: Suita
country: Japan
facility: Novartis Investigative Site
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Caceras
country: Spain
facility: Novartis Investigative Site
city: La Coruna
country: Spain
facility: Novartis Investigative Site
city: La Laguna
country: Spain
facility: Novartis investigative site
city: Las Palmas de Gran Canarias
country: Spain
facility: Novartis Investigative Site
city: Madrid
country: Spain
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
city: Santa Cruz de Tenerife
country: Spain
facility: Novartis Investigative Site
city: Santander
country: Spain
facility: Novartis Investigative Site
city: Sevilla
country: Spain
facility: Novartis Investigative Site
city: Valencia
country: Spain
facility: Novartis investigative site
city: Valladolid
country: Spain
facility: Novartis Investigative Site
city: Lund
country: Sweden
facility: Novartis Investigative Site
city: Stockholm
country: Sweden
facility: Novartis Investigative Site
city: Umea
country: Sweden
facility: Novartis Investigative Site
city: Uppsala
country: Sweden
facility: Novartis Investigative Site
city: Basel
country: Switzerland
facility: University Hospital Basel
city: Bern
country: Switzerland
facility: Novartis Investigative Site
city: Lausanne
country: Switzerland
facility: Novartis Investigative Site
city: St. Gallen
country: Switzerland
facility: Novartis Investigative Site
city: Cambridge
country: United Kingdom
facility: Novartis Investigative Site
city: Clydebank
country: United Kingdom
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
city: Newcastle Upon Tyne
country: United Kingdom
facility: Novartis Investigative Site
city: Sheffield
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References:
citation: Querejeta Roca G, Campbell P, Claggett B, Solomon SD, Shah AM. Right Atrial Function in Pulmonary Arterial Hypertension. Circ Cardiovasc Imaging. 2015 Nov;8(11):e003521; discussion e003521. doi: 10.1161/CIRCIMAGING.115.003521.
citation: Querejeta Roca G, Campbell P, Claggett B, Vazir A, Quinn D, Solomon SD, Shah AM. Impact of lowering pulmonary vascular resistance on right and left ventricular deformation in pulmonary arterial hypertension. Eur J Heart Fail. 2015 Jan;17(1):63-73. doi: 10.1002/ejhf.177. Epub 2014 Nov 4.
citation: Shah AM, Campbell P, Rocha GQ, Peacock A, Barst RJ, Quinn D, Solomon SD; IMPRES Investigators. Effect of imatinib as add-on therapy on echocardiographic measures of right ventricular function in patients with significant pulmonary arterial hypertension. Eur Heart J. 2015 Mar 7;36(10):623-32. doi: 10.1093/eurheartj/ehu035. Epub 2014 Feb 23.
citation: Hoeper MM, Barst RJ, Bourge RC, Feldman J, Frost AE, Galie N, Gomez-Sanchez MA, Grimminger F, Grunig E, Hassoun PM, Morrell NW, Peacock AJ, Satoh T, Simonneau G, Tapson VF, Torres F, Lawrence D, Quinn DA, Ghofrani HA. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation. 2013 Mar 12;127(10):1128-38. doi: 10.1161/CIRCULATIONAHA.112.000765. Epub 2013 Feb 12.