Imatinib (QTI571) in Pulmonary Arterial Hypertension

Study Overview
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Brief Summary
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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).

Official Title
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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)

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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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

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: imatinib mesylate<br>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<br>* Two or 4 imatinib mesylate (QTI571) 100 mg film coated tablets once daily.<br>|
| Placebo Comparator: Placebo<br>Placebo to imatinib mesylate taken once daily. Participants receiving placebo were allowed to receive already approved PAH treatments. | Drug: Placebo<br>* Placebo to imatinib 100 mg film coated tablets<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary arterial hypertension, Imatinib, 6MWD, Borg scale, Pulmonary hypertension