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

• Register: EUCTR
• Last refreshed on: 28 August 2012
• Main ID: EUCTR2009-012057-38-DE
• Date of registration: 10/06/2009
• Prospective Registration: Yes
• Primary sponsor: Novartis Pharma Services AG
• Public 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
• Scientific 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
• Date of first enrolment: 13/08/2009
• Target sample size: 200
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2009-012057-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no

Countries of recruitment

Austria, Belgium, France, Germany, Italy, Netherlands, Spain, Sweden, United Kingdom

Key inclusion & exclusion criteria

Inclusion criteria:
1) Male or female 18 years of age or older
2) A current diagnosis of Pulmonary Arterial Hypertension according to the Dana Point 2008 Meeting: 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 associated systemic sclerosis, PAH following one year repair of congenital heart defect (ASD, VSD or PDA), or PAH associated with diet therapies or other drugs
3) A PVR =800 dynes.sec.cm-5 despite treatment with two or more specific PAH therapies, including endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5), or subcutaneous, inhaled, intravenous or oral prostacyclin analogues for = 3 months. Background therapy doses must be stable for = 30 days except for warfarin and prostacyclin analogues ( = 30 days but doses can vary even within the month before enrollment)
4) WHO Functional Class II-IV. For WHO Functional Class IV, one of the 2 or more specific PAH therapies must be an inhaled, subcutaneous, intravenous or oral prostacyclin analogue, unless the subject has been shown to be intolerant of prostacyclin analogues.
5) 6MWD = 150 meters and = 450 meters at screening. Distances of two consecutive 6MWTs should be within 15% of one another.
6) Ability to provide written informed consent by the patient or a legal guardian

Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant. UNLESS they are
a. women whose career, lifestyle, or sexual orientation precludes intercourse with a male partner
b. women whose partners have been sterilized by vasectomy or other means
c. two birth control methods.
2. pregnant or nursing (lactating) women,
3. have previously received treatment with imatinib
4. in treatment with chronic nitric oxide therapy
5. with a diagnosis of pre-existing severe lung disease including parasitic diseases affecting lungs, congenital abnormalities of the lungs, thorax or diaphragm or bronchial asthma that may significantly contribute to severity of PAH in the opinion of the investigator
6. with a pulmonary capillary wedge pressure > 15 mm Hg to rule out PAH secondary to left ventricular dysfunction If pulmonary capillary wedge pressure is not attainable,
then a left atrial pressure measurement may be used in its place
7. with a diagnosis of pulmonary artery or vein stenosis
8. with other diagnosis of PAH in WHO Diagnostic Group 1 or 1' are excluded including congenital systemic to pulmonary shunts (large, small that are not surgically repaired), portal hypertension, HIV infection, hereditary hemorrhagic telangiectasia, hemoglobinopathies, veno-occlusive disease)
9. With a diagnosis of PAH associated with: venous hypertension (WHO Diagnostic
Group II, including LVEF < 45%), hypoxia (WHO Diagnostic Group III), chronic
pulmonary thromboembolic disease (WHO Diagnostic Group IV) or other
miscellaneous causes (WHO Diagnostic Class V, which includes sarcoidosis,
histiocytosis X, lymphangiomatosis, compression of pulmonary vessels, glycogen
storage disease, Gaucher’s disease, myeloproliferative disorders).
9. with thrombocytopenia < 50 x109/L
10. with a history of left heart failure in the past 3 months
11. with ucontrolled systemic arterial hypertension, systolic > 160 mmHg or diastolic >90 mmHg
12. with hemoglobin < 100 g/L
13. with deficiencies of blood coagulation [for details, please report to the protocol]
14. with disseminated intravascular coagulation
15. with evidence of major bleeding or intracranial hemorrhage
16. with a history of elevated intracranial pressure
17. with a history of latent bleeding risk [for details, please report to the protocol]
18. with a history of moderate or greater hepatic insufficiency transaminase levels for details, please report to the protocol]
19. with a history of renal insufficiency
20. previous therapeutic radiation of lungs or mediastinum
21. with a history of sickle cell anemia
22. with a QTcF > 450 msec for males and > 470 msec for females at screening and baseline in the absence of right bundle branch block.
23. with a history of ventricular tachycardia, ventricular fibrillation or ventricular flutter
24. having a syncope in the 3 months prior to the screening visit
25. with a history of Torsades de Pointes
26. with a history of long QT syndrome
27. having undergone atrial septostomy in the 3 months prior to the screening visit
28. having undergone radiofrequency catheter ablation for atrial or sinus arrhythmias in the 3 months prior to screening visit
29. with an advanced, severe, or unstable disease of any type that may interfere with the primary and secondary endpoint evaluations
30. with a history of immunodeficiency diseases, including HIV
31. with a known hypersensitivity to QTI571 or drugs similar to the study drug
32. with a disability that

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Pulmonary arterial hypertension (PAH) patients who have a PVR =800 dynes.sec.cm-5 despite treatment with two or more specific PAH therapies
MedDRA version: 9.1 Level: LLT Classification code 10064911 Term: Pulmonary arterial hypertension

Intervention(s)

Trade Name: Glivec® 100 mg Filmtabletten
Product Code: QTI571
Pharmaceutical Form: Film-coated tablet
INN or Proposed INN: Imatinib mesilate
CAS Number: 220127-57-1
Current Sponsor code: QTI571
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 100-
Pharmaceutical form of the placebo: Film-coated tablet
Route of administration of the placebo: Oral use

Primary Outcome(s)

Secondary Objective: • To evaluate the time to clinical worsening (TTCW), defined as all cause mortality, overnight hospitalization for worsening PAH (established by external adjudication committee), worsening of WHO functional class or a drop in 6MWD by 15% during 24 weeks of treatment with QTI571 as compared to placebo
• To assess changes in health-related quality of life after 24 weeks of treatment (using CAMPHOR) with QTI571 compared with placebo
• To assess the safety and tolerability of QTI571
• To evaluate change in pulmonary hemodynamics from baseline in patients after 24 weeks of treatment with QTI571 as compared to placebo
• To assess change in Borg dyspnea score during 6MWT, monthly, with QTI571 as compared to placebo.
• To assess the pharmacokinetics of QTI571 and the potential for interaction of QTI571 on sildenafil and bosentan
• To assess the pharmacogenetics of QTI571
• To assess the use of different possible definitions of time TTCW as a measure of efficacy in treatment of PAH

Main Objective: • To evaluate the efficacy of QTI571 compared to placebo as measured by the change in 6-minute walk distance (6MWD) from baseline to 24-weeks

Primary end point(s): • 6MWD – a marker of exercise tolerance (the distance walked in 6 minutes during a 6-minute walk test according to ATS guidelines)

Secondary ID(s)

CQTI571A2301