Positioning Imatinib for Pulmonary Arterial Hypertension (PIPAH)

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring Pulmonary Arterial Hypertension, PAH, Imatinib, TKI, Genotype Read More

Inclusion Criteria:

1. Subjects aged between 18-80 years old
2. PAH which is idiopathic; PAH heritable; PAH associated with connective tissue disease; PAH after ≥ 1 year repair of congenital systemic to pulmonary shunt, or PAH associated with anorexigens or other drugs
3. Subjects willing to be genotyped for genes that influence PDGF activity
4. Resting mean pulmonary artery pressure ≥25 mmHg, Pulmonary capillary wedge pressure ≤15 mmHg, PVR >5 wood units, and normal or reduced cardiac output , as measured by right heart catheterisation (RHC) at entry
5. Six-minute walking distance >50m at entry
6. Stable on an unchanged PAH therapeutic regime comprising at least 2 therapies licensed for PAH (any combination of endothelin receptor antagonist, phosphodiesterase inhibitor or prostacyclin analogue) for at least 1 month prior to screening
7. Able to provide written informed consent prior to any study mandated procedures
8. Contraception: Fertile females (women of childbearing potential) are eligible to participate after a negative highly sensitive pregnancy test, if they are taking a highly effective method of contraception during treatment and until the end of relevant systemic exposure. Fertile males who make use of condom and contraception methods during treatment and until the end of relevant systemic exposure in women of childbearing potential -full details are in included in the research protocol-

Exclusion criteria:

1. Unable to provide informed consent and/or are non-fluent speakers of the English language
2. Hypersensitivity to Imatinib or to any of the excipients
3. Clinically-significant renal disease (confirmed by creatinine clearance <30 ml/min per 1.73m2)
4. Clinically-significant liver disease (confirmed by serum transaminases >3 times than upper normal limit)
5. Patients receiving oral and/or parenteral anticoagulants (this does not apply to single antiplatelet therapy)
6. Anaemia confirmed by haemoglobin concentration <10 g/dl
7. History of thrombocytopenia
8. Individuals known to have haemoglobinopathy sickle cell disease, thalassaemia
9. Hospital admission related to PAH or change in PAH therapy within 3 months prior to screening

10. History of left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:

    1. Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis, mild mitral stenosis, moderate mitral regurgitation
    2. Mechanical or bioprosthetic cardiac valve
    3. Pericardial constriction, effusion with tamponade physiology, or abnormal left atrial size.
    4. Restrictive or congestive cardiomyopathy
    5. Left ventricular ejection fraction ≤50% (measured in echocardiogram at screening)
    6. Symptomatic coronary disease
    7. Significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation
    8. Acutely decompensated left heart failure within 1 month of screening
    9. History of untreated obstructive sleep apnoea
11. Evidence of significant lung disease on high-resolution CT (if available) or recent (performed within 12 months) lung function, where FEV1 < 50% predicted and FVC < 70% predicted, and DLCO (or TLCO) < 50% predicted if any CT abnormalities; judged by the Site Physician
12. Patients with a history of uncontrolled systemic hypertension
13. Acute infection (including eye, dental, and skin infections)
14. Chronic inflammatory disease including HIV, and Hepatitis B
15. Women of childbearing potential who are pregnant or breastfeeding (if applicable)
16. Previous intracerebral haemorrhage
17. Patients who have received an Investigational Medicinal Product (IMP) within 5 half-lives of the last dose of the IMP or 1 month (whichever is greater) before the baseline visit