Pulmonary Arterial Hypertension (PAH) is a rare condition in which a narrowing of blood vessels carrying blood through the lungs puts an increased work load on the heart; it has to work harder to pump blood through the lungs. While current treatments relieve some of the symptoms, they do not stop or reverse the disease in the affected blood vessels. Imatinib is a medicine licensed for some types of cancers. A published study has shown that imatinib can have beneficial effects on blood flow through the lungs and exercise capacity in patients with PAH, even when added to existing treatments. However, there have been concerns about its safety and tolerability. Imatinib continues to be prescribed occasionally on compassionate grounds, usually when other treatment options have been exhausted, and some patients feel better on the drug. To improve the investigator's understanding, the investigators of this study re-visits the use of Imatinib as a potential treatment for patients with PAH.

What does the study involve?

The study involves treatment of PAH patients with imatinib (study drug) for up to 24 weeks, and clinical assessments and tests to assess the drug's safety and tolerability.

PAH patients will be seen at their local hospital by the PAH clinical research team. Before someone can start study, the study doctor (or clinical study team) will describe the clinical trial in detail. If a potential subject decides to participate, he/she will be asked to sign the informed consent form before any study procedures are done.

Participants will be asked to come to their local hospital for clinical appointments. This includes a screening visit, a baseline visit, three clinical assessments and an end-of-study visit. In between, and at the very end of these, there will be six tele-visits (assessments over the phone). Each clinical appointment will be on a weekday morning or afternoon. No major lifestyle restrictions are required for these appointments.

Participants will undergo clinical examinations and tests to monitor the severity of PAH and the response to the study drug. Clinical procedures include:

• Questions about demographics, medical and medication history
• Physical examination and record of vital signs (blood pressure, temperature, heart and respiratory rate)
• Questionnaire about quality of life,
• Assessments of PAH severity (WHO Functional Class, six-minute walk test, and Borg dyspnoea index)
• Right heart catheterisation to assess response to the drug
• Haematology and clinical chemistry blood tests to ensure safety
• Serum pregnancy test and urine pregnancy tests (if applicable) to exclude pregnancy
• Blood samples to measure the levels of the study drug in the circulation
• Additional blood samples for future research on PAH and/or the mechanism of action of the drug
• Electrocardiogram (ECG), and echocardiogram to assess the size, shape, pumping action and the extent of any damage to the heart
• Brain MRI scan (or CT scan if MR is not indicated/tolerated) to exclude bleeding in the brain

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