Pulmonary arterial hypertension Circulatory System
Conditions
Interventions
This study involves one treatment arm so no randomisation
it is open-label. All subjects start on an oral dose of 200 mg imatinib mesylate (100 mg (x2) per dose) daily for 8 weeks. The dosing frequency is then adjusted and titrated to the change in total pul
once every other day
once every four days
or once weekly.
In more detail, patients will be asked at Baseline to take Imatinib 100 mg (x2) once daily. All patients will be assessed at the end of Week 8.
- Patients who demonstrate a reduction
Sponsors
Imperial College London
Eligibility
Sex/Gender
All
Age
18 Years to 80 Years
Inclusion criteria
Inclusion criteria: 1. Subjects aged between 18-80 years old 2. Idiopathic PAH; 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. PAH management assisted by remote monitoring using implanted devices i.e. a CardioMEMS™ device to measure pulmonary artery pressure, and a LINQ™ device to measure heart rate and physical activity 4. Resting mean pulmonary artery pressure =25 mmHg, TPR >5 wood units, and normal or reduced cardiac output 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 condoms and contraception methods during treatment and until the end of relevant systemic exposure in women of childbearing potential.
Exclusion criteria
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 3 times the upper normal limit) 5. Patients receiving oral and/or parenteral anticoagulants* 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: 10.. Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis, mild mitral stenosis, moderate mitral regurgitation 10.1. Mechanical or bioprosthetic cardiac valve. 10.2. Pericardial constriction, effusion with tamponade physiology, or abnormal left atrial size. 10.3. Restrictive or congestive cardiomyopathy 10.4. Left ventricular ejection fraction =50% (measured in echocardiogram at screening) 10.5. Symptomatic coronary disease 10.6. Significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation 10.7. Acutely decompensated left heart failure within 1 month of screening 10.8. 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 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 diseases 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. *This does not apply to single antiplatelet therapy
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Total pulmonary resistance (TPR) measured using CardioMEMS medical device measurements at baseline and 8 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. The distance walked on a flat surface in 6 minutes measured using the six-minute walk test (6MWD) at baseline, and at weeks 8 and 24 (or earlier if there is an early termination). 2. Right ventricular ejection fraction (RVEF) values measured using MR imaging of the heart (cardiac MRI scan) at baseline assessment, and at weeks 8 and 24 (or earlier if there is an early termination). 3. Plasma brain natriuretic peptide (NT-proBNP) levels measured using a validated assay on peripheral blood samples at baseline, and at weeks 8 and 24 (or earlier if there is an early termination). 4. Quality of Life (QoL) scores measured using the EmPHasis-10 Quality of Life questionnaire at baseline, and at weeks 8 and 24 (or earlier if there is an early termination). Exploratory: 1. The proportion of patients who respond and require dosing with Imatinib 200mg less frequently than once daily measured using CardioMEMs-derived TPR values weekly, from baseline to Week 24 (or earlier, if there is an early termination). 2. Total pulmonary resistance (TPR) measured using the CardioMEMS devices in relation to genes that regulate PDGF activity at baseline, and at weeks 8 and 24 (or earlier, if there is an early termination). 3. Total pulmonary resistance (TPR) measured using the CardioMEMS devices according to circulating plasma proteins measured using peripheral plasma samples at baseline, and at weeks 8 and 24 (or earlier, if there is an early termination) | — |
Countries
England, Scotland, United Kingdom
Contacts
Public ContactAndreas Roussakis
Outcome results
None listed