Positioning Imatinib for Pulmonary Arterial Hypertension

NCT04416750 | Unknown Phase 2 DMC

• 4 other identifiers: IRAS ID: 2740932020-001157-4820HH589620/SC/0240
• Study Type: interventional
• Target: 17
• Locations: 1 country
• Sites: 4

Brief Summary

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.

Conditions

Pulmonary Arterial Hypertension

Keywords

Pulmonary Arterial Hypertension; PAH; Imatinib; TKI; Genotype

Outcome Measures

Primary Outcomes (2)

• Identifying the highest tolerated dose

  Part 1: Discontinuation of the drug for more than 5 consecutive days due to Grade 2 or above Adverse Events, defined by NCI criteria (version 5.0, 2017) adapted for the study.

  12 months

• Change in pulmonary vascular resistance (PVR)

  Part 2: The primary efficacy endpoint is a binary variable. For patients with a baseline pulmonary vascular resistance (PVR) \>1000 dynes·s·cm-5, success is defined by an absolute reduction in PVR of ≥300 dynes·s·cm-5 at 24 weeks. For patients with a baseline PVR ≤1000 dynes·s·cm-5, success is a 30% reduction in PVR at 24 weeks.

  24 months

Secondary Outcomes (4)

• Change in exercise test

  24 weeks

• Change in ejection fraction measures

  24 weeks

• Change in brain natriuretic peptide (BNP) values

  24 weeks

• Change in quality of life scores

  24 weeks

Other Outcomes (1)

• Plasma proteome measures

  24 weeks

Study Arms (1)

Treatment

EXPERIMENTAL

Open label; Imatinib tablets administered once daily; Dosage: in the range of 100mg-400mg; Group evaluated: adults with PAH

Drug: Imatinib Mesylate

Interventions

Imatinib Mesylate DRUG

Treatment with Imatinib

Also known as: Oral treatment

Treatment

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects aged between 18-80 years old
• 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
• Subjects willing to be genotyped for genes that influence PDGF activity
• 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
• Six-minute walking distance \>50m at entry
• 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
• Able to provide written informed consent prior to any study mandated procedures
• 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-

You may not qualify if:

• Unable to provide informed consent and/or are non-fluent speakers of the English language
• Hypersensitivity to Imatinib or to any of the excipients
• Clinically-significant renal disease (confirmed by creatinine clearance \<30 ml/min per 1.73m2)
• Clinically-significant liver disease (confirmed by serum transaminases \>3 times than upper normal limit)
• Patients receiving oral and/or parenteral anticoagulants (this does not apply to single antiplatelet therapy)
• Anaemia confirmed by haemoglobin concentration \<10 g/dl
• History of thrombocytopenia
• Individuals known to have haemoglobinopathy sickle cell disease, thalassaemia
• Hospital admission related to PAH or change in PAH therapy within 3 months prior to screening
• History of left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following:
• Aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis, mild mitral stenosis, moderate mitral regurgitation
• Mechanical or bioprosthetic cardiac valve
• Pericardial constriction, effusion with tamponade physiology, or abnormal left atrial size.
• Restrictive or congestive cardiomyopathy
• Left ventricular ejection fraction ≤50% (measured in echocardiogram at screening)

Sponsors & Collaborators

• Imperial College London: lead
• National Institute for Health Research, United Kingdom: collaborator
• Medical Research Council: collaborator
• University of Cambridge: collaborator
• University of Sheffield: collaborator

Study Sites (4)

Hammersmith Hospital, Imperial College Healthcare NHS Trust

London, Greater London, W12 0HS, United Kingdom

Location

Royal Papworth Hospital, Royal Papworth Hospital NHS Foundation Trust

Cambridge, CB2 0AY, United Kingdom

Location

Royal Brompton Hospital, Royal Brompton & Harefield NHS Foundation Trust

London, SW3 6NP, United Kingdom

Location

Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation

Sheffield, S10 2JF, United Kingdom

Location

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

Imatinib Mesylate; Therapeutics

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Martin R Wilkins, MD, FRCP

  Imperial College London

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: The highest tolerated dose of Imatinib determined using a Bayesian continual reassessment method. In the first part, 13 patients were recruited sequentially by protocol at a minimum of 4 week intervals. Each patient was administered a dose of imatinib between 100mg and 400mg daily. The selected dose for each patient was based upon the safety and tolerability of doses administered to preceding recruits using a Bayesian continuous reassessment method. The inclusion of patients with implanted monitoring devices allowed us to collect data on an early efficacy marker alongside data on safety and tolerability. With a small extension, we gained further data on the effect of imatinib on cardiopulmonary haemodynamics and activity in PAH patients, covering the full 100mg to 400mg dose range.

Study Record Dates

• First Submitted: May 28, 2020
• First Posted: June 4, 2020
• Study Start: January 20, 2021
• Primary Completion: July 1, 2024
• Study Completion: July 1, 2024
• Last Updated: October 10, 2023

Record last verified: 2023-10

Locations

GB (4)