E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary Arterial Hypertension (Idiopathic, heritable, or assosicated with anorexigens) |
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E.1.1.1 | Medical condition in easily understood language |
Pulmonary Arterial Hypertension is a condition in which blood pressure is increased in the arteries of the lungs |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036727 |
E.1.2 | Term | Primary pulmonary hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10037400 |
E.1.2 | Term | Pulmonary hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10037400 |
E.1.2 | Term | Pulmonary hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10068739 |
E.1.2 | Term | Chronic thromboembolic pulmonary hypertension |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10050701 |
E.1.2 | Term | Congenital pulmonary hypertension |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10050701 |
E.1.2 | Term | Congenital pulmonary hypertension |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The over-aching hypothesis is that there is a subgroup of patients, identifiable by genotype, with pulmonary arterial hypertension that will benefit from a safe and tolerated dose of Imatinib.
Imatinib is thought to work by blocking a protein called platelet derived growth factor receptor B. There is a gene that regulates the blood levels of this protein, called the “PDGFRB”. Patients can be divided into 3 groups based on variants of this PDGFRB gene; the 3 groups are called CC, CT and TT. Patients with CC have higher levels of PDGFRB than patients with TT. It is possible that Imatinib works better in patients with CC than TT, and that patients who are in the CT group lie in between.
The study has two parts.
Part 1 will identify a maximum tolerated dose (MTD) of Imatinib in patients with pulmonary arterial hypertension. The MTD is defined by a dose with a 20% probability of leading to discontinuation of treatment for more than 5 consecutive days due to side effects.
Part 2 will ev |
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E.2.2 | Secondary objectives of the trial |
-Change in the six-minute walk test, a measure of exercise capacity -Change in echocardiogram (type of ultrasound heart test) values, a measure of how well the heart is working -Change in "BNP" blood test values, another measure of heart function -Change in Quality of Life scores
The above refer to change from baseline at 24 weeks. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subjects aged between 18-75^ years old 2. PAH which is idiopathic, heritable or associated with anorexigens 3. Subjects homozygous at rs3816018 locus (PDGFRB genotype)* *genotyped through the National Cohort Study 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. Women of child-bearing potential are eligible to participate, if they agree to use one of the following contraception methods: Abstinence OR Highly effective contraceptive methods with typical-use failure rate <1% i.e. • Male or female sterilisation and long-acting reversible contraceptive methods (intrauterine devices and implants)prior to the female subject's entry into the study • Progestogen-only injections if repeat rejections are documented as having been administered on schedule by a healthcare professional.
^The upper age limit stems from PAH Registries and previous clinical trials in the field. |
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E.4 | Principal exclusion criteria |
1. Unable to provide informed consent and/or non-fluent speaker 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 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: a. aortic or mitral valve disease (stenosis or regurgitation) defined as greater than mild aortic insufficiency, mild aortic stenosis, mild mitral stenosis, moderate mitral regurgitation b. Mechanical or bioprosthetic cardiac valve c. Pericardial constriction, effusion with tamponade physiology, or abnormal left atrial size. d. Restrictive or congestive cardiomyopathy e. Left ventricular ejection fraction ≤50% (measured in echocardiogram at screening) f. Symptomatic coronary disease g. Significant (2+ for regurgitation) valvular disease other than tricuspid or pulmonary regurgitation h. Acutely decompensated left heart failure within 1 month of screening i. 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 16. Previous intracerebral haemorrhage 17. Patients who have received an Investigational Medicinal Product (IMP) within 1 month before the baseline visit |
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E.5 End points |
E.5.1 | Primary end point(s) |
From a statistical point of view, the study has two parts.
Part 1: Discontinuation of the drug for more than 5 consecutive days due to Grade 2 or above Adverse Events defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (version .5.0, 2017), adapted for this study
Part 2: The primary efficacy endpoint is a binary variable. For patients with a baseline 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
After 24 weeks of treatment. |
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E.5.2 | Secondary end point(s) |
-Change in 6MWD at 24 weeks. -Change in right ventricular ejection fraction (RVEF) values, measured in echocardiogram (at screening visit and at 24 weeks). -Change in plasma brain natriuretic peptide (proNT-BNP) levels from baseline at 24 weeks. -Change in Quality of Life (QoL) scores from baseline at 24 weeks |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After 24 weeks of treatment. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description |
Trial to find the maximum tolerated dose of imatinib in patients with PAH. |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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Subjects will be considered complete for the purpose of this study once they have completed all procedures of the Follow-up Tele-visit at the end of Week 28 (or 4 Weeks after early termination).
The end of study the clinical trial is defined as the last visit of the last subject undergoing the trial. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 1 |