E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Pulmonary arterial hypertension |
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E.1.1.1 | Medical condition in easily understood language |
Elevated blood pressure in the lung |
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E.1.1.2 | Therapeutic area | Body processes [G] - Circulatory and Respiratory Physiological Phenomena [G09] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10037454 |
E.1.2 | Term | Pulmonary vascular disorders |
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 | HLT |
E.1.2 | Classification code | 10037401 |
E.1.2 | Term | Pulmonary hypertensions |
E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal 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 |
To obtain pilot safety and efficacy data on treatment of patients with pulmonary arterial hypertension (PAH) by 6-Mercaptopurine (6-MP) |
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E.2.2 | Secondary objectives of the trial |
To determine whether platelet transcriptome analysis will identify a subset of PAH patients that responds to 6-MP treatment with hemodynamic and functional improvement |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age > 18 years - Diagnosis of idiopathic, hereditary or drug-induced PAH - New York Heart Association functional class (FC) II, III or IV - Prior to their screening right heart catheterization, patients in FC II received ≥ 3 months of at least oral monotherapy (PDE5-inhibitors, soluble guanyl cyclase stimulators, endothelin receptor antagonists or prostacyclin receptor agonist), patients in FC III received ≥ 3 months of at least oral combination therapy, patients in FC IV received ≥ 3 months triple therapy including a parenteral prostacyclin, unless intolerant for these medications - Stable on mono- or any combination therapy for at least 30 days prior to enrollment, as evidenced by stable drug doses (PAH medications and diuretics), no change in FC, < 15% change in 6 minute walk distance (6MWD) - Right heart catheterization no longer than 4 weeks prior to enrollment showing precapillary pulmonary hypertension with mPAP ≥ 25 mmHg (at rest), Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, PVR > 6 WU - Negative test results in regard to HIV, Hepatitis C/B, not older than 4 weeks - Able to understand and willing to sign the Informed Consent Form - PAH following one year repair of congenital heart defect (atrial septal defect, ventricle septal defect or persistent ductus arteriosus) - PAH responsive to calcium antagonsists. |
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E.4 | Principal exclusion criteria |
- PAH of any cause other than permitted in the entry criteria - Contraindication for right heart catheterization or CMR imaging - Any subject who had received any investigational medication within 1 month prior to the start of this study or who is scheduled to receive another investigational drug during the course of this study - Known intolerance to 6-MP or TPMT deficiency - Active liver disease, porphyria or elevations of serums transaminases >3 x ULN (upper limit of normal) or bilirubin > 1.5 x ULN - History or suspicion of inability to cooperate adequately. - Cancer or other malignant haematological disease - eGFR <30 ml/min - White blood count < 4.0 109/l - Hemoglobin < 6.0 mmol/l - Thrombocytes < 100 109/l - Transfer capacity for carbon monoxide (TLCO) < 40% of predicted - Total lung capacity (TLC) < 60% of predicted - Use of xanthineoxidase inhibitors - Pregnant female subjects - Breastfeeding female subjects - Female subjects unwilling or unable to use a highly effective method of contraception |
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E.5 End points |
E.5.1 | Primary end point(s) |
Pulmonary Vascular Resistance |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
• A change in mean pulmonary artery pressure (mPAP) • A change in cardiac output (CO) • A change in right atrial pressure (RAP) • A change in Functional Class • Hospitalization for congestive heart failure (CHF) • A change in VO2 max • A change in 6 minute walking distance • Change in NT-proBNP (pmol/L) • A change in right ventricular ejection fraction (RVEF) (%) • A change in right ventricular end diastolic volume (RVEDV) (ml) • A change in right ventricular end systolic volume (RVESV) (ml) • A change in EuroQol five dimensions questionnaire (EQ-5D) • A change in Living with Pulmonary Hypertension questionnaire (LPH) • A change in BORG dyspnea score |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
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 | |
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 | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
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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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 | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |