No registrations found.
Source
Brief title
Health condition
Pulmonary arterial hypertension
Sponsors and support
Intervention
No registrations found.
Outcome measures
Primary outcome
The primary endpoint of the study is the change in PVR, measured by right heart catheterization.
Secondary outcome
The key secondary endpoints of this study are:
Hemodynamically:
• A change in mean pulmonary artery pressure (mPAP)
• A change in cardiac output (CO)
• A change in right atrial pressure (RAP)
Clinical:
• A change in FC
• Hospitalization for congestive heart failure (CHF)
• A change in VO2 max
• A change in 6 minute walking distance
Laboratory:
• NT-proBNP (pmol/L)
• Whole blood count
• Kidney function
• Liver tests
• Platelet transcriptome
Cardiovascular magnetic resonance imaging (CMR):
• 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)
Questionnaires:
• A change in Living with Pulmonary Hypertension questionnaire (LPH)
• A change in BORG dyspnea score
Background summary
Rationale:
Background: Pulmonary arterial hypertension is an incurable disease of pulmonary vascular remodelling and right heart failure. Exuberant lung microvascular endothelial proliferation is one of the lead causes of PAH but is currently not specifically targeted by medical treatment. Treatment with 6 mercaptopurine (6-MP) showed encouraging results, mitigating endothelial proliferation in vitro and reversing pulmonary vascular remodelling in relevant animal models. Lung vascular proliferation in PAH patients is heterogeneous, however, and can be estimated by transcriptome analysis of lung educated platelets (LEPs). Patients with a LEPs profile consistent with exuberant proliferation are expected to respond better to 6-MP treatment than patients with LEPs profiles consistent with quiescent lung vascular remodeling.
Objective: The primary objective of this clinical trial is to obtain pilot safety and efficacy data on treatment of PAH patients by 6-MP. The secondary objective of this clinical trial is to determine whether LEPs transcriptome analysis will identify a subset of PAH patients that responds to 6-MP treatment with hemodynamic and functional improvement.
Study design: Open label proof of concept study.
Study population: Patients with hereditary, idiopathic or drug induced PAH on optimal conventional PAH treatment and in functional class II, III or IV.
Intervention: 4 months 6-MP treatment, in a dose of 1.5mg/kg (up to 150mg) once daily.
Main study parameters/endpoints: Changes in right heart catheterization data, cardiac magnetic resonance imaging, exercise tolerance and quality of life.
Nature and extent of the burden and risks associated with participation, benefit and group relatedness: 6-MP is currently used in haematological disorders and inflammatory bowel disease with an acceptable and manageable toxicity profile. No specific toxicity is expected in PAH. If effective, 6-MP could improve morbidity and mortality of PAH.
Study objective
The primary objective of this clinical trial is to obtain pilot safety and efficacy data on treatment of PAH patients by 6-MP. The secondary objective of this clinical trial is to determine whether LEPs transcriptome analysis will identify a subset of PAH patients that responds to 6-MP treatment with hemodynamic and functional improvement.
Study design
after 4 months
Intervention
4 months 6-MP treatment, in a dose of 1.5mg/kg (up to 150mg) once daily.
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 ¡Ý 30 days of at least oral monotherapy (PDE5-inhibitors, soluble guanyl cyclase stimulators, endothelin receptor antagonists or prostacyclin receptor agonist), patients in FC III received ¡Ý 30 days of at least oral combination therapy, patients in FC IV received ¡Ý 30 days 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 ¡Ý 25 mmHg (at rest), Pulmonary artery wedge pressure (PAWP) ¡Ü 15 mmHg, PVR > 6 WU
- Negative test results in regard to HIV, Hepatitis C/B, not older than 4 weeks
- Thiopurine S-methyltransferase genotyping and activity (TPMT) is tested via peripheral blood testingAble 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.
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 enzyme 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
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
Register | ID |
---|---|
NTR-new | NL6753 |
NTR-old | NTR6931 |
Other | 2017.059 : PRECISE-MP |