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6-MP Trial


- candidate number28393
- NTR NumberNTR6931
- ISRCTNISRCTN no longer applicable
- Date ISRCTN created
- date ISRCTN requested
- Date Registered NTR2-jan-2018
- Secondary IDsPRECISE-MP 2017.059
- Public Title6-MP Trial
- Scientific TitlePulmonary Hypertension REversal in Clusters of Patients With Identical Pathobiological Substrates

6-Mercaptopurine Proof-of-Concept Trial
- ACRONYMPRECISE-MP Trial
- hypothesisThe 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.
- Healt Condition(s) or Problem(s) studiedPulmonary arterial hypertension (PAH)
- 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 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 30 days of at least oral combination therapy, patients in FC IV received 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 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
- 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
- mec approval receivedyes
- multicenter trialno
- randomisedno
- groupParallel
- TypeSingle arm
- Studytypeintervention
- planned startdate 1-jul-2017
- planned closingdate1-jul-2019
- Target number of participants50
- Interventions4 months 6-MP treatment, in a dose of 1.5mg/kg (up to 150mg) once daily.
- Primary outcomeThe primary endpoint of the study is the change in PVR, measured by right heart catheterization.
- Secondary outcomeThe 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
- Timepointsafter 4 months
- Trial web sitena
- statusopen: patient inclusion
- CONTACT FOR PUBLIC QUERIES L Botros
- CONTACT for SCIENTIFIC QUERIES L Botros
- Sponsor/Initiator VU University Medical Center
- Funding
(Source(s) of Monetary or Material Support)
VU University Medical Center
- Publications
- Brief summaryRationale:
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.
- Main changes (audit trail)
- RECORD2-jan-2018 - 11-jan-2018


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