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 clfnical trial is to determine whether LEPs transcriptome analysis will identify a subset…
ID
Source
Brief title
Condition
- Pulmonary vascular disorders
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Changes in pulmonary vascular resistance
Secondary outcome
Change in cardiac function (right heart catheterization, MRI), exercise
tolerance and quality of life.
Background summary
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 bul is currently not
specifically targeted by medica! treatment. Treatment with 6 mercaptopurine
(6-MP) showed encouraging results, mitigating endothelial proliferation in
vitro and reversing pulmonary vascular remodelling in relevant anima! 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.
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 clfnical 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 of treatment for 4 months with 6-MP, in a
dose of 1.5mg/kg (up to 150mg) once daily.
Intervention
-
Study burden and risks
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. lf effective, 6-MP could improve morbidity and
mortality of PAH. For individual patients, participation in this study involves
one or two extra right heart catheterizations and before and at the end of the
study performance of exercise tests, MRI and quality of life assessment. In our
experience, these procedures are safe.
de Boelelaan 1117
Amsterdam 1007 MB
NL
de Boelelaan 1117
Amsterdam 1007 MB
NL
Listed location countries
Age
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.
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
- 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
- Thiopurine S-methyltransferase (TPMT) enzyme deficiency
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| EudraCT | EUCTR2017-000137-31-NL |
| CCMO | NL60538.029.17 |