Clinical trials with drugs targeting metabolic dysfunction in pulmonary arterial hypertension (PAH)

Drug identifierStudy designStudy durationMain inclusion criteriaPrimary outcome measureSecondary outcome measures
Fatty acid oxidation: ranolazine and trimetazidine
 RanolazineNCT02829034Multicentre RCT versus placebo26 weeksPH on stable specific therapies but with RV dysfunction (RVEF <45%)Percentage change in RVEF (assessed by MRI)
 RanolazineNCT01839110Multicentre RCT versus placebo26 weeksPH on stable specific therapies but with RV dysfunction (RVEF <45%)Number and percentage of subjects with high-risk profile at end of the studyBaseline comparison of the metabolic profiling, microRNA and iPSCs of subjects with and without RV dysfunction
 RanolazineNCT02133352Single-centre open-label phase 426 weeksPH with LV diastolic dysfunctionPercentage change in mPAP, PAOP and PVR (RHC)Other haemodynamic variables, 6MWD, MRI, echocardiography and NT-proBNP
 RanolazineNCT01757808Phase 112 weeksPAH on one or more background specific therapies (including i.v./s.c. prostacyclins)Change in PVR (RHC)Change in CPET, RV echocardiography parameters and 6MWD
 TrimetazidineNCT03273387Single-centre phase 2 and 312 weeksPAHChanges in RV function (MRI)Changes in cardiac fibrosis level (MRI), NYHA FC and LDH level
Glycolysis: dichloroacetate
 DichloroacetateNCT01083524Two-centre open-label phase 116 weeksPAH on one or more background oral specific therapiesSafety and tolerabilityChange in PVR, 6MWD, RV size and function (MRI), NT-proBNP and lung/RV metabolism (FDG-PET)
Modulation of Nrf2 pathway/NF-κB pathway: bardoxolone methyl
 Bardoxolone methylNCT02036970 (LARIAT)Multicentre phase 2 RCT versus placebo16 weeksPAH, PH-ILD, subset of patients with group 3 or 5 PHChange in 6MWDDetermine recommended dose range
 Bardoxolone methylNCT02657356 (CATALYST)Multicentre phase 3 RCT versus placebo24 weeksPAH-CTDChange in 6MWD
 Bardoxolone methylNCT03068130 (RANGER)Multicentre phase 3 open-label extensionUp to 5 yearsPatients with PH who previously participated in RCTs with bardoxoloneLong-term safety
Metabolic syndrome: AMPK signalling and metformin
 Hormonal, metabolic and signalling interactions in PAHNCT01884051Observational5 yearsPAH and healthy subjectsSafety and biomarkers of mechanism
 MetforminNCT03349775Early phase 112 weeksPH and obesityPulmonary vascular haemodynamics at rest and on exerciseEffect on PA endothelial cell phenotypes

RCT: randomised controlled trial; PH: pulmonary hypertension; RV: right ventricle; RVEF: right ventricular ejection fraction; MRI: magnetic resonance imaging; iPSC: induced pluripotent stem cell; LV: left ventricle; mPAP: mean pulmonary arterial pressure; PAOP: pulmonary artery occlusion pressure; PVR: pulmonary vascular resistance; RHC: right heart catheterisation; 6MWD: 6-min walk distance; NT-proBNP: N-terminal pro-brain natriuretic peptide; CPET: cardiopulmonary exercise testing; NYHA: New York Heart Association; FC: functional class; LDH: lactate dehydrogenase; FDG: 18F-2-fluoro-2-deoxy-d-glucose; PET: positron emission tomography; Nrf2: nuclear factor erythroid 2-related factor 2; ILD: interstitial lung disease; AMPK: AMP-activated protein kinase; PA: pulmonary artery.