Idiopathic Pulmonary Arterial Hypertension increased pulmonary artery pressure of unknown cause
Conditions
Interventions
Oral empagliflozin 10 mg tablet once daily for 12 weeks. All patients receive
the same intervention.
Sponsors
Amsterdam UMC, locatie VUmc
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Age >= 18 years 2. Diagnosis of idiopathic PAH 3. Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming diagnosis of WHO diagnostic pulmonary hypertension Group I: PAH with subtype idiopathic PAH. The documented RHC shows all of the following criteria: a. mPAP > 20 mmHg at rest b. Pulmonary artery wedge pressure (PAWP) or left ventricular end-diastolic pressure (LVEDP) = 240 dyn·sec/cm5 (3 Wood units) at rest 4. Symptomatic pulmonary hypertension classified as World Health Organization (WHO) functional class (FC) II, III or IV 5. PAH therapy is at stable (per investigator) dose levels of standard of care (SoC) therapies for at least 90 days prior screening. SoC therapy refers to a therapy consisting of at least 1 agent from a list including: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5 (PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist (SC/inhaled/PO).
Exclusion criteria
Exclusion criteria: 1. Any subject who 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. Patients participating in a purely observational trial will not be excluded 2. Females of childbearing potential, defined as a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 months), unable or unwillingly to either: a. Use highly effective methods of birth control according to the International Conference on harmonisation of pharmaceuticals for human use (ICH) that result in a low failure rate of less than 1% per year when used consistently and correctly 43. Highly effective methods include hormonal contraception (for example, birth control pills, injection, implant, transdermal patch, vaginal ring); intrauterine device (IUD); tubal ligation (having your tubes tied); or a partner with a vasectomy who has completed follow-up to confirm a successful procedure b. Have a negative pregnancy tests as verified by the investigator prior to starting study therapy and agrees to have an extra pregnancy test 8 weeks after start of the study 3. Contraindication for CMR imaging as defined in the protocol of the Amsterdam UMC *Kwaliteitsdocument Cardiale MRI (Versie 1)*. The list of contra-indications includes: claustrophobia, ferromagnetic implants, implanted cardioverter defibrillator (ICD) or pacemaker (except for the MR conditional) and ball-in-cage mechanic heart valve. 4. Impaired renal function, defined as eGFR 10, Appendix 1) or active liver disease defined as serums transaminases >5 x upper limit of normal (ULN) or bilirubin > 1.5 x ULN 6. History of ketoacidosis 7. Known allergy, intolerance or hypersensitivity to empagliflozin or other SGLT-2 inhibitors 8. Use of lithium compounds and being unable or unwillingly to increase the monitoring frequency of lithium levels 9. Current or scheduled use of the following Uridine glucuronosyltransferase (UGT) inducers: phenytoin, rifampicin, carbamazepine, lamotrigine, ritonavir, efavirenz, tipranavir, phenobarbital, testosterone propionate and nelfinavir. 10. Current or prior use of a SGLT-2 inhibitor 11. Heart transplant recipient or listed for heart transplant 12. Chronic pulmonary disease requiring home oxygen or steroid maintenance therapy 13. Symptomatic hypotension and/or a systolic blood pressure (SBP) =2 infections in si
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The main study objectives and endpoints of this trial are to determine during a follow up of 12 weeks: • Tolerability. Endpoints: the number of patients who have to prematurely discontinue treatment due to intolerability or adverse events. • Feasibility: Endpoints: time needed to include all patients and number of patients needed to screen. • Safety. Endpoints: the number of adverse events (AEs), severe adverse events (SAEs), adverse event of special interest (AESI) and suspected unexpected serious adverse reactions (SUSARs). | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary objectives include change over time (from baseline to end of study follow up) of: • Right heart function measured using CMR: Endpoints: RVESVi, RVEDVi, RVSVi, RVEF, RV mass index, RVFAC, RV longitudinal strain, right atrial area, TAPSE, LVESVi, LVEDVi, LVSVi and LVEF. Timepoints: baseline and week 12. • Right heart function measured using transthoracic ultrasound. Endpoints: left heart mitral inflow: Septal and lateral e* velocity, E/e* ratio, E-wave DT in the left heart. Septal flattening (yes/no), Notch in PA signal (yes/no), Pulmonary artery acceleration time, early diastolic pulmonary regurgitation velocity, S wave velocity of the RV, tricuspid annular plane systolic excursion (TAPSE), severity of tricuspid valve regurgitation (mild/moderate/severe), peak tricuspid valve regurgitation velocity (TRV), inferior cava diameter, Collapse of inferior vena cava (50%), estimated RAP, estimated mPAP, estimated sPAP. Timepoints: baseline and week 12. • Blood biomarkers. Endpoints: Expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1a) and bone morphogenetic protein receptor II (BMPR2) in peripheral blood mononuclear cells (PMBC) and glycated hemoglobin (HbA1c). Timepoints: baseline and week 12. • Blood and urine safety biomarkers. Endpoints: Fasting glucose, N-terminal prohormone of Brain Natriuretic Peptide (NT-proBNP) and creatinine in blood. Ketones, nitrites, leukocytes and glucose in urine test strip (dipstick). Timepoints: baseline, week 2, 6 and 12. • Functional class. Endpoint: World Health Organization Function Classification of Pulmonary Hypertension. Timepoints: baseline, week 2, 6 and 12. • Six-Minute Walk Distance. Endpoint: 6MWD. Timepoints: baseline and week 12. • Quality of life. Endpoint: EMPHASIS-10 and CAMPHOR questionnaires score. Timepoints: baseline and week 12. | — |
Countries
Netherlands
Outcome results
None listed