Master - 2/2 Empaglifozin To Improve Right Ventricular Function in Pulmonary Arterial Hypertension

DCC Project Summary Abstract Despite advances in medical therapy for pulmonary arterial hypertension (PAH), mortality rates remain high. Empagliflozin to Improve Right Ventricular Function in Pulmonary Arterial Hypertension (EmPAH) is a 3-center blinded, placebo-controlled, randomized Phase II trial testing whether 10 mg empagliflozin taken daily for 24

weeks will improve PAH patient heart function and other outcomes. The trial's primary endpoint is change in Right Ventricular Ejection Fraction measured by Cardiac Magnetic Resonance (CMR) imaging. Secondary endpoints include: changes in Tricuspid Annular Plane Systolic Excursion (TAPSE) measured by echocardio-

gram, 6 Minute Walk Distance, quality of life (SF-36 Physical Health Composite and EmPHAsis10), and N- terminal pro B-type natriuretic peptide (NT-proBNP), each measured at baseline, weeks 12, week 24; a “time to clinical worsening” composite, defined multicomponent improvement, and proportion of patients meeting

the three criteria of the French Risk Score. Seven additional exploratory endpoints have been specified, and the Data Coordinating Center (DCC) will also carry out exploratory analyses of clinical and cardiac imaging phenotypes associated with response to empagliflozin therapy. The DCC will oversee study

design and carry out all statistical analyses and contribute to EmPAH publications and dissemination. The DCC will play a leadership role in the development of the trial protocol, manual of operations, and case report forms, and will monitor recruitment, retention, adherence, and especially safety, as well as track and

implement procedures to improve the quality of data, samples, and images. The DCC will prepare DSMB reports and manage virtual DSMB meetings and as well as the annual DSMB meetings in Bethesda. DCC statistical, database, and administrative personnel will ensure the trial fully exemplifies regulatory compliance

and best practices for data collection and database management. The Biorepository - a section of the DCC - will train sites in biological sample collection, local storage, and monthly shipment to the Biorepository which will analyze triglycerides, LDL, HDL, total cholesterol and NT-proBNP and will archive samples for sharing.

Echocardiograms and CMR images will be read centrally at the Imaging Center – a section of the CCC – who will train sites to collect appropriately-formatted images following EmPAH procedures, securely transfer images to the CMR and Echo Core labs and will transmit results to the DCC. The DCC will develop and maintain the

trial's distributed data entry and database management systems. Triple blinding of randomized treatment (empagliflozin vs. placebo) will reduce the potential for bias due to knowledge of treatment, even at the subconscious level, among participants, investigators, health care providers, outcome measurers, and

biostatisticians. EmPAH's Phase II trial sample size of 78 has 85% power to show a difference of 11 percentage points between empagliflozin and placebo and will provide data on safety and logistic issues related to carrying out a Phase III trial of empagliflozin in PAH.