Pulmonary Hypertension: Intensification and Personalisation of Combination Rx (PHoenix): A phase IV randomised trial for the evaluation of dose-response and clinical efficacy of riociguat and selexipag using implanted technologies

Abstract

Approved therapies for pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. Patients identified as intermediate-low risk, according to a four-strata risk assessment model, with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides opportunity for evaluation of individualised therapeutic effect. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefit. Regulatory approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2x2 randomised crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS (a wireless pulmonary artery sensor) and ConfirmRx (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory approved online clinical portals. The primary aim will be establishing the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including haemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.