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

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. Lay Summary This is a study to test if monitors placed in the lungs and the heart can help to choose the best medications for patients with a diagnosis of pulmonary arterial hypertension (PAH). PAH is a condition that results in high blood pressure in the blood vessels that supply the lungs. This study is for patients with PAH who are already taking two PAH medications (called dual therapy) but continue to have symptoms limiting their daily life and ability to exercise. There are two additional medications called selexipag and riociguat that may be prescribed when patients are not responding well to dual therapy; if selexipag is used, it is added to the existing dual therapy (Arm A), but if riociguat is used it replaces one of the drugs in the dual therapy (Arm B). It is not known which one of these treatment approaches is better. This 3-year study is called a crossover study design to look at responses of 40 individual patients to each of these two treatment approaches. Before starting the study treatment, patients will be implanted with monitoring devices. These approved devices will allow heart rate, pressure in the lungs, and other measures to be taken and seen by the clinical team from any location, without patients needing to attend hospital. Patients will be randomly selected to either start Arm A or Arm B, as shown in Figure 1 , before being swapped to the other treatment arm; there is no placebo. For example, for patients starting on Arm A, one of their medications (called phosphodiesterase type-5 inhibitor [PDE5i] e.g., sildenafil/tadalafil) will be stopped for a short time before riociguat is started. The dose of riociguat will gradually be increased to maximum dose and at 12 weeks they will have a magnetic resonance imaging (MRI) scan will measure treatment effect. The patient will then switch over to Arm B, where their PDE5i is restarted prior to treatment with selexipag. The MRI scan captures an image of the heart at the start and end of both Arm A and Arm B to look for improvements in the heart function with therapy. The study will also use patient-reported outcomes to record how patients feel and any side effects, blood tests related to heart health, and exercise tests to look at exercise ability. Each patient will be in the study for a total of 6 months, following which ongoing treatment choice will be decided at the discretion of the clinical care team.