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. ### Competing Interest Statement Dr Frances Varian: MRC clinical research fellow, conference funding from Janssen and Janssen Dr Jennifer Dick: none declared Mr Christian Battersby: none declared Mr Stefan Roman: none declared Miss Jenna Ablott: none declared Dr Lisa Watson: none declared Mrs Sarah Bizmahfooz: none declared Dr Hamza Zafar: none declared Dr Gerry Colgan: no direct conflicts, has undertaken consultancy work & honoraria for Janssen Ltd, Bayer Ltd, MSD. Received research funding from Janssen Ltd. Dr John Cannon: support to attend conferences from Janssen and been paid for advisory boards by Janssen and Ferrer. Jay Suntharalingam: none declared Dr Jim Lordan: none declared Professor Luke Howard: I have received honoraria for advisory boards, steering committees and speaking from Janssen. My department has received research funding support from Janssen. I have received personal support for travel, accommodation and registration at international meetings. I have received honoraria for advisory boards and speaking from MSD. I have received honoraria for advisory boards from Endotronix. Colm McCabe: none declared Dr John Wort: I have received honoraria from Janssen, MSD, Ferrer and Acceleron, research grants from Janssen and Ferrer and travel and accommodation grants from Janssen Laura Price: none declared Dr Colin Church: none declared Dr Neil Hamilton: Honoraria from MSD and Janssen, travel and accommodation grants from Janssen, participation on advisory boards for Bayer, MSD, Janssen and Vifor and is a board member on the NHS Specialist respiratory clinical reference group. Iain Armstrong Dr Abdul Hameed: none declared, https://orcid.org/0000-0002-2128-2081 Dr Judith Hurdman: none declared Dr Charlie Elliot: none declared Prof Robin Condliffe: No COI. Received honoraria for speaking and advisory boards from Janssen and MS Prof Martin Wilkins: support from NIHR for clinical research facility and biomedical research centre infrastructure support BHF centre support (RE/18/4/34215), consulting fees for MorphogenIX, Janssen and Janssen, Kinaset, Chiesi, Aerami, BenevolentAI, Novartis, and VIVS, participation on data safety monitoring board for Acceleron and GSK, Associate Professor Alastair Webb: none declared Dr David Adlam: none declared Professor Ray L Benza: steering and adjudication committees ABBOTT Professor Kazem Rahimi: receives grants from the Oxford Martin School and the British Heart Foundation. KR is an associate editor of Heart and specialty editor of PLOS Medicine. KR is a co-founder of Zeesta and sits on the advisory board of Medtronic Dr Moha Shojaei: none declared Dr Nan Lin: none declared Prof James Wason: none declared Dr Alasdair McIntosh: none declared Prof Alex McConnachie: none declared Dr Jennifer Middleton: none declared Dr Roger Thompson: I have received honoraria, travel support and grant funding from Janssen Prof David Kiely: Support and grants received from NIHR Sheffield Biomedical Research Centre, Janssen Pharmaceuticals; additional grants from Ferrer; consulting fees, honoraria payments and supports for attending meetings received from Janssen Pharmaceuticals, Ferrer, Altavant, MSD and united Therapeutics, participants on advisory boards with Janssen and MSD; members of clinical reference group for specialist respiratory medicine (NHS England) and lead of UK national audit of pulmonary hypertension. Dr Mark Toshner: Funding from NIHR Cambridge BRC, NIHR HTA; consulting fees from MorphogenIX and Jansen, participation on data safety monitoring board/advisory board with ComCov and FluCov. Dr Alex Rothman: Research funding: Wellcome Trust Clinical Research Career Development Fellowship (206632/Z/17/Z), Medical Research Council (UK) Experimental Medicine Award (MR/W026279/1), NIHR Biomedical Research Center Sheffield, Contribution in kind: Medtronic, Abbott, Endotronix, Novartis, Janssen. Research support and consulting: NXT Biomedical, Endotronix, SoniVie, Neptune, Gradient. MT: Research funding: NIHR Biomedical Research Center Cambridge, NIHR HTA. Personal support: GCK and Jansen. DSMB: ComCov, FluCov. PDM: personal support: Abbott. ### Clinical Trial NCT05825417 ### Funding Statement The study is funded by an MRC Experimental Medicine Project award MR/W026279/1. Devices are provided by Abbot. Wellcome Trust Clinical Research Career Development Fellowship (AR: 206632/Z/17/Z; AS: 205188/Z/16/Z, PDM: 214567/Z/18/Z), BHF Intermediate Fellowship (AART: FS/18/13/33281), National Institute for Health Research (JMSW: NIHR301614). AR is grateful to Richard Hughes, whose generous philanthropic support has helped to make this work possible. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRAS project ID: 325120. York Research Ethics Committee Reference: 23/NE/0067 I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Methods paper therefore not applicable.