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Pulmonary Hypertension: Intensification and Personalisation of Combination Rx (PHoenix)

Primary Purpose

Pulmonary Arterial Hypertension

Status
Recruiting
Phase
Phase 4
Locations
United Kingdom
Study Type
Interventional
Intervention
Selexipag
Riociguat
CardioMEMS pulmonary artery pressure monitor
Confirm Rx
Sponsored by
Sheffield Teaching Hospitals NHS Foundation Trust
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pulmonary Arterial Hypertension focused on measuring remote monitoring, therapeutic development, personalised medicine

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Able to provide informed consent Age 18-80 years PAH which is idiopathic, heritable or associated with drugs, toxins or connective tissue disease Stable PAH therapeutic regime comprising any combination of ERA and PDE5i for at least 1 month prior to screening (unless unable to tolerate therapy) WHO functional class III Resting mPAP ≥20 mmHg, pulmonary capillary wedge pressure ≤15 mmHg, pulmonary vascular resistance ≥2 Wood Units measured by right heart catheterisation at time of diagnosis 6MWT >50m at entry Estimated glomerular filtration rate (eGFR)>30 ml/min/1.73 m² at entry (Appendix C) Inadequate treatment response (clinically determined) Exclusion Criteria: Unable to provide informed consent Pregnancy Unprovoked pulmonary embolism (at any time) Acute infection at time of screening (rescreening is permitted) PAH due to human immunodeficiency virus, portal hypertension, schistosomiasis, congenital heart disease Pulmonary hypertension due to left heart, lung, thromboembolic or unclear/multifactorial disease (Group II-V) Unable to tolerate aspirin or P2Y12 inhibitor Hypersensitivity to selexipag or riociguat Clinically-significant renal disease (eGFR≤30 ml/min/1.73m2) Anaemia (haemoglobin <10 g/dl) Left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following: aortic or mitral valve disease greater than mild aortic insufficiency; mild aortic stenosis; mild mitral stenosis; or moderate mitral regurgitation

Sites / Locations

  • Sheffield Teaching Hospitals NHS FTRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Active Comparator

Arm Label

Arm A (selexipag/riociguat)

Arm B (riociguat/selexipag)

Arm Description

Baseline - established PDE/ERA therapy Week 1 - initiate OPA (PDE/ERA/OPA therapy) Weeks 2-12 - uptitration of OPA to maximal therapy (PDE/ERA/OPA therapy) Weeks 13-14 - reduce OPA (PDE/ERA/OPA therapy) Week 15 - washout OPA (PDE/OPA therapy) Week 16 - washout PDE (ERA therapy) Week 17 - initiate sGCS (ERA/sGCS therapy) Weeks 18-27 - uptitration of sGCS to maximal therapy (ERA/sGCS therapy)

Baseline - established PDE/ERA therapy Week 1 - washout PDE (ERA therapy only) Week 2 - initiate sGCS (ERA/sGCS therapy) Weeks 3-12 - uptitration of sGCS to maximal therapy (ERA/sGCS therapy) Week 13 - reduce sGCS (ERA/sGCS therapy) Week 14 - reduce and washout sGCS (ERA therapy) Week 15 - initiate PDE (PDE/ERA therapy) Week 16 - initiate OPA (PDE/ERA/OPA therapy) Weeks 17-27 - uptitration of OPA to maximal therapy (PDE/ERA/OPA therapy)

Outcomes

Primary Outcome Measures

Right Ventricular Stroke Volume (RVSV) flow on each therapy measured by MRI RSVS (flow) on each therapy measured by MRI
This provides a robust, objective assessment of clinical efficacy which, if met, will mean that a change in therapy has provided a clinically meaningful change in physiology

Secondary Outcome Measures

Haemodynamics - Total Pulmonary Resistance (TPR)
Change in TPR (Woods Units) on each therapy to determine clinical efficacy
Haemodynamics - mean Pulmonary Artery Pressure (mPAP)
Change in mPAP (mmHg) on each therapy to determine clinical efficacy
Haemodynamics - Cardiac Output (CO)
Change in CO (L/min) on each therapy to determine clinical efficacy
Haemodynamics - Cardiac Index
Change in cardiac index (L/min/m^2) on each therapy to determine clinical efficacy
Haemodynamics - Stroke Volume (SV)
Change in SV (mL) on each therapy to determine clinical efficacy
Haemodynamics - Heart Rate (HR)
Change in HR (bpm) on each therapy to determine clinical efficacy
6 Minute Walk Test
Change on each therapy to determine clinical efficacy
NTpro-BNP
Change on each therapy to determine clinical efficacy
MRI - Right Ventricular Ejection Fraction (RVEF)
RVEF (%) on each therapy to determine clinical efficacy
MRI - Right Ventricular End Systolic Volume (RVESV)
RVESV (mL/m^2) on each therapy to determine clinical efficacy
MRI - Right Ventricular End Diastolic Volume (RVEDV)
RVEDV (mL/m^2) on each therapy to determine clinical efficacy
MRI - Right Ventricular Stroke Volume (RVSV)
RVSV (mL) on each therapy to determine clinical efficacy
MRI - Left Ventricular Volume Fraction (LVEF)
LVEF (%) on each therapy to determine clinical efficacy
MRI - Left Ventricular End Systolic Volume (LVESV)
LVESV (mL/m^2) on each therapy to determine clinical efficacy
MRI - Left Ventricular End Diastolic Volume LVEDV
LVEDV (mL/m^2) on each therapy to determine clinical efficacy
MRI - Left Ventricular Stroke Volume (LVSV)
LVSV (mL) on each therapy to determine clinical efficacy
MRI - Left Ventricular Stroke Volume (LVSV) flow
LVSV flow on each therapy to determine clinical efficacy
Patient Reported Outcomes (PRO) - Quality of Life (QoL) (EmPHasis-10)
Change of QoL score on each therapy to determine clinical efficacy. This will be done using EmPHasis-10 questionnaire (10 questions using a 0 (poor) - 5 (good) scale)
Patient Reported Outcomes (PRO) - Medication Compliance (PHoenix PRO)
Change of medication compliance score on each therapy to determine clinical efficacy. This will be done using PHoenix PRO questionnaire (10 questions using a 0 (poor) - 5 (good) scale)
Patient Reported Outcomes (PRO) - Medication Side Effects
Change of medication side effects on each therapy to determine clinical efficacy. This will be done using PHoenix Medication side effects questionnaires (4 Yes/No or Better/Worse style questions)
Patient Reported Outcomes (PRO) - Depression symptoms (GAD-2/7)
Change of depression symptoms on each therapy to determine clinical efficacy. This will be done using the GAD-2/7 questionnaire (2 screening questions to determine if symptoms present. If present, 7 additional questions to determine level of depression using a 0 (not at all) - 3 (nearly every day) scale)
Patient Reported Outcomes (PRO) - Anxiety symptoms (PHQ-2/9)
Change of anxiety symptoms on each therapy to determine clinical efficacy. This will be done using the PHQ-2/9 questionnaire (2 screening questions to determine if symptoms present. If present, 9 additional questions to determine level of anxiety using a 0 (not at all) - 3 (nearly every day) scale)
WHO functional class
Change on each therapy to determine clinical efficacy. Functional assessment of PAH will be made according to the WHO classification system: Class I - Patients with PAH without limitation of physical activity. Ordinary physical activity does not cause increased dyspnoea or fatigue, chest pain, or near syncope / Class II - Patients with PAH resulting in slight limitation of physical activity. No discomfort at rest. Normal physical activity causes increased dyspnoea or fatigue, chest pain, or near syncope / Class III - Patients with PAH resulting in marked limitation of physical activity. There is no discomfort at rest. Less than ordinary activity causes increased dyspnoea or fatigue, chest pain, or near syncope / Class IV - Patients with PAH with inability to carry out any physical activity without discomfort. Indications of manifest right heart failure. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by the least physical activity.

Full Information

First Posted
March 24, 2023
Last Updated
August 18, 2023
Sponsor
Sheffield Teaching Hospitals NHS Foundation Trust
Collaborators
University of Glasgow, University of Sheffield, University of Newcastle Upon-Tyne, University of Cambridge
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1. Study Identification

Unique Protocol Identification Number
NCT05825417
Brief Title
Pulmonary Hypertension: Intensification and Personalisation of Combination Rx
Acronym
PHoenix
Official Title
A Multicentre Randomised Cross-over Trial of Disease Specific Therapy in Patients With Pulmonary Arterial Hypertension (PAH) Implanted With Pulmonary Artery Pressure and Cardiac Rhythm Monitoring Devices (CardioMEMS/ConfirmRx)
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
June 14, 2023 (Actual)
Primary Completion Date
January 2026 (Anticipated)
Study Completion Date
January 2026 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sheffield Teaching Hospitals NHS Foundation Trust
Collaborators
University of Glasgow, University of Sheffield, University of Newcastle Upon-Tyne, University of Cambridge

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
Yes
Product Manufactured in and Exported from the U.S.
Yes
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The goal of this clinical trial is to evaluate the capacity of implantable/remote technology for early evaluation of drug therapies in patients with pulmonary arterial hypertension (PAH). The main question it aims to answer is whether structured changes in clinical therapy will be detectable using implanted regulatory approved devices. Participants will will be implanted with approved medical devices and will enter into a study of approved drugs to assess physiology, activity and patient reported quality-of-life (QoL) outcomes. Researchers will compare two therapeutic strategies in each individual patient to see if the study design provides enough evidence to personalise drug treatment plans
Detailed Description
In this study, patients established on guideline recommended therapy will be implanted with devices and remote monitoring established. Patients will then enter into a 2x2 crossover study of approved drugs during which standard clinical investigations will be undertaken at baseline and maximal therapy on each drug. The cross-over design will provide multiple increases and decreases of drugs known to alter haemodynamics and 6MWT. The study is powered to detect improvement in right ventricular stroke volume measured by MRI from baseline to maximal therapy for each drug. It will then be established if changes in remote monitored measures provide an early indication of clinical efficacy when compared to the MRI, haemodynamics, NTproBNP and 6MWT made at 12-weeks. Remote measurement of haemodynamics during the two periods of de-escalation will inform understanding of physiology and inform clinical practice. The comparison of the two therapeutic strategies in individual patients in one study will facilitate novel clinical study designs and provide evidence for data-driven personalised medicine in the area.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension
Keywords
remote monitoring, therapeutic development, personalised medicine

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Model Description
2x2 crossover study in which the effects of adding an oral drug targeting the prostacyclin pathway and the switching of PDE5i to sGCS will be examined following 12-weeks on treatment.
Masking
None (Open Label)
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Arm A (selexipag/riociguat)
Arm Type
Active Comparator
Arm Description
Baseline - established PDE/ERA therapy Week 1 - initiate OPA (PDE/ERA/OPA therapy) Weeks 2-12 - uptitration of OPA to maximal therapy (PDE/ERA/OPA therapy) Weeks 13-14 - reduce OPA (PDE/ERA/OPA therapy) Week 15 - washout OPA (PDE/OPA therapy) Week 16 - washout PDE (ERA therapy) Week 17 - initiate sGCS (ERA/sGCS therapy) Weeks 18-27 - uptitration of sGCS to maximal therapy (ERA/sGCS therapy)
Arm Title
Arm B (riociguat/selexipag)
Arm Type
Active Comparator
Arm Description
Baseline - established PDE/ERA therapy Week 1 - washout PDE (ERA therapy only) Week 2 - initiate sGCS (ERA/sGCS therapy) Weeks 3-12 - uptitration of sGCS to maximal therapy (ERA/sGCS therapy) Week 13 - reduce sGCS (ERA/sGCS therapy) Week 14 - reduce and washout sGCS (ERA therapy) Week 15 - initiate PDE (PDE/ERA therapy) Week 16 - initiate OPA (PDE/ERA/OPA therapy) Weeks 17-27 - uptitration of OPA to maximal therapy (PDE/ERA/OPA therapy)
Intervention Type
Drug
Intervention Name(s)
Selexipag
Other Intervention Name(s)
Uptravi, oral prostacyclin IP receptor agonist (OPA)
Intervention Description
If Arm A - Up-titration to maximum tolerated dose followed by de-escalation If Arm B - Up-titration to maximum tolerated dose followed by observation, modification or transition at discretion of responsible care team where necessary.
Intervention Type
Drug
Intervention Name(s)
Riociguat
Other Intervention Name(s)
Adempas, soluble guanylate cyclase stimulator (sGCS)
Intervention Description
If Arm A - Up-titration to maximum tolerated dose followed by de-escalation If Arm B - Up-titration to maximum tolerated dose followed by observation, modification or transition at discretion of responsible care team where necessary.
Intervention Type
Device
Intervention Name(s)
CardioMEMS pulmonary artery pressure monitor
Intervention Description
Implantation and remote monitoring established with patient initiated daily readings
Intervention Type
Device
Intervention Name(s)
Confirm Rx
Intervention Description
Implantation and remote monitoring established with automated daily readings / downloads
Primary Outcome Measure Information:
Title
Right Ventricular Stroke Volume (RVSV) flow on each therapy measured by MRI RSVS (flow) on each therapy measured by MRI
Description
This provides a robust, objective assessment of clinical efficacy which, if met, will mean that a change in therapy has provided a clinically meaningful change in physiology
Time Frame
Baseline to Week 12
Secondary Outcome Measure Information:
Title
Haemodynamics - Total Pulmonary Resistance (TPR)
Description
Change in TPR (Woods Units) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
Haemodynamics - mean Pulmonary Artery Pressure (mPAP)
Description
Change in mPAP (mmHg) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
Haemodynamics - Cardiac Output (CO)
Description
Change in CO (L/min) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
Haemodynamics - Cardiac Index
Description
Change in cardiac index (L/min/m^2) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
Haemodynamics - Stroke Volume (SV)
Description
Change in SV (mL) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
Haemodynamics - Heart Rate (HR)
Description
Change in HR (bpm) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
6 Minute Walk Test
Description
Change on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
NTpro-BNP
Description
Change on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
MRI - Right Ventricular Ejection Fraction (RVEF)
Description
RVEF (%) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
MRI - Right Ventricular End Systolic Volume (RVESV)
Description
RVESV (mL/m^2) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
MRI - Right Ventricular End Diastolic Volume (RVEDV)
Description
RVEDV (mL/m^2) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
MRI - Right Ventricular Stroke Volume (RVSV)
Description
RVSV (mL) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
MRI - Left Ventricular Volume Fraction (LVEF)
Description
LVEF (%) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
MRI - Left Ventricular End Systolic Volume (LVESV)
Description
LVESV (mL/m^2) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
MRI - Left Ventricular End Diastolic Volume LVEDV
Description
LVEDV (mL/m^2) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
MRI - Left Ventricular Stroke Volume (LVSV)
Description
LVSV (mL) on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
MRI - Left Ventricular Stroke Volume (LVSV) flow
Description
LVSV flow on each therapy to determine clinical efficacy
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
Patient Reported Outcomes (PRO) - Quality of Life (QoL) (EmPHasis-10)
Description
Change of QoL score on each therapy to determine clinical efficacy. This will be done using EmPHasis-10 questionnaire (10 questions using a 0 (poor) - 5 (good) scale)
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
Patient Reported Outcomes (PRO) - Medication Compliance (PHoenix PRO)
Description
Change of medication compliance score on each therapy to determine clinical efficacy. This will be done using PHoenix PRO questionnaire (10 questions using a 0 (poor) - 5 (good) scale)
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
Patient Reported Outcomes (PRO) - Medication Side Effects
Description
Change of medication side effects on each therapy to determine clinical efficacy. This will be done using PHoenix Medication side effects questionnaires (4 Yes/No or Better/Worse style questions)
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
Patient Reported Outcomes (PRO) - Depression symptoms (GAD-2/7)
Description
Change of depression symptoms on each therapy to determine clinical efficacy. This will be done using the GAD-2/7 questionnaire (2 screening questions to determine if symptoms present. If present, 7 additional questions to determine level of depression using a 0 (not at all) - 3 (nearly every day) scale)
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
Patient Reported Outcomes (PRO) - Anxiety symptoms (PHQ-2/9)
Description
Change of anxiety symptoms on each therapy to determine clinical efficacy. This will be done using the PHQ-2/9 questionnaire (2 screening questions to determine if symptoms present. If present, 9 additional questions to determine level of anxiety using a 0 (not at all) - 3 (nearly every day) scale)
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Title
WHO functional class
Description
Change on each therapy to determine clinical efficacy. Functional assessment of PAH will be made according to the WHO classification system: Class I - Patients with PAH without limitation of physical activity. Ordinary physical activity does not cause increased dyspnoea or fatigue, chest pain, or near syncope / Class II - Patients with PAH resulting in slight limitation of physical activity. No discomfort at rest. Normal physical activity causes increased dyspnoea or fatigue, chest pain, or near syncope / Class III - Patients with PAH resulting in marked limitation of physical activity. There is no discomfort at rest. Less than ordinary activity causes increased dyspnoea or fatigue, chest pain, or near syncope / Class IV - Patients with PAH with inability to carry out any physical activity without discomfort. Indications of manifest right heart failure. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by the least physical activity.
Time Frame
From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Able to provide informed consent Age 18-80 years PAH which is idiopathic, heritable or associated with drugs, toxins or connective tissue disease Stable PAH therapeutic regime comprising any combination of ERA and PDE5i for at least 1 month prior to screening (unless unable to tolerate therapy) WHO functional class III Resting mPAP ≥20 mmHg, pulmonary capillary wedge pressure ≤15 mmHg, pulmonary vascular resistance ≥2 Wood Units measured by right heart catheterisation at time of diagnosis 6MWT >50m at entry Estimated glomerular filtration rate (eGFR)>30 ml/min/1.73 m² at entry (Appendix C) Inadequate treatment response (clinically determined) Exclusion Criteria: Unable to provide informed consent Pregnancy Unprovoked pulmonary embolism (at any time) Acute infection at time of screening (rescreening is permitted) PAH due to human immunodeficiency virus, portal hypertension, schistosomiasis, congenital heart disease Pulmonary hypertension due to left heart, lung, thromboembolic or unclear/multifactorial disease (Group II-V) Unable to tolerate aspirin or P2Y12 inhibitor Hypersensitivity to selexipag or riociguat Clinically-significant renal disease (eGFR≤30 ml/min/1.73m2) Anaemia (haemoglobin <10 g/dl) Left-sided heart disease and/or clinically significant cardiac disease, including but not limited to any of the following: aortic or mitral valve disease greater than mild aortic insufficiency; mild aortic stenosis; mild mitral stenosis; or moderate mitral regurgitation
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jennifer Dick, PhD
Phone
+44 (0) 114 2159550
Email
jennifer.dick@sheffield.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alexander Rothman, MD / PhD
Organizational Affiliation
University of Sheffield
Official's Role
Principal Investigator
Facility Information:
Facility Name
Sheffield Teaching Hospitals NHS FT
City
Sheffield
ZIP/Postal Code
S10 2JF
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alex Rothman

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
Research samples will be transferred to the Sheffield Biorepository with no identifiable personal data. Data will be collected and hosted and processed by University of Oxford (data supplier). Authorised data originators include, but are not limited to PIs and delegated staff; Participants; and Core Imaging Laboratory. The trial manager will lead the data verification process. Remote monitoring data will be managed through the Merlin.net system (Device supplier - Abbott). Pseudonymised data will then be transferred, held, analysed and archived securely at the University of Glasgow (processor). Data will also be transferred to the University of Sheffield and Newcastle University (processor) for study analysis. The University of Sheffield shall own all right, title and interest in and to all of the University of Sheffield Data. For the purposes of the Data Protection Legislation, Sheffield Teaching Hospitals (sponsor) is the Data Controller.
Citations:
PubMed Identifier
33632769
Citation
Swift AJ, Wilson F, Cogliano M, Kendall L, Alandejani F, Alabed S, Hughes P, Shahin Y, Saunders L, Oram C, Capener D, Rothman A, Garg P, Johns C, Austin M, Macdonald A, Pickworth J, Hickey P, Condliffe R, Cahn A, Lawrie A, Wild JM, Kiely DG. Repeatability and sensitivity to change of non-invasive end points in PAH: the RESPIRE study. Thorax. 2021 Oct;76(10):1032-1035. doi: 10.1136/thoraxjnl-2020-216078. Epub 2021 Feb 25.
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Pulmonary Hypertension: Intensification and Personalisation of Combination Rx

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