Pulmonary Hypertension: Intensification and Personalisation of Combination Rx

Pulmonary Arterial Hypertension Clinical Trial

— 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)

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05825417
• Other study ID #: STH21653
• Secondary ID: MR/W026279/13251
• Status: Recruiting
• Phase: Phase 4
• Start date: June 14, 2023
• Est. completion date: January 2026

Study information

• Verified date: August 2023
• Source: Sheffield Teaching Hospitals NHS Foundation Trust
• Contact: Jennifer Dick, PhD
• Phone: +44 (0) 114 2159550
• Email: jennifer.dick[@]sheffield.ac.uk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: January 2026
• Est. primary completion date: January 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Selexipag
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.
• Riociguat
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.

Device:
• CardioMEMS pulmonary artery pressure monitor
Implantation and remote monitoring established with patient initiated daily readings
• Confirm Rx
Implantation and remote monitoring established with automated daily readings / downloads

Locations

Country	Name	City	State
United Kingdom	Sheffield Teaching Hospitals NHS FT	Sheffield

Sponsors (5)

Lead Sponsor	Collaborator
Sheffield Teaching Hospitals NHS Foundation Trust	University of Cambridge, University of Glasgow, University of Newcastle Upon-Tyne, University of Sheffield

Country where clinical trial is conducted

United Kingdom, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Baseline to Week 12
Secondary	Haemodynamics - Total Pulmonary Resistance (TPR)	Change in TPR (Woods Units) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	Haemodynamics - mean Pulmonary Artery Pressure (mPAP)	Change in mPAP (mmHg) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	Haemodynamics - Cardiac Output (CO)	Change in CO (L/min) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	Haemodynamics - Cardiac Index	Change in cardiac index (L/min/m^2) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	Haemodynamics - Stroke Volume (SV)	Change in SV (mL) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	Haemodynamics - Heart Rate (HR)	Change in HR (bpm) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	6 Minute Walk Test	Change on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	NTpro-BNP	Change on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	MRI - Right Ventricular Ejection Fraction (RVEF)	RVEF (%) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	MRI - Right Ventricular End Systolic Volume (RVESV)	RVESV (mL/m^2) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	MRI - Right Ventricular End Diastolic Volume (RVEDV)	RVEDV (mL/m^2) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	MRI - Right Ventricular Stroke Volume (RVSV)	RVSV (mL) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	MRI - Left Ventricular Volume Fraction (LVEF)	LVEF (%) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	MRI - Left Ventricular End Systolic Volume (LVESV)	LVESV (mL/m^2) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	MRI - Left Ventricular End Diastolic Volume LVEDV	LVEDV (mL/m^2) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	MRI - Left Ventricular Stroke Volume (LVSV)	LVSV (mL) on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	MRI - Left Ventricular Stroke Volume (LVSV) flow	LVSV flow on each therapy to determine clinical efficacy	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	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)	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	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)	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	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)	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	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)	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	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)	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Secondary	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.	From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks