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)
Overview
- Phase
- Phase 4
- Intervention
- Selexipag
- Conditions
- Pulmonary Arterial Hypertension
- Sponsor
- Sheffield Teaching Hospitals NHS Foundation Trust
- Enrollment
- 40
- Locations
- 1
- Primary Endpoint
- Right Ventricular Stroke Volume (RVSV) flow on each therapy measured by MRI RSVS (flow) on each therapy measured by MRI
- Status
- Recruiting
- Last Updated
- last year
Overview
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.
Investigators
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)
Arms & Interventions
Arm A (selexipag/riociguat)
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)
Intervention: Selexipag
Arm A (selexipag/riociguat)
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)
Intervention: Riociguat
Arm A (selexipag/riociguat)
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)
Intervention: CardioMEMS pulmonary artery pressure monitor
Arm A (selexipag/riociguat)
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)
Intervention: Confirm Rx
Arm B (riociguat/selexipag)
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: Selexipag
Arm B (riociguat/selexipag)
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: Riociguat
Arm B (riociguat/selexipag)
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: CardioMEMS pulmonary artery pressure monitor
Arm B (riociguat/selexipag)
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: Confirm Rx
Outcomes
Primary Outcomes
Right Ventricular Stroke Volume (RVSV) flow on each therapy measured by MRI RSVS (flow) on each therapy measured by MRI
Time Frame: Baseline to Week 12
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 Outcomes
- Haemodynamics - Total Pulmonary Resistance (TPR)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- Haemodynamics - Cardiac Index(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- Haemodynamics - Stroke Volume (SV)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- Haemodynamics - Heart Rate (HR)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- MRI - Right Ventricular Ejection Fraction (RVEF)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- MRI - Right Ventricular End Diastolic Volume (RVEDV)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- MRI - Left Ventricular Volume Fraction (LVEF)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- MRI - Left Ventricular End Systolic Volume (LVESV)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- MRI - Left Ventricular End Diastolic Volume LVEDV(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- Haemodynamics - Cardiac Output (CO)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- Patient Reported Outcomes (PRO) - Medication Compliance (PHoenix PRO)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- Patient Reported Outcomes (PRO) - Medication Side Effects(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- Patient Reported Outcomes (PRO) - Depression symptoms (GAD-2/7)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- 6 Minute Walk Test(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- NTpro-BNP(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- MRI - Right Ventricular End Systolic Volume (RVESV)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- MRI - Right Ventricular Stroke Volume (RVSV)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- MRI - Left Ventricular Stroke Volume (LVSV)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- MRI - Left Ventricular Stroke Volume (LVSV) flow(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- Patient Reported Outcomes (PRO) - Quality of Life (QoL) (EmPHasis-10)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- Haemodynamics - mean Pulmonary Artery Pressure (mPAP)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- Patient Reported Outcomes (PRO) - Anxiety symptoms (PHQ-2/9)(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)
- WHO functional class(From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)