Clinical trial NCT05825417: Pulmonary Hypertension: Intensification and Personalisation of Combination Rx
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
Overall status: RECRUITING
Phase: PHASE4
Conditions: Pulmonary Arterial Hypertension
Keywords: remote monitoring
therapeutic development
personalised medicine
Lead sponsor: Sheffield Teaching Hospitals NHS Foundation Trust
Sponsor class: OTHER
Collaborators: name: University of Glasgow
name: University of Sheffield
name: University of Newcastle Upon-Tyne
name: University of Cambridge
First posted: 2023-04-24
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention 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.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Right Ventricular Stroke Volume (RVSV) flow on each therapy measured by MRI RSVS (flow) on each therapy measured by MRI
timeFrame: Baseline to Week 12
Secondary outcomes:
measure: Haemodynamics - Total Pulmonary Resistance (TPR)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: Haemodynamics - mean Pulmonary Artery Pressure (mPAP)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: Haemodynamics - Cardiac Output (CO)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: Haemodynamics - Cardiac Index
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: Haemodynamics - Stroke Volume (SV)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: Haemodynamics - Heart Rate (HR)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: 6 Minute Walk Test
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: NTpro-BNP
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: MRI - Right Ventricular Ejection Fraction (RVEF)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: MRI - Right Ventricular End Systolic Volume (RVESV)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: MRI - Right Ventricular End Diastolic Volume (RVEDV)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: MRI - Right Ventricular Stroke Volume (RVSV)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: MRI - Left Ventricular Volume Fraction (LVEF)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: MRI - Left Ventricular End Systolic Volume (LVESV)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: MRI - Left Ventricular End Diastolic Volume LVEDV
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: MRI - Left Ventricular Stroke Volume (LVSV)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: MRI - Left Ventricular Stroke Volume (LVSV) flow
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: Patient Reported Outcomes (PRO) - Quality of Life (QoL) (EmPHasis-10)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: Patient Reported Outcomes (PRO) - Medication Compliance (PHoenix PRO)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: Patient Reported Outcomes (PRO) - Medication Side Effects
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: Patient Reported Outcomes (PRO) - Depression symptoms (GAD-2/7)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: Patient Reported Outcomes (PRO) - Anxiety symptoms (PHQ-2/9)
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
measure: WHO functional class
timeFrame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
Other outcomes:
Locations:
city: Sheffield
country: United Kingdom
facility: Sheffield Teaching Hospitals NHS FT
Study officials:
affiliation: University of Sheffield
name: Alexander Rothman, MD / PhD
role: PRINCIPAL_INVESTIGATOR
References:
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.