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
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
40
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.
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.
Implantation and remote monitoring established with patient initiated daily readings
Implantation and remote monitoring established with automated daily readings / downloads
Sheffield Teaching Hospitals NHS FT
Sheffield, United Kingdom
RECRUITINGRight 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
Time frame: Baseline to Week 12
Haemodynamics - Total Pulmonary Resistance (TPR)
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
Haemodynamics - mean Pulmonary Artery Pressure (mPAP)
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
Haemodynamics - Cardiac Output (CO)
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
Haemodynamics - Cardiac Index
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
Haemodynamics - Stroke Volume (SV)
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
Haemodynamics - Heart Rate (HR)
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
6 Minute Walk Test
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
NTpro-BNP
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
MRI - Right Ventricular Ejection Fraction (RVEF)
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
MRI - Right Ventricular End Systolic Volume (RVESV)
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
MRI - Right Ventricular End Diastolic Volume (RVEDV)
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
MRI - Right Ventricular Stroke Volume (RVSV)
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
MRI - Left Ventricular Volume Fraction (LVEF)
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
MRI - Left Ventricular End Systolic Volume (LVESV)
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
MRI - Left Ventricular End Diastolic Volume LVEDV
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
MRI - Left Ventricular Stroke Volume (LVSV)
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
MRI - Left Ventricular Stroke Volume (LVSV) flow
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
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)
Time frame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
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)
Time frame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
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)
Time frame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
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)
Time frame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
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)
Time frame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
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.
Time frame: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks
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