Pulmonary Arterial Hypertension
Conditions
Keywords
remote monitoring, therapeutic development, personalised medicine
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. Part 1 (Randomised crossover Phase) : Patients will 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. Part 2 (Extension Phase- Sotatercept):Following completion of Part 1 (or via direct entry for eligible patients in WHO FC II/III on background PAH therapy), patients enter an open-label , single arm extension phase evaluating treatment escalation with sotatercept (Winrevair).Subcutaneous sotatercept will be initiated at a starting dose of 0.3 mg/kg once every 3 weeks and escalated after 3 weeks to a target maintenance dose of 0.7 mg/kg based on clinical response, weight, and safety parameter verification (haematoglobin and platelet counts). Unlike the multi-drug crossover design in Part 1, Part 2 specifically isolates the longitudinal hemodynamic, functional, and quality-of-life (emPHasis-10, EQ-5D-5L) trajectory following the introduction of a novel activin-signaling inhibitor. This phase will establish the rate and velocity of physiological change under single-agent titration to determine whether continuous daily remote metrics can detect early treatment response compared to standard 24-week clinical endpoint assessments.
Interventions
DRUGSelexipag
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.
DRUGRiociguat
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.
DEVICECardioMEMS pulmonary artery pressure monitor
Implantation and remote monitoring established with patient initiated daily readings
DEVICEConfirm Rx
Implantation and remote monitoring established with automated daily readings / downloads
DRUGSotatercept
Subcutaneous injection of sotatercept administered once every 3 weeks for 24 weeks. Treatment is initiated at a starting dose of 0.3 mg/kg at Week 0 and escalated at Week 3 to a target maintenance dose of 0.7 mg/kg, contingent on body weight, clinical response, and pre-dose safety parameters (haematoglobin and platelet counts). Maintenance dosing at 0.7 mg/kg continues every 3 weeks through Week 21, alongside continuous daily remote hemodynamic and physiological monitoring via implanted CardioMEMS and cardiac rhythm devices.
Sponsors
Sheffield Teaching Hospitals NHS Foundation Trust
University of Glasgow
University of Sheffield
University of Newcastle Upon-Tyne
University of Cambridge
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Part 1 : 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. Part 2 :Following completion of Part 1 (or via direct entry for eligible patients), participants transition into a single-arm, treatment-escalation extension phase. All participants receive subcutaneous sotatercept initiated at a dose of 0.3 mg/kg every 3 weeks and escalated to a target maintenance dose of 0.7 mg/kg based on clinical response, body weight, and safety monitoring . Continuous daily remote hemodynamic and physiological monitoring is maintained throughout the 24-week extension period.
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Part 1: 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 Part 2: 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 doses of background PAH therapy for at least 30 days prior to screening with inadequate treatment response (clinically determined) * WHO FC II or III despite treatment with diuretics * Field Walk Distance thresholds: 6MWT \>50m at entry or ISWT \>180m or equivalent ESWD * Patients of childbearing potential must: 1. Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting the study. 2. Agree to ongoing pregnancy testing during the course of the study and until 8 weeks after the last dose of sotatercept 3. If sexually active, have used and agree to use, highly effective contraception without interruption for at least 28 days prior to starting sotatercept, during the study and for 16 weeks (112 days) after discontinuation * Patients of non-childbearing potential must: 1. Agree to use a condom, defined as a male latex condom or non-latex condom NOT made from natural (animal) membrane (e.g. polyurethane), during sexual contact with a pregnant person of childbearing potential while participating in the study, during dose interruptions and for at least 16 weeks (112 days) following discontinuation of sotatercept 2. Refrain from donating blood or sperm for the duration of the study and for 112 days after the last dose of sotatercept * Ability to adhere to study visit schedule and comply with all protocol requirements for sotatercept monitoring
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Right Ventricular Stroke Volume (RVSV) flow on each therapy measured by MRI RSVS (flow) on each therapy measured by MRI | Baseline to Week 12 of each crossover period | 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 |
| Daily Hemodynamic Detection of Treatment Response During Sotatercept Escalation | Baseline (Week 0) through Week 24 | Within-patient changes in continuous, remote-monitored Total Pulmonary Resistance (TPR), mean Pulmonary Artery Pressure (mPAP), Cardiac Output (CO), Stroke Volume (SV), and Heart Rate (HR) detected by the CardioMEMS sensor following treatment escalation with sotatercept, correlated with end-of-treatment RVSV measured by cardiac MRI. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Haemodynamics - Total Pulmonary Resistance (TPR) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks. | Change in TPR (Woods Units) on each therapy to determine clinical efficacy |
| Haemodynamics - mean Pulmonary Artery Pressure (mPAP) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks. | Change in mPAP (mmHg) on each therapy to determine clinical efficacy |
| Haemodynamics - Cardiac Output (CO) | Part 1 : From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks. | Change in CO (L/min) on each therapy to determine clinical efficacy |
| Haemodynamics - Cardiac Index | Part 1 : From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | Change in cardiac index (L/min/m\^2) on each therapy to determine clinical efficacy |
| Haemodynamics - Stroke Volume (SV) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks. | Change in SV (mL) on each therapy to determine clinical efficacy |
| Haemodynamics - Heart Rate (HR) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks. | Change in HR (bpm) on each therapy to determine clinical efficacy |
| 6 Minute Walk Test | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks. | Change on each therapy to determine clinical efficacy |
| NTpro-BNP | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks. | Change on each therapy to determine clinical efficacy |
| MRI - Right Ventricular Ejection Fraction (RVEF) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | RVEF (%) on each therapy to determine clinical efficacy |
| MRI - Right Ventricular End Systolic Volume (RVESV) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | RVESV (mL/m\^2) on each therapy to determine clinical efficacy |
| MRI - Right Ventricular End Diastolic Volume (RVEDV) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | RVEDV (mL/m\^2) on each therapy to determine clinical efficacy |
| MRI - Right Ventricular Stroke Volume (RVSV) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | RVSV (mL) on each therapy to determine clinical efficacy |
| MRI - Left Ventricular Volume Fraction (LVEF) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | LVEF (%) on each therapy to determine clinical efficacy |
| MRI - Left Ventricular End Systolic Volume (LVESV) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | LVESV (mL/m\^2) on each therapy to determine clinical efficacy |
| MRI - Left Ventricular End Diastolic Volume LVEDV | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | LVEDV (mL/m\^2) on each therapy to determine clinical efficacy |
| MRI - Left Ventricular Stroke Volume (LVSV) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | LVSV (mL) on each therapy to determine clinical efficacy |
| MRI - Left Ventricular Stroke Volume (LVSV) flow | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | LVSV flow on each therapy to determine clinical efficacy |
| Patient Reported Outcomes (PRO) - Quality of Life (QoL) (EmPHasis-10) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | 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) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks | 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 | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | 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) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | 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) | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | 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 | Part 1: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks Part 2: From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | 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. |
| EuroQoL-5D-5L | Part 2 only : From baseline and area under the curve to 3 weeks, 6 weeks, 12 weeks, 18 weeks, and 24 weeks | The EuroQoL-5D-5L is included for future health economic evaluation of sotatercept. (free for non-commercial use |
| PHoenix UTAUT questionnaire | Part 1 only: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks | Evaluation of remote monitoring technology and devices. |
Countries
United Kingdom
Contacts
PRINCIPAL_INVESTIGATORAlexander Rothman, MD / PhD
University of Sheffield
Outcome results
None listed