Pulmonary Hypertension: Intensification and Personalisation of Combination Rx

Phase 4Active Not RecruitingNCT05825417

Sheffield Teaching Hospitals NHS Foundation Trust70 enrolled

Overview

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. 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

SelexipagDRUG

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.

RiociguatDRUG

CardioMEMS pulmonary artery pressure monitorDEVICE

Implantation and remote monitoring established with patient initiated daily readings

Confirm RxDEVICE

Implantation and remote monitoring established with automated daily readings / downloads

SotaterceptDRUG

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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 Exclusion criteria: * Unable to provide informed consent * Pregnancy or breast feeding * 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 * Any of the following clinical laboratory defined values at the screening visit. 1. Platelet count \<50 x 109/L 2. Haemoglobin above gender-specific upper limit of normal as per local laboratory test 3. eGFr \<30mL/min/m2 (as defined by MDRD equation) 4. serum ALT or AST \>3x upper limit of normal 5. total bilirubin \>1.5x upper limit of normal * Currently enrolled in or have completed any other investigational product study within 30 days for small-molecule drugs or within 5 half-lives for biologics prior to the date of signed informed consent * Known allergic reaction to sotatercept (ACE-011) or luspatercept (ACE-536) * 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

Outcomes

Primary Outcomes

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

Time frame: Baseline to Week 12 of each crossover period

Daily Hemodynamic Detection of Treatment Response During Sotatercept Escalation

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.

Time frame: Baseline (Week 0) through Week 24

Secondary Outcomes

Haemodynamics - Total Pulmonary Resistance (TPR)

Change in TPR (Woods Units) on each therapy to determine clinical efficacy

Time frame: 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.

Haemodynamics - mean Pulmonary Artery Pressure (mPAP)

Change in mPAP (mmHg) on each therapy to determine clinical efficacy

Time frame: 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.

Haemodynamics - Cardiac Output (CO)

Change in CO (L/min) on each therapy to determine clinical efficacy

Time frame: 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.

Haemodynamics - Cardiac Index

Change in cardiac index (L/min/m\^2) on each therapy to determine clinical efficacy

Time frame: 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

Haemodynamics - Stroke Volume (SV)

Change in SV (mL) on each therapy to determine clinical efficacy

Time frame: 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.

Haemodynamics - Heart Rate (HR)

Change in HR (bpm) on each therapy to determine clinical efficacy

Time frame: 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.

6 Minute Walk Test

Change on each therapy to determine clinical efficacy

Time frame: 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.

NTpro-BNP

Change on each therapy to determine clinical efficacy

Time frame: 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.

MRI - Right Ventricular Ejection Fraction (RVEF)

RVEF (%) on each therapy to determine clinical efficacy