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)
试验速览
- 阶段
- 4 期
- 状态
- 进行中（未招募）
- 入组人数
- 70
- 试验地点
- 1
- 主要终点
- Right Ventricular Stroke Volume (RVSV) flow on each therapy measured by MRI RSVS (flow) on each therapy measured by MRI
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
- •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:
- •Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting the study.
- •Agree to ongoing pregnancy testing during the course of the study and until 8 weeks after the last dose of sotatercept
- •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:
- •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
- •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.
- •Platelet count <50 x 109/L
- •Haemoglobin above gender-specific upper limit of normal as per local laboratory test
- •eGFr <30mL/min/m2 (as defined by MDRD equation)
- •serum ALT or AST >3x upper limit of normal
- •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
研究组 & 干预措施
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)
干预措施: CardioMEMS pulmonary artery pressure monitor (Device)
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)
干预措施: CardioMEMS pulmonary artery pressure monitor (Device)
Arm C : Sotatercept
Baseline - established background therapy; initiate sotatercept 0.3 mg/kg Week 3 - evaluate safety parameters (Hb/platelets) & uptitrate sotatercept to target dose 0.7 mg/kg .
Weeks 6, 9, 12, 15, 18, 21 - maintenance sotatercept 0.7 mg/kg every 3 weeks with safety monitoring Week 24 - final maintenance dose and endpoint assessments
干预措施: CardioMEMS pulmonary artery pressure monitor (Device)
Arm C : Sotatercept
Baseline - established background therapy; initiate sotatercept 0.3 mg/kg Week 3 - evaluate safety parameters (Hb/platelets) & uptitrate sotatercept to target dose 0.7 mg/kg .
Weeks 6, 9, 12, 15, 18, 21 - maintenance sotatercept 0.7 mg/kg every 3 weeks with safety monitoring Week 24 - final maintenance dose and endpoint assessments
干预措施: Confirm Rx (Device)
Arm C : Sotatercept
Baseline - established background therapy; initiate sotatercept 0.3 mg/kg Week 3 - evaluate safety parameters (Hb/platelets) & uptitrate sotatercept to target dose 0.7 mg/kg .
Weeks 6, 9, 12, 15, 18, 21 - maintenance sotatercept 0.7 mg/kg every 3 weeks with safety monitoring Week 24 - final maintenance dose and endpoint assessments
干预措施: Sotatercept (Drug)
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)
干预措施: Riociguat (Drug)
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)
干预措施: Confirm Rx (Device)
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)
干预措施: Confirm Rx (Device)
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)
干预措施: Selexipag (Drug)
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)
干预措施: Selexipag (Drug)
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)
干预措施: Riociguat (Drug)
结局指标
主要结局
Right Ventricular Stroke Volume (RVSV) flow on each therapy measured by MRI RSVS (flow) on each therapy measured by MRI
时间窗: 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
时间窗: 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.
次要结局
- 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.)
- 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.)
- 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.)
- 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)
- 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.)
- 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.)
- 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.)
- 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.)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- 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)
- PHoenix UTAUT questionnaire(Part 1 only: From baseline and area under the curve to 4 weeks, 8 weeks and 12 weeks)