RECOMPENSE: Right vEntricular COMPENsation with SotatercEpt. A prospective single arm open label phase IV study to evaluate the effects of sotatercept on right ventricular function in pulmonary arterial hypertension

Phase 4

Recruiting

Conditions: Pulmonary arterial hypertension

Registration Number: 2024-512543-23-00

Lead Sponsor: Amsterdam UMC Stichting

Brief Summary: To assess the effects sotatercept on cardiac work and right ventricular- pulmonary artery coupling

Detailed Description: Recent phase 2 and phase 3 studies showed that treatment of PAH patients with the Activin ligand trap sotatercept results in significant reductions in PVR in addition to improvements in exercise capacity, as measured by 6MWD, and other clinical outcomes while effects on cardiac output were only minimal.

These results contrast sharply with the results of studies with other PAH specific drugs, in which improvements in 6MWD were always reflected by profound increases in cardiac output. The fact that resting cardiac output after sotatercept treatment is not increased, may partly be attributed to a concomitant increase in blood hemoglobin levels, allowing a lower cardiac output to preserve oxygen delivery to the tissues. Moreover, conventional PAH drugs are not entirely pulmonary specific and cause systemic vasodilation, requiring an increase in cardiac output to maintain systemic blood pressure. Moreover, conventional PAH drugs are not entirely pulmonary specific and cause systemic vasodilation, requiring an increase in cardiac output to maintain systemic blood pressure. In contrast, a slight increase in systemic blood pressure was observed in PAH patients treated with sotatercept. Considering these fundamental differences resulting from treatment with sotatercept, we hypothesize that the effects of sotatercept on cardiac function are much more beneficial than the effects of conventional PAH specific drugs.

Although an improvement in cardiac output is often interpreted as a sign of benefit in PAH trials, it may actually be detrimental to long-term cardiac function and adaptation, because a higher cardiac output means more cardiac oxygen consumption. PAH drugs improve exercise capacity and quality of life, but have a limited impact on survival. This s paradox relates to the fact that upon treatment with conventional PAH drugs, RV work and energy consumption increase. RV work is calculated as the product of mPAP and stroke volume (SV). When a modest decrease in PVR is accompanied by an increase in cardiac output and stroke volume and a relatively unchanged (as occurs with most PAH drugs), RV stroke work remains unchanged. Because of the tendency of physiological systems to preserve energy, the increase in cardiac output that is seen upon PAH specific treatment is probably not explained by a reduction in RV load only, but also by a need to preserve systemic blood pressure in the context of systemic vasodilation: a common side effect of all PAH specific drugs, since these vasodilators are not entirely pulmonary specific.

Cardiac work is not reduced because a decrease in mPAP is always accompanied by a proportional increase in stroke volume. As such, current PAH medications do not reduce cardiac power output per beat (mPAP x stroke volume) and probably have no effects on contractility. While the publications on the phase 2 and 3 studies of sotatercept do not provide full hemodynamic data (heart rate is lacking), the provided data indicate a significant drop in mPAP together with an improvement of mixed saturation without a significant increase in cardiac index. Together this suggests a reduction in RV power output per beat.

Assessment of intrinsic RV function is essential to understanding the effects of sotatercept on the myocardium. In order to make this assessment in a load-independent fashion, pressure-volume loops must be used. RV-PA coupling, the relationship between RV end systolic elastance and pulmonary arterial elastance, describes the relationship between RV contractility and RV afterload. The preservation of RV function rests on the delicate balance of RV coupling. In order to preserve RV function in PAH, an increase in afterload will be met with increased RV contractility. Uncoupling occurs in PAH when RV contractility fails to increase to match an elevated afterload leading to maladaptation and RV failure. Decreases in mPAP typically lead to decreases in RV contractility while exercise or sympathetic stimulation will lead to increased contractility.

This is a prospective, single center, single-arm, open-label, phase 4 study to evaluate the effects of sotatercept on RV function and dimensions in PAH. Twenty PAH patients will be enrolled at the Amsterdam UMC and receive open label subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) for 24 weeks. After signing informed consent and completion of screening, and before receiving the first drug dose, patients undergo right heart catheterization (RHC), and cMRI to determine pump function graphs and cardiac volumes and RV fibrosis. These procedures are repeated after the end of the treatment (EOT). The treatment period starts with the first dose of IMP and ends on the last day of IMP which is the day of the last dose of IMP at premature discontinuation or at week 24 ± 7 days. There is an additional follow-up period of 5 weeks after study completion.

Patients enrolled in the study will receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) for 24 weeks. After giving informed consent and before receiving the first drug dose, patients undergo RHC and cMRI to determine pump function graphs and cardiac volumes and assess fibrosis. Additionally, patients will undergo a physician assessment and blood sampling. All of these procedures will be repeated at the end of the treatment (EOT) visit after 24 weeks.

Recent phase 2 and phase 3 studies showed that treatment of pulmonary arterial hypertension (PAH) patients with the activin ligand trap sotatercept results in significant reductions in pulmonary vascular resistance (PVR) in addition to improvements in exercise capacity, as measured by the six minute walk distance (6MWD), and other clinical outcomes while effects on cardiac output (CO) are only minimal. These results contrast sharply with the results of studies with other PAH specific drugs, in which improvements in 6MWD were always reflected by profound increases in cardiac output. The fact that resting cardiac output after sotatercept treatment is not increased, may partly be attributed to a concomitant increase in blood hemoglobin levels, allowing a lower cardiac output to preserve oxygen delivery to the tissues. Moreover, conventional PAH drugs are not entirely pulmonary specific and cause systemic vasodilation, requiring an increase in cardiac output to maintain systemic blood pressure. In contrast, a slight increase in systemic blood pressure was observed in PAH patients treated with sotatercept. Considering these fundamental differences resulting from treatment with sotatercept, we hypothesize that the effects of sotatercept on cardiac function are much more beneficial than the effects of conventional PAH specific drugs.

This is a prospective, single center, single-arm, open-label, phase 4 study to evaluate the effects of sotatercept on RV function and dimensions in PAH. Twenty PAH patients will be enrolled at the Amsterdam UMC and receive open label subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) for 24 weeks

Patients enrolled in the study will receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) for 24 weeks. After giving informed consent and before receiving the first drug dose, patients undergo RHC and cMRI to determine pump function graphs and cardiac volumes and assess fibrosis. Additionally, patients will undergo a physician assessment and blood sampling. All of these procedures will be repeated at the end of the treatment (EOT) visit after 24 weeks.

Recruitment & Eligibility

Status: Authorised, recruiting

Sex: Not specified

Target Recruitment: 20

Inclusion Criteria

Adult patients between 18-70 years of age with a diagnosis of idiopathic or hereditary pulmonary arterial hypertension

Able to provide signed informed consent

WHO functional class between II and IV

Hemodynamic diagnosis of PAH confirmed by right heart catheterization at screening showing an mPAP > 20 mmHg, Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) ≤ 15 mmHg and a PVR ≥ 4WU (320 dyn.sec.cm-

Stable background therapy for at least 3 months before the screening period

NTproBNP > 300 ng/L

PAH etiology of either idiopathic or heritable PAH

Exclusion Criteria

Pregnancy, breastfeeding, or intention to become pregnant during the study

Responders to acute vasoreactivity testing based on medical history

Systolic blood pressure < 90 mmHg

Recently started (< 8 weeks prior to informed consent signature) or planned cardio-pulmonary rehabilitation program

Known concomitant life-threatening disease with a life expectancy < 12 months

Hospitalization for PAH within 3 months prior to informed consent signature

Left atrial volume per body surface area ≥ 43mL/m2 by echocardiography or CMR

History of pulmonary embolism or deep vein thrombosis

History of major bleeding

Hemoglobin above upper limit of normal for age and gender

Atrial fibrillation, multiple premature ventricular or atrial contractions

Study & Design

Study Type: INTERVENTIONAL

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Change in power per beat after 24 weeks of sotatercept		Change in power per beat after 24 weeks of sotatercept
Change in right ventricular pulmonary artery coupling index (Ees/Ea) after 24 weeks of sotatercept		Change in right ventricular pulmonary artery coupling index (Ees/Ea) after 24 weeks of sotatercept

Secondary Outcome Measures

Name	Time	Method
∆ Stroke Volume determined from aortic flow		∆ Stroke Volume determined from aortic flow
∆ Right Ventricular End Diastolic Volume (RVEDV)		∆ Right Ventricular End Diastolic Volume (RVEDV)
∆ Right Ventricular End Systolic Volume (RVESV)		∆ Right Ventricular End Systolic Volume (RVESV)
∆ Right Ventricular Ejection Fraction (RVEF)		∆ Right Ventricular Ejection Fraction (RVEF)
∆ Right Ventricular mass		∆ Right Ventricular mass
∆ Left Ventricular End Diastolic Volume (LVEDV)		∆ Left Ventricular End Diastolic Volume (LVEDV)
∆ Left Ventricular End Systolic Volume (LVESV)		∆ Left Ventricular End Systolic Volume (LVESV)
∆ Left Ventricular Ejection Fraction (LVEF)		∆ Left Ventricular Ejection Fraction (LVEF)
∆ Left ventricular mass		∆ Left ventricular mass
∆ End-systolic elastance (Ees)		∆ End-systolic elastance (Ees)
∆ Arterial elastance (Ea)		∆ Arterial elastance (Ea)
∆ End diastolic elastance (Eed)		∆ End diastolic elastance (Eed)
∆ Extracellular volume as measured by cardiac magnetic resonance imaging		∆ Extracellular volume as measured by cardiac magnetic resonance imaging

Trial Locations

Locations (1): Amsterdam UMC Stichting
🇳🇱
Amsterdam, Netherlands
Amsterdam UMC Stichting
🇳🇱Amsterdam, Netherlands
Harm Jan Bogaard
Site contact
+31204444782
hj.bogaard@amsterdamumc.nl