A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH)

Study Overview
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Brief Summary
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Study A011-09 is designed to assesses the efficacy and safety of sotatercept (ACE-011) relative to placebo in adults with pulmonary arterial hypertension (PAH). Eligible participants will receive study treatment for 24 weeks during the placebo-controlled treatment period, and then will be eligible to enroll into a 30-month extension period during which all participants will receive sotatercept. All treated patients will also undergo a follow-up period after last study drug treatment.

Detailed Description
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This is a Phase 2, double-blind, randomized, placebo-controlled, parallel-group study of sotatercept plus standard of care (SOC) versus placebo plus SOC in participants with PAH of World Health Organization (WHO) Group 1, functional class II-III. Participants will be randomly assigned in a 3:3:4 ratio to receive placebo, sotatercept 0.3 mg/kg, or sotatercept 0.7 mg/kg by subcutaneous (SC) injection every 21 days for a period of 24 weeks in the placebo-controlled treatment period of the study while on SOC therapy. Evaluations will include changes in pulmonary vascular resistance (PVR), 6-minute walk distance (6MWD), quality of life questionnaires, echocardiographic parameters, and safety. Participants who have not discontinued early from the placebo-controlled treatment period and have had their post-treatment period PVR assessment will be able to continue into the 30-month extension period in which sotatercept-treated participants will receive their latest dose level of sotatercept SC every 21 days and placebo-treated participants will be re-randomized 1:1 to receive sotatercept 0.3 mg/kg SC or sotatercept 0.7 mg/kg SC every 21 days while on SOC therapy.

Official Title
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A Phase 2, Double-Blind, Placebo-Controlled, Randomized Study to Compare the Efficacy and Safety of Sotatercept (ACE-011) Versus Placebo When Added to Standard of Care for the Treatment of Pulmonary Arterial Hypertension (PAH)

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Placebo
* Drug: Sotatercept
* Other: SOC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Documented diagnostic right heart catheterization (RHC) at any time prior to Screening confirming diagnosis of WHO diagnostic pulmonary hypertension Group I: PAH in any of the following subtypes: i. Idiopathic ii. Heritable PAH iii. Drug- or toxin-induced PAH iv. PAH associated with connective tissue disease v. PAH associated with simple, congenital systemic-to-pulmonary shunts at least 1 year following shunt repair Symptomatic pulmonary hypertension classified as WHO functional class II or III Screening RHC documenting a minimum PVR of ≥400 dyn·sec/cm5 (5 Wood units) Pulmonary function tests (PFTs) within 6 months prior to Screening as follows: Total lung capacity (TLC) >70% predicted; or if between 60 to 70% predicted, or not possible to be determined, confirmatory high-resolution computed tomography (CT) indicating no more than mild interstitial lung disease (ILD), per investigator interpretation, or Forced expiratory volume (first second) (FEV1)/ forced vital capacity (FVC) >70% predicted Ventilation-perfusion (VQ) scan (or, if unavailable a negative CT pulmonary angiogram [CTPA] result, or pulmonary angiography result), any time prior to Screening Visit or conducted during the Screening Period, with normal or low probability result), No contraindication per investigator for RHC during the study 6MWD ≥150 and ≤550 meters repeated twice at Screening and both values within 15% of each other, calculated from the highest value PAH therapy at stable (per investigator) dose levels of SOC therapies Exclusion Criteria: Stopped receiving any pulmonary hypertension chronic general supportive therapy (e.g, diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to study visit Cycle 1 Day 1 (C1D1) Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to study visit C1D1 History of atrial septostomy within 180 days prior to Screening History of more than mild obstructive sleep apnea that is untreated Known history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication), defined as mild to severe hepatic impairment (Child-Pugh Class A-C) History of human immunodeficiency virus infection-associated PAH Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536) Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to C1D1 or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible). Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) >160 mm Hg or sitting diastolic blood pressure >100 mm Hg during Screening Visit after a period of rest Systolic BP <90 mmHg during Screening or at baseline History of known pericardial constriction Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) >480 msec during Screening Period or C1D1 Personal or family history of long QTc syndrome or sudden cardiac death Cerebrovascular accident within 3 months of C1D1 History of restrictive or congestive cardiomyopathy Left ventricular ejection fraction (LVEF) <45% on historical echocardiogram (ECHO) within 6 months prior to Screening Period (or done as a part of the Screening Period) or pulmonary capillary wedge pressure (PCWP) >15 mmHg as determined in the Screening Period RHC. Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) Acutely decompensated heart failure within 30 days prior to study visit C1D1, as per investigator assessment Significant (≥2+ regurgitation) mitral regurgitation (MR) or aortic regurgitation (AR) valvular disease Any of the following clinical laboratory values during the Screening Period prior to C1D1: Baseline Hgb >16.0 g/dL Serum alanine aminotransferase or aspartate aminotransferase levels >3X upper limit of normal (ULN) or total bilirubin >1.5X ULN within 28 days of C1D1 Estimated glomerular filtration rate <30 ml/min/1.73m2 (4-variable Modification of Diet in Renal Disease equation) within 28 days of C1D1 or required renal replacement therapy within 90 days WBC count <4000/mm3 Platelets <100,000/μL Absolute neutrophil count <1500/mm3 History of opportunistic infection (e.g., invasive candidiasis or pneumocystis pneumonia) within 6 months prior to Screening; serious local infection (e.g., cellulitis, abscess) or systemic infection (e.g., septicemia) within 3 months prior to Screening History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product Major surgery within 8 weeks prior to C1D1. Participants must have completely recovered from any previous surgery prior to C1D1. Prior heart or heart-lung transplants or life expectancy of <12 month Pregnant or breastfeeding females If on corticosteroids, and at any time in the last 30 days prior to the Screening Period: have been receiving doses of >20 mg/day of prednisone (or equivalent) or on a new or changing dose of ≤20 mg/day; only participants receiving stable doses of ≤20 mg prednisone (or equivalent) in last 30 days prior to the Screening Period permitted in the study History of active malignancy, with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤2 squamous cell carcinomas of the skin History of clinically significant (as determined by the investigator) non-PAH related cardiac, endocrine, hematologic, hepatic, (auto)immune, metabolic, urologic, pulmonary, neurologic, neuromuscular, dermatologic, psychiatric, renal, and/or another disease that may limit participation in the study. Autoimmune diseases are excluded with the exception of those related to PAH etiologies included in this study. Participation in another clinical trial involving intervention with another investigational drug, approved therapy for investigational use, or investigational device within 4 weeks prior to C1D1, or if the half-life of the previous product is known, within 5 times the half-life prior to C1D1, whichever is longer Weight >140 kg at Screening

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive placebo plus SOC by SC injection during the 24-week treatment period. Dosing will occur once every 3 weeks. | Drug: Placebo<br>* Placebo<br>Other: SOC<br>* SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.<br>|
| Experimental: Sotatercept 0.3 mg/kg<br>Participants will receive sotatercept 0.3 mg/kg plus SOC by SC injection during the 24-week treatment period. Per protocol, participants may have their doses titrated. Dosing will occur once every 3 weeks. | Drug: Sotatercept<br>* Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1.<br>* Other names: ACE-011;Other: SOC<br>* SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.<br>|
| Experimental: Sotatercept 0.7 mg/kg<br>Participants will receive sotatercept 0.7 mg/kg plus SOC by SC injection during the 24-week treatment period. Per protocol, participants may have their doses titrated. Dosing will occur once every 3 weeks. | Drug: Sotatercept<br>* Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1.<br>* Other names: ACE-011;Other: SOC<br>* SOC therapy refers to approved PAH-specific medications and may consist of monotherapy or combination therapy with endothelin-receptor antagonists, phosphodiesterase 5 (PDE5) inhibitors, soluble guanylate cyclase stimulators, and/or prostacyclin analogues or receptor agonists.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Base Study: Change From Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks | Each participant's PVR, at resting supine, was measured by right heart catheterization at baseline and at 24 weeks. | Baseline and 24 weeks | 
| Extension Period: Change From Baseline in PVR (Delayed-Start Analysis) | Each participant's PVR, at resting supine, was measured by right heart catheterization at baseline and the timepoint at which the third right heart catheterization was performed, which occurred between Month 18 and Month 24. | Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24 | 
| Extension Period: Change From Baseline in PVR (Placebo-Crossed Analysis) | Each participant's PVR, at resting supine, was measured by right heart catheterization at baseline and the timepoint at which the third right heart catheterization was performed, which occurred between Month 18 and Month 24. | Baseline and the timepoint at which the third right heart catheterization was performed, which occurred between Month 18 and Month 24. | 
| Extension Period: Number of Participants Who Experienced One or More Adverse Events (AEs) | An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. | Up to approximately 32 months | 
| Extension Period: Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. | Up to 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Base Study: Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks | 6MWD is measured by an exercise test known as 6-Minute Walk Test (6MWT) that assesses aerobic capacity and endurance. It measures the distance covered over a time of 6 minutes and is used as an outcome measure by which to compare changes in performance capacity. Each participant's 6MWD was measured at baseline and at 24 weeks. An increase in the distance walked during the 6MWT indicates improvement in basic mobility. | Baseline and 24 weeks | 
| Base Study: Change From Baseline in Concentration of Amino-Terminal Brain Natriuretic Propeptide (NT-proBNP) at 24 Weeks | Each participant's laboratory biomarkers N-terminal prohormone brain-type natriuretic peptide (NT-proBNP) or brain-type natriuretic peptide (BNP) were measured at baseline and at 24 weeks. | Baseline and 24 Weeks | 
| Base Study: Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 24 Weeks | Each participant's TAPSE, which is commonly used to evaluate tricuspid valve annulus movement as an indicator of right heart function, was measured by echocardiography at baseline and 24 weeks. | Baseline and 24 weeks | 
| Base Study: Change From Baseline in Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Score at Cycle 9 | The CAMPHOR is participant-reported questionnaire that contains 65 items in total, 25 relating to symptoms, 25 relating to quality of life (QoL), and 15 relating to activities. Symptom items are scored from 0-25, with a higher score indicating worse symptoms. QoL items are also scored from 0-25, with a higher score indicating a worse QoL and greater functional limitation. Activity items are scored from 0-30, with a higher score indicating poorer functioning. The combined score is obtained by summing up the symptoms score, QoL score and activity score. The lowest combined score possible is 0, while the highest combined score possible is 80. Each participant's CAMPHOR score was recorded at baseline and on Day 1 of Cycle 9. | Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.) | 
| Base Study: Change From Baseline in 36-Item Short Form Health Survey (SF-36) Score | The SF-36 questionnaire is a participant-reported survey of a participant's health. The survey evaluates 8 aspects of functional health and well-being that relate to either physical health or mental health. The physical component summary is based primarily on physical functioning, bodily pain, and general health. The mental component summary encompasses vitality, social functioning, and emotional and mental health. Total scores for the physical component range from 0-100, with 100 representing the highest level of physical functioning. The total scores for the mental component also range from 0-100, with 100 representing the highest level of mental functioning. Each participant's SF-36 was recorded at baseline and on Day 1 of Cycle 9. Each cycle was 21 days. | Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.) | 
| Base Study: Number of Participants Who Experienced Events Indicative of Clinical Worsening of Pulmonary Arterial Hypertension (PAH) | Events that indicate clinical worsening of PAH include death, need for and/or worsening-related listing for lung and/or heart transplant, need to initiate an approved PAH SOC rescue therapy, PAH-specific hospitalization, or functional deterioration (worsened WHO Functional Class AND 15% decrease in 6MWD). | Up to 24 weeks | 
| Base Study: Number of Participants Who Experienced an Improvement From Baseline in World Health Organization (WHO) Functional Class at 24 Weeks | The WHO Functional Class describes the severity of a person's pulmonary hypertension symptoms. There are four different classes: I is the mildest and IV the most severe form of pulmonary hypertension. | Baseline and 24 Weeks | 
| Base Study: Number of Participants Who Experienced One or More AEs | An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. | Up to 24 weeks | 
| Base Study: Number of Participants Who Discontinued Study Treatment Due to an AE | An AE is any untoward medical occurrence in a study participant administered a pharmaceutical product that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product, whether or not related to the medicinal product. | Up to 24 weeks | 
| Base Study: Change From Baseline in Body Mass Index (BMI) at Cycle 9 | Each participant's BMI was measured at baseline and at 24 weeks. | Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.) | 
| Base Study: Change From Baseline in Systolic and Diastolic Blood Pressure at Cycle 9 | Each participant's systolic and diastolic blood pressure was taken at baseline and on Day 1 of Cycle 9. Each cycle was 21 days. | Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.) | 
| Base Study: Change From Baseline in Respiratory Rate at Cycle 9 | Each participant's respiratory rate (number of breaths per minute) was measured at baseline and on Day 1 of Cycle 9. Each cycle was 21 days. | Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.) | 
| Base Study: Change From Baseline in QTcF Interval at Cycle 9 | Each participant's QTcF Interval was measured at baseline and on Day 1 of Cycle 9. | Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.) | 
| Base Study: Maximum Plasma Concentration (Cmax) of Sotatercept | Cmax is a measure of the maximum amount of drug in the plasma after the dose is given. Based on population pharmacokinetic (PopPK) modeling of previous sotatercept studies, Cmax occurs at Day 8 of Cycle 1 after a sotatercept dose is given. The sotatercept concentration at Day 8 of Cycle 1 (each cycle was 21 days) is presented here as Cmax. | Day 8 of Cycle 1 (Each cycle was 21 days.) | 
| Extension Period: Change From Baseline in 6MWD (Delayed-Start Analysis) | 6MWD is measured by an exercise test known as 6MWT that assesses aerobic capacity and endurance. It measures the distance covered over a time of 6 minutes and is used as an outcome measure by which to compare changes in performance capacity. Each participant's 6MWD was measured at baseline and the timepoint at which the third RCH was performed. This occurred between Month 18 and Month 24, at which time each participant's 6MWD was also measured. An increase in the distance walked during the 6MWT indicates improvement in basic mobility. | Baseline and the timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24 | 
| Extension Period: Change From Baseline in 6MWD (Placebo-Crossed Analysis) | 6MWD is measured by an exercise test known as 6MWT that assesses aerobic capacity and endurance. It measures the distance covered over a time of 6 minutes and is used as an outcome measure by which to compare changes in performance capacity. Each participant's 6MWD was measured at baseline and the timepoint at which the third right heart catheterization was performed. This occurred between Month 18 and Month 24, at which time each participant's 6MWD was also measured. An increase in the distance walked during the 6MWT indicates improvement in basic mobility. | Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24 | 
| Extension Period: Number of Participants Who Experienced an Improvement From Baseline in WHO Functional Class (Delayed-Start Analysis) | The WHO Functional Class describes the severity of a person's pulmonary hypertension symptoms. There are four different classes: I is the mildest and IV the most severe form of pulmonary hypertension. Each participant's WHO Functional Class was assessed at baseline and the timepoint at which the third right heart catheterization was performed. This occurred between Month 18 and Month 24, at which time each participant's WHO Functional Class was also assessed. | Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24 | 
| Extension Period: Change From Baseline in WHO Functional Class (Placebo-Crossed Analysis) | The WHO Functional Class describes the severity of a person's pulmonary hypertension symptoms. There are four different classes: I is the mildest and IV the most severe form of pulmonary hypertension. Each participant's WHO Functional Class was assessed at baseline and the timepoint at which the third right heart catheterization was performed. This occurred between Month 18 and Month 24, at which time each participant's WHO Functional Class was also assessed. | Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PAH