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

Phase 2

Completed

Conditions: Pulmonary Arterial Hypertension

Interventions: Drug: Sotatercept
Drug: Placebo
Other: SOC

Registration Number: NCT03496207

Lead Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 106

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:
1. 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
2. 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:
1. Baseline Hgb >16.0 g/dL
2. Serum alanine aminotransferase or aspartate aminotransferase levels >3X upper limit of normal (ULN) or total bilirubin >1.5X ULN within 28 days of C1D1
3. 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
4. WBC count <4000/mm3
5. Platelets <100,000/μL
6. 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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sotatercept 0.7 mg/kg	Sotatercept	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.
Placebo	Placebo	Participants will receive placebo plus SOC by SC injection during the 24-week treatment period. Dosing will occur once every 3 weeks.
Placebo	SOC	Participants will receive placebo plus SOC by SC injection during the 24-week treatment period. Dosing will occur once every 3 weeks.
Sotatercept 0.7 mg/kg	SOC	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.
Sotatercept 0.3 mg/kg	SOC	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.
Sotatercept 0.3 mg/kg	Sotatercept	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.

Primary Outcome Measures

Name	Time	Method
Extension Period: Change From Baseline in PVR (Delayed-Start Analysis)	Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24	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.
Extension Period: Change From Baseline in PVR (Placebo-Crossed Analysis)	Baseline and the timepoint at which the third right heart catheterization was performed, which occurred between Month 18 and Month 24.	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.
Extension Period: Number of Participants Who Experienced One or More Adverse Events (AEs)	Up to approximately 32 months	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.
Extension Period: Number of Participants Who Discontinued Study Treatment Due to an AE	Up to 30 months	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.
Base Study: Change From Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks	Baseline and 24 weeks	Each participant's PVR, at resting supine, was measured by right heart catheterization at baseline and at 24 weeks.

Secondary Outcome Measures

Name	Time	Method
Base Study: Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks	Baseline and 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.
Base Study: Change From Baseline in Concentration of Amino-Terminal Brain Natriuretic Propeptide (NT-proBNP) at 24 Weeks	Baseline and 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.
Base Study: Number of Participants Who Experienced an Improvement From Baseline in World Health Organization (WHO) Functional Class at 24 Weeks	Baseline and 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.
Base Study: Number of Participants Who Experienced One or More AEs	Up to 24 weeks	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.
Base Study: Change From Baseline in Body Mass Index (BMI) at Cycle 9	Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)	Each participant's BMI was measured at baseline and at 24 weeks.
Base Study: Change From Baseline in Systolic and Diastolic Blood Pressure at Cycle 9	Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)	Each participant's systolic and diastolic blood pressure was taken at baseline and on Day 1 of Cycle 9. Each cycle was 21 days.
Base Study: Number of Participants Who Discontinued Study Treatment Due to an AE	Up to 24 weeks	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.
Extension Period: Number of Participants Who Experienced an Improvement From Baseline in WHO Functional Class (Delayed-Start Analysis)	Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24	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.
Base Study: Change From Baseline in 36-Item Short Form Health Survey (SF-36) Score	Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)	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.
Base Study: Number of Participants Who Experienced Events Indicative of Clinical Worsening of Pulmonary Arterial Hypertension (PAH)	Up to 24 weeks	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).
Base Study: Change From Baseline in Respiratory Rate at Cycle 9	Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)	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.
Extension Period: Change From Baseline in WHO Functional Class (Placebo-Crossed Analysis)	Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24	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.
Base Study: Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 24 Weeks	Baseline and 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.
Base Study: Change From Baseline in QTcF Interval at Cycle 9	Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)	Each participant's QTcF Interval was measured at baseline and on Day 1 of Cycle 9.
Base Study: Maximum Plasma Concentration (Cmax) of Sotatercept	Day 8 of Cycle 1 (Each cycle was 21 days.)	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.
Base Study: Change From Baseline in Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Score at Cycle 9	Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)	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.
Extension Period: Change From Baseline in 6MWD (Placebo-Crossed Analysis)	Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24	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.
Extension Period: Change From Baseline in 6MWD (Delayed-Start Analysis)	Baseline and the timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24	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.

Trial Locations

Locations (43): Hospital Universitario 12 de Octubre
🇪🇸
Madrid, Spain
Imperial College Healthcare NHS Trust
🇬🇧
London, United Kingdom
Golden Jubilee National Hospital - PPDS
🇬🇧
Clydebank, United Kingdom
Hospital Madre Teresa
🇧🇷
Belo Horizonte, Minas Gerais, Brazil
University of Arizona
🇺🇸
Tucson, Arizona, United States
UF Health Shands Hospital
🇺🇸
Gainesville, Florida, United States
Medical University of South Carolina
🇺🇸
Charleston, South Carolina, United States
University of Michigan
🇺🇸
Ann Arbor, Michigan, United States
St. Vincent's Hospital Sydney
🇦🇺
Darlinghurst, New South Wales, Australia
Prince Charles Hospital
🇦🇺
Chermside, Queensland, Australia
John Hunter Hospital
🇦🇺
New Lambton, New South Whales, Australia
Westmead Hospital
🇦🇺
Westmead, New South Wales, Australia
Irmandade Da Santa Casa de Misericordia de Porto Alegre
🇧🇷
Porto Alegre, Riogrande Do Sul, Brazil
Instituto do Coracao - HCFMUSP
🇧🇷
Cerqueira César, Brazil
Hospital Sao Lucas da PUCRS
🇧🇷
Jardim Botânico, Brazil
Hôpital Arnaud de Villeneuve
🇫🇷
Montpellier, Hérault, France
Centre Hospitalier Universitaire de Bicêtre
🇫🇷
Le Kremlin-Bicêtre, France
Hospital São Paulo
🇧🇷
Sao Paulo, Brazil
CHU Michallon
🇫🇷
La Tronche, France
Medizinische Hochschule Hannover
🇩🇪
Hannover, Niedersachsen, Germany
Universitatsklinikum Halle (Saale)
🇩🇪
Halle, Sachsen-Anhalt, Germany
Universitatsklinikum Leipzig
🇩🇪
Leipzig, Sachsen, Germany
Universitätsklinikum Carl Gustav Carus an der TU Dresden
🇩🇪
Dresden, Germany
Lady Davis Carmel Medical Center
🇮🇱
Haifa, Israel
Barzilai Medical Center
🇮🇱
Ashkelon, Israel
Meir Medical Center
🇮🇱
Kefar Sava, Israel
Rabin Medical Center - PPDS
🇮🇱
Petach-Tikva, Israel
Hospital Universitario Marques de Valdecilla
🇪🇸
Santander, Cantabria, Spain
Hospital Universitario Vall d'Hebron - PPDS
🇪🇸
Barcelona, Spain
Hospital Universitario Puerta de Hierro-Majadahonda
🇪🇸
Majadahonda, Madrid, Spain
Chaim Sheba Medical Center
🇮🇱
Ramat Gan, Israel
Hospital Clinic de Barcelona
🇪🇸
Barcelona, Spain
Centre Hospitalier Universitaire de Saint Etienne
🇫🇷
Saint-Étienne, France
Pulmonary Associates, PA
🇺🇸
Phoenix, Arizona, United States
Arizona Pulmonary Specialists
🇺🇸
Phoenix, Arizona, United States
Banner-University Medical Center Phoenix
🇺🇸
Phoenix, Arizona, United States
University of California, San Francisco Medical Center
🇺🇸
San Francisco, California, United States
University of Colorado Hospital
🇺🇸
Aurora, Colorado, United States
Lindner Clinical Trial Center
🇺🇸
Cincinnati, Ohio, United States
Houston Methodist Hospital
🇺🇸
Houston, Texas, United States
Hospital Dia do Pulmão
🇧🇷
Blumenau, Santa Catarina, Brazil
Royal Free London NHS Foundation Trust
🇬🇧
London, United Kingdom
University of Kansas Medical Center
🇺🇸
Kansas City, Kansas, United States