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

• ClinicalTrials.gov Identifier: NCT03496207
• Recruitment Status: Completed
• First Posted: April 12, 2018
• Last Update Posted: January 12, 2023
• Sponsor: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Information provided by (Responsible Party): Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Study Description

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 6 months in the Placebo-Controlled Treatment Period, and then will be eligible to enroll into an 18- month Extension Period during which all participants will receive sotatercept. All treated patients will be also undergo follow-up period after last study drug treatment.

Condition or disease	Intervention/treatment	Phase
Pulmonary Arterial Hypertension	Drug: Placebo; Drug: Sotatercept	Phase 2

Detailed Description:

This is a Phase 2, double blind, randomized, placebo-controlled, parallel-group study of sotatercept plus SOC versus placebo plus SOC in participants with PAH of WHO Group 1, functional class II-III.

Participants will be randomly assigned in a 3:3:4 ratio to receive placebo every 21 days, sotatercept 0.3 mg/kg subcutaneously (SC) every 21 days, or sotatercept 0.7 mg/kg SC every 21 days, for a period of 24 weeks in the Placebo-Controlled Treatment Period of the study while on standard of care therapy. Evaluations will include changes in pulmonary vascular resistance (PVR), six-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 18-month Extension Period in which sotatercept-treated participants will receive their latest dose level of sotatercept SC every 21 days and placebo-treated participants willbe re-randomized 1:1 to receive sotatercept 0.3 mg/kg SC every 21 days or sotatercept 0.7 mg/kg SC every 21 days while on standard of care therapy.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 106 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: June 13, 2018
• Actual Primary Completion Date: March 9, 2022
• Actual Study Completion Date: March 9, 2022

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo; Placebo SC every 21 days plus SOC for 24 weeks	Drug: Placebo; Placebo
Experimental: Sotatercept 0.3 mg/kg; Sotatercept, 0.3 mg/kg SC every 21 days plus SOC for 24 weeks	Drug: Sotatercept; 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; Other Name: ACE-011
Experimental: Sotatercept 0.7 mg/kg; Sotatercept, 0.7 mg/kg SC every 21 days plus SOC for 24 weeks	Drug: Sotatercept; 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; Other Name: ACE-011

Outcome Measures

Primary Outcome Measures :

1. Change from baseline in Pulmonary Vascular Resistance (PVR) as measured by right heart catheterization [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
2. Extension Period - Change from baseline in PVR at Cycle 25 (or next cycles up to Cycle 33) for the Delayed-Start efficacy analysis [ Time Frame: Through study completion up to 24 months. ]
3. Extension Period - Change from baseline in PVR at Cycle 25 (or next cycles up to Cycle 33) for the Placebo-Crossed efficacy analysis [ Time Frame: Through study completion up to 24 months. ]
4. Extension Period - Safety and tolerability assessments based on AEs, clinical laboratory values, and vital signs [ Time Frame: Through study completion up to 24 months. ]

Secondary Outcome Measures :

1. Change from baseline in 6-Minute Walk Distance (6MWD) [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
2. Change from baseline in amino-terminal brain natriuretic propeptide (NT-proBNP) [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
3. Change from baseline in tricuspid annular plane systolic excursion (TAPSE) by echocardiography (ECHO) [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
4. Change from baseline in Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) patient-reported outcome (PRO) score [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
   The CAMPHOR questionnaire contains 65 items in total, 25 relating to symptoms, 15 relating to activities, and 25 relating to Quality of Life (QoL). It is negatively weighted; a higher score indicates worse QoL and greater functional limitation. Symptom and QoL items are both scored out of 25: "yes/true" scores 1 and "no/not true" scores 0. Activity items have three possible responses (score 0-2), giving a score out of 30.
5. Change from baseline in 36-Item Short Form Health Survey (SF-36) patient-reported outcome (PRO) score [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
   The SF-36 questionnaire is a 36-item, patient-reported survey of patient health. The questionnaire consists of eight scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale on the assumption that each question carries equal weight. The lower the score the more disability. The higher the score the less disability i.e., a score of zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
6. Clinical worsening (e.g., hospitalizations, change in WHO functional class, and as defined in Section 8.5.4) from C1D1 to C9D1A [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
7. Change in WHO functional class at 24 weeks (C9D1A) vs. screening [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
8. Safety and tolerability assessments based on adverse events (AEs). [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
9. Assessment of vital signs - weight [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
10. Assessment of vital signs - blood pressure (systolic/diastolic) [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
11. Assessment of vital signs - respiratory rate [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
12. Assessment of vital signs - EKG (QTcF interval) [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
13. Assessment of PK parameter(s) Maximum Plasma Concentration [Cmax] [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
14. Extension Period - Change from baseline in 6MWD at Cycle 25 (or next cycles up to Cycle 33) for the Delayed-Start efficacy analysis [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
15. Extension Period - Change from baseline in 6MWD at Cycle 25 (or next cycles up to Cycle 33) for the Placebo-Crossed efficacy analysis [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
16. Extension Period - Change from baseline in WHO FC at Cycle 25 (or next cycles up to Cycle 33) for the Delayed-Start efficacy analysis [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
17. Extension Period - Change from baseline in WHO FC at Cycle 25 (or next cycles up to Cycle 33) for the Placebo-Crossed efficacy analysis [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Age ≥ 18 years

2. 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

3. Symptomatic pulmonary hypertension classified as WHO functional class II or III
4. Screening RHC documenting a minimum PVR of ≥ 400 dyn·sec/cm5 (5 Wood units)

5. Pulmonary function tests (PFTs) within 6 months prior to Screening as follows:

   1. Total lung capacity (TLC) > 70% predicted; or if between 60 to70% 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
6. 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),
7. No contraindication per investigator for RHC during the study
8. 6MWD ≥ 150 and ≤ 550 meters repeated twice at Screening and both values within 15% of each other, calculated from the highest value
9. PAH therapy at stable (per investigator) dose levels of SOC therapies

Exclusion Criteria:

1. Stopped receiving any pulmonary hypertension chronic general supportive therapy (e.g, diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to study visit C1D1
2. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to study visit C1D1
3. History of atrial septostomy within 180 days prior to Screening
4. History of more than mild obstructive sleep apnea that is untreated
5. 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)
6. History of human immunodeficiency virus infection-associated PAH
7. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536)
8. 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).
9. 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
10. Systolic BP < 90 mmHg during Screening or at baseline
11. History of known pericardial constriction
12. Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 480 msec during Screening Period or C1D1
13. Personal or family history of long QTc syndrome or sudden cardiac death
14. Cerebrovascular accident within 3 months of C1D1
15. History of restrictive or congestive cardiomyopathy
16. 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.
17. 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)
18. Acutely decompensated heart failure within 30 days prior to study visit C1D1, as per investigator assessment
19. Significant (≥ 2+ regurgitation) mitral regurgitation (MR) or aortic regurgitation (AR) valvular disease

20. 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
21. 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
22. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product
23. Major surgery within 8 weeks prior to C1D1. Participants must have completely recovered from any previous surgery prior to C1D1.
24. Prior heart or heart-lung transplants or life expectancy of < 12 month
25. Pregnant or breastfeeding females
26. 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
27. 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
28. 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.
29. 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
30. Weight > 140 kg at Screening

Contacts and Locations

Locations

United States, Arizona

Pulmonary Associates, PA

Phoenix, Arizona, United States, 85006

Arizona Pulmonary Specialists

Phoenix, Arizona, United States, 85012

Banner-University Medical Center Phoenix

Phoenix, Arizona, United States, 85381

University of Arizona

Tucson, Arizona, United States, 85724

United States, California

University of California, San Francisco Medical Center

San Francisco, California, United States, 94143

United States, Colorado

University of Colorado Hospital

Aurora, Colorado, United States, 80045

United States, Florida

UF Health Shands Hospital

Gainesville, Florida, United States, 32610

United States, Kansas

University of Kansas Medical Center

Kansas City, Kansas, United States, 66160

United States, Michigan

University of Michigan

Ann Arbor, Michigan, United States, 48109

United States, Ohio

Lindner Clinical Trial Center

Cincinnati, Ohio, United States, 45129

United States, South Carolina

Medical University of South Carolina

Charleston, South Carolina, United States, 29425

United States, Texas

Houston Methodist Hospital

Houston, Texas, United States, 77030

Australia, New South Wales

St. Vincent's Hospital Sydney

Darlinghurst, New South Wales, Australia, 2010

Westmead Hospital

Westmead, New South Wales, Australia, 2145

Australia, New South Whales

John Hunter Hospital

New Lambton, New South Whales, Australia, 2305

Australia, Queensland

Prince Charles Hospital

Chermside, Queensland, Australia, 4032

Brazil

Hospital Madre Teresa

Belo Horizonte, Minas Gerais, Brazil, 30430

Irmandade Da Santa Casa de Misericordia de Porto Alegre

Porto Alegre, Riogrande Do Sul, Brazil, 90035

Hospital Dia do Pulmão

Blumenau, Santa Catarina, Brazil, 89010

Instituto do Coracao - HCFMUSP

Cerqueira César, Brazil, 05403-900

Hospital Sao Lucas da PUCRS

Jardim Botânico, Brazil, 05403-900

Hospital São Paulo

Sao Paulo, Brazil, 04037

France

Hôpital Arnaud de Villeneuve

Montpellier, Hérault, France, 34295

CHU Michallon

La Tronche, France, 38700

Centre Hospitalier Universitaire de Bicêtre

Le Kremlin-Bicêtre, France, 94275

Centre Hospitalier Universitaire de Saint Etienne

Saint-Étienne, France, 42055

Germany

Medizinische Hochschule Hannover

Hannover, Niedersachsen, Germany, 30625

Universitatsklinikum Halle (Saale)

Halle, Sachsen-Anhalt, Germany, 06120

Universitatsklinikum Leipzig

Leipzig, Sachsen, Germany, 04103

Universitätsklinikum Carl Gustav Carus an der TU Dresden

Dresden, Germany, 01307

Israel

Barzilai Medical Center

Ashkelon, Israel, 78278

Lady Davis Carmel Medical Center

Haifa, Israel, 34362

Meir Medical Center

Kefar Sava, Israel, 4428100

Rabin Medical Center - PPDS

Petach-Tikva, Israel, 49100

Chaim Sheba Medical Center

Ramat Gan, Israel, 52621

Spain

Hospital Universitario Marques de Valdecilla

Santander, Cantabria, Spain, 39008

Hospital Universitario Puerta de Hierro-Majadahonda

Majadahonda, Madrid, Spain, 28222

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, Spain, 08035

Hospital Clinic de Barcelona

Barcelona, Spain, 08036

Hospital Universitario 12 de Octubre

Madrid, Spain, 28041

United Kingdom

Golden Jubilee National Hospital - PPDS

Clydebank, United Kingdom, G81 4DY

Royal Free London NHS Foundation Trust

London, United Kingdom, NW32QG

Imperial College Healthcare NHS Trust

London, United Kingdom, W2 1NY

Sponsors and Collaborators

Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

More Information

Publications:

Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman AB, Ghofrani HA, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, de Oliveira Pena J, Badesch DB. Sotatercept for the treatment of pulmonary arterial hypertension: PULSAR open-label extension. Eur Respir J. 2023 Jan 6;61(1):2201347. doi: 10.1183/13993003.01347-2022. Print 2023 Jan.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitland M, Hoeper MM, Preston IR, Souza R, Waxman A, Escribano Subias P, Feldman J, Meyer G, Montani D, Olsson KM, Manimaran S, Barnes J, Linde PG, de Oliveira Pena J, Badesch DB; PULSAR Trial Investigators. Sotatercept for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2021 Apr 1;384(13):1204-1215. doi: 10.1056/NEJMoa2024277.

• Responsible Party: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• ClinicalTrials.gov Identifier: NCT03496207
• Other Study ID Numbers: A011-09; 2017-004738-27 ( EudraCT Number )
• First Posted: April 12, 2018
• Last Update Posted: January 12, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.):

PAH

Additional relevant MeSH terms:

Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension; Vascular Diseases; Cardiovascular Diseases; Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases