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

NCT03496207 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: A011-092017-004738-27
• Study Type: interventional
• Target: 106
• Locations: 8 countries
• Sites: 43

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.

Conditions

Pulmonary Arterial Hypertension

Keywords

PAH

Outcome Measures

Primary Outcomes (5)

• 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 Outcomes (18)

• Base Study: Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks

  Baseline and 24 weeks

• Base Study: Change From Baseline in Concentration of Amino-Terminal Brain Natriuretic Propeptide (NT-proBNP) at 24 Weeks

  Baseline and 24 Weeks

• Base Study: Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 24 Weeks

  Baseline and 24 weeks

• 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.)

• 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.)

Study Arms (3)

Placebo

PLACEBO COMPARATOR

Participants will receive placebo plus SOC by SC injection during the 24-week treatment period. Dosing will occur once every 3 weeks.

Drug: Placebo; Other: SOC

Sotatercept 0.3 mg/kg

EXPERIMENTAL

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; Other: SOC

Sotatercept 0.7 mg/kg

EXPERIMENTAL

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; Other: SOC

Interventions

Placebo DRUG

Placebo

Placebo

Sotatercept DRUG

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.

Also known as: ACE-011

Sotatercept 0.3 mg/kg; Sotatercept 0.7 mg/kg

SOC OTHER

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.

Placebo; Sotatercept 0.3 mg/kg; Sotatercept 0.7 mg/kg

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• MWD ≥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

You may not qualify if:

• 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

Sponsors & Collaborators

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

Study Sites (43)

Pulmonary Associates, PA

Phoenix, Arizona, 85006, United States

Location

Arizona Pulmonary Specialists

Phoenix, Arizona, 85012, United States

Location

Banner-University Medical Center Phoenix

Phoenix, Arizona, 85381, United States

Location

University of Arizona

Tucson, Arizona, 85724, United States

Location

University of California, San Francisco Medical Center

San Francisco, California, 94143, United States

Location

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

UF Health Shands Hospital

Gainesville, Florida, 32610, United States

Location

University of Kansas Medical Center

Kansas City, Kansas, 66160, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Lindner Clinical Trial Center

Cincinnati, Ohio, 45129, United States

Location

Medical University of South Carolina

Charleston, South Carolina, 29425, United States

Location

Houston Methodist Hospital

Houston, Texas, 77030, United States

Location

St. Vincent's Hospital Sydney

Darlinghurst, New South Wales, 2010, Australia

Location

Westmead Hospital

Westmead, New South Wales, 2145, Australia

Location

John Hunter Hospital

New Lambton, New South Whales, 2305, Australia

Location

Prince Charles Hospital

Chermside, Queensland, 4032, Australia

Location

Hospital Madre Teresa

Belo Horizonte, Minas Gerais, 30430, Brazil

Location

Irmandade Da Santa Casa de Misericordia de Porto Alegre

Porto Alegre, Riogrande Do Sul, 90035, Brazil

Location

Hospital Dia do Pulmão

Blumenau, Santa Catarina, 89010, Brazil

Location

Instituto do Coracao - HCFMUSP

Cerqueira César, 05403-900, Brazil

Location

Hospital Sao Lucas da PUCRS

Jardim Botânico, 05403-900, Brazil

Location

Hospital São Paulo

São Paulo, 04037, Brazil

Location

Hôpital Arnaud de Villeneuve

Montpellier, Hérault, 34295, France

Location

CHU Michallon

La Tronche, 38700, France

Location

Centre Hospitalier Universitaire de Bicêtre

Le Kremlin-Bicêtre, 94275, France

Location

Centre Hospitalier Universitaire de Saint Etienne

Saint-Etienne, 42055, France

Location

Medizinische Hochschule Hannover

Hanover, Lower Saxony, 30625, Germany

Location

Universitatsklinikum Leipzig

Leipzig, Saxony, 04103, Germany

Location

Universitatsklinikum Halle (Saale)

Halle, Saxony-Anhalt, 06120, Germany

Location

Universitätsklinikum Carl Gustav Carus an der TU Dresden

Dresden, 01307, Germany

Location

Barzilai Medical Center

Ashkelon, 78278, Israel

Location

Lady Davis Carmel Medical Center

Haifa, 34362, Israel

Location

Meir Medical Center

Kefar Sava, 4428100, Israel

Location

Rabin Medical Center - PPDS

Petah Tikva, 49100, Israel

Location

Chaim Sheba Medical Center

Ramat Gan, 52621, Israel

Location

Hospital Universitario Marques de Valdecilla

Santander, Cantabria, 39008, Spain

Location

Hospital Universitario Puerta de Hierro-Majadahonda

Majadahonda, Madrid, 28222, Spain

Location

Hospital Universitario Vall d'Hebron - PPDS

Barcelona, 08035, Spain

Location

Hospital Clinic de Barcelona

Barcelona, 08036, Spain

Location

Hospital Universitario 12 de Octubre

Madrid, 28041, Spain

Location

Golden Jubilee National Hospital - PPDS

Clydebank, G81 4DY, United Kingdom

Location

Royal Free London NHS Foundation Trust

London, NW32QG, United Kingdom

Location

Imperial College Healthcare NHS Trust

London, W2 1NY, United Kingdom

Location

Related Publications (2)

• 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.

  PMID: 36041750 RESULT

• 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.

  PMID: 33789009 DERIVED

MeSH Terms

Conditions

Pulmonary Arterial Hypertension

Interventions

ACE-011

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2018
• First Posted: April 12, 2018
• Study Start: June 13, 2018
• Primary Completion: March 9, 2022
• Study Completion: March 9, 2022
• Last Updated: April 19, 2023
• Results First Posted: April 19, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share

Locations

GB (3); BR (6); US (12); DE (4); AU (4); FR (4); IL (5); ES (5)