Clinical trial NCT03496207: A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Keywords: PAH
Lead sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Sponsor class: INDUSTRY
First posted: 2018-04-12
Enrollment: 106
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility 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 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
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 Cycle 1 Day 1 (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

Primary outcomes:
measure: Base Study: Change From Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Extension Period: Change From Baseline in PVR (Delayed-Start Analysis)
timeFrame: Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
measure: Extension Period: Change From Baseline in PVR (Placebo-Crossed Analysis)
timeFrame: Baseline and the timepoint at which the third right heart catheterization was performed, which occurred between Month 18 and Month 24.
measure: Extension Period: Number of Participants Who Experienced One or More Adverse Events (AEs)
timeFrame: Up to approximately 32 months
measure: Extension Period: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to 30 months
Secondary outcomes:
measure: Base Study: Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Base Study: Change From Baseline in Concentration of Amino-Terminal Brain Natriuretic Propeptide (NT-proBNP) at 24 Weeks
timeFrame: Baseline and 24 Weeks
measure: Base Study: Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 24 Weeks
timeFrame: Baseline and 24 weeks
measure: Base Study: Change From Baseline in Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Score at Cycle 9
timeFrame: Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
measure: Base Study: Change From Baseline in 36-Item Short Form Health Survey (SF-36) Score
timeFrame: Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
measure: Base Study: Number of Participants Who Experienced Events Indicative of Clinical Worsening of Pulmonary Arterial Hypertension (PAH)
timeFrame: Up to 24 weeks
measure: Base Study: Number of Participants Who Experienced an Improvement From Baseline in World Health Organization (WHO) Functional Class at 24 Weeks
timeFrame: Baseline and 24 Weeks
measure: Base Study: Number of Participants Who Experienced One or More AEs
timeFrame: Up to 24 weeks
measure: Base Study: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to 24 weeks
measure: Base Study: Change From Baseline in Body Mass Index (BMI) at Cycle 9
timeFrame: Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
measure: Base Study: Change From Baseline in Systolic and Diastolic Blood Pressure at Cycle 9
timeFrame: Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
measure: Base Study: Change From Baseline in Respiratory Rate at Cycle 9
timeFrame: Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
measure: Base Study: Change From Baseline in QTcF Interval at Cycle 9
timeFrame: Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
measure: Base Study: Maximum Plasma Concentration (Cmax) of Sotatercept
timeFrame: Day 8 of Cycle 1 (Each cycle was 21 days.)
measure: Extension Period: Change From Baseline in 6MWD (Delayed-Start Analysis)
timeFrame: Baseline and the timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
measure: Extension Period: Change From Baseline in 6MWD (Placebo-Crossed Analysis)
timeFrame: Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
measure: Extension Period: Number of Participants Who Experienced an Improvement From Baseline in WHO Functional Class (Delayed-Start Analysis)
timeFrame: Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
measure: Extension Period: Change From Baseline in WHO Functional Class (Placebo-Crossed Analysis)
timeFrame: Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Pulmonary Associates, PA
state: Arizona
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists
state: Arizona
city: Phoenix
country: United States
facility: Banner-University Medical Center Phoenix
state: Arizona
city: Tucson
country: United States
facility: University of Arizona
state: Arizona
city: San Francisco
country: United States
facility: University of California, San Francisco Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital
state: Colorado
city: Gainesville
country: United States
facility: UF Health Shands Hospital
state: Florida
city: Kansas City
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Cincinnati
country: United States
facility: Lindner Clinical Trial Center
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Darlinghurst
country: Australia
facility: St. Vincent's Hospital Sydney
state: New South Wales
city: Westmead
country: Australia
facility: Westmead Hospital
state: New South Wales
city: New Lambton
country: Australia
facility: John Hunter Hospital
state: New South Whales
city: Chermside
country: Australia
facility: Prince Charles Hospital
state: Queensland
city: Belo Horizonte
country: Brazil
facility: Hospital Madre Teresa
state: Minas Gerais
city: Porto Alegre
country: Brazil
facility: Irmandade Da Santa Casa de Misericordia de Porto Alegre
state: Riogrande Do Sul
city: Blumenau
country: Brazil
facility: Hospital Dia do Pulmão
state: Santa Catarina
city: Cerqueira César
country: Brazil
facility: Instituto do Coracao - HCFMUSP
city: Jardim Botânico
country: Brazil
facility: Hospital Sao Lucas da PUCRS
city: Sao Paulo
country: Brazil
facility: Hospital São Paulo
city: Montpellier
country: France
facility: Hôpital Arnaud de Villeneuve
state: Hérault
city: La Tronche
country: France
facility: CHU Michallon
city: Le Kremlin-Bicêtre
country: France
facility: Centre Hospitalier Universitaire de Bicêtre
city: Saint-Étienne
country: France
facility: Centre Hospitalier Universitaire de Saint Etienne
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover
state: Niedersachsen
city: Halle
country: Germany
facility: Universitatsklinikum Halle (Saale)
state: Sachsen-Anhalt
city: Leipzig
country: Germany
facility: Universitatsklinikum Leipzig
state: Sachsen
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus an der TU Dresden
city: Ashkelon
country: Israel
facility: Barzilai Medical Center
city: Haifa
country: Israel
facility: Lady Davis Carmel Medical Center
city: Kefar Sava
country: Israel
facility: Meir Medical Center
city: Petach-Tikva
country: Israel
facility: Rabin Medical Center - PPDS
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
state: Cantabria
city: Majadahonda
country: Spain
facility: Hospital Universitario Puerta de Hierro-Majadahonda
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Universitario Vall d'Hebron - PPDS
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Clydebank
country: United Kingdom
facility: Golden Jubilee National Hospital - PPDS
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.