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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT03496207




Registration number
NCT03496207
Ethics application status
Date submitted
29/03/2018
Date registered
12/04/2018

Titles & IDs
Public title
A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH)
Scientific 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)
Secondary ID [1] 0 0
2017-004738-27
Secondary ID [2] 0 0
A011-09
Universal Trial Number (UTN)
Trial acronym
PULSAR
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cardiovascular 0 0 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Placebo
Treatment: Drugs - Sotatercept
Other interventions - SOC

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

Experimental: Sotatercept 0.3 mg/kg - 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.

Experimental: Sotatercept 0.7 mg/kg - 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.


Treatment: Drugs: Placebo
Placebo

Treatment: Drugs: 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 interventions: SOC
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.

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Base Study: Change From Baseline in Pulmonary Vascular Resistance (PVR) at 24 Weeks
Timepoint [1] 0 0
Baseline and 24 weeks
Primary outcome [2] 0 0
Extension Period: Change From Baseline in PVR (Delayed-Start Analysis)
Timepoint [2] 0 0
Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
Primary outcome [3] 0 0
Extension Period: Change From Baseline in PVR (Placebo-Crossed Analysis)
Timepoint [3] 0 0
Baseline and the timepoint at which the third right heart catheterization was performed, which occurred between Month 18 and Month 24.
Primary outcome [4] 0 0
Extension Period: Number of Participants Who Experienced One or More Adverse Events (AEs)
Timepoint [4] 0 0
Up to approximately 32 months
Primary outcome [5] 0 0
Extension Period: Number of Participants Who Discontinued Study Treatment Due to an AE
Timepoint [5] 0 0
Up to 30 months
Secondary outcome [1] 0 0
Base Study: Change From Baseline in 6-Minute Walk Distance (6MWD) at 24 Weeks
Timepoint [1] 0 0
Baseline and 24 weeks
Secondary outcome [2] 0 0
Base Study: Change From Baseline in Concentration of Amino-Terminal Brain Natriuretic Propeptide (NT-proBNP) at 24 Weeks
Timepoint [2] 0 0
Baseline and 24 Weeks
Secondary outcome [3] 0 0
Base Study: Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 24 Weeks
Timepoint [3] 0 0
Baseline and 24 weeks
Secondary outcome [4] 0 0
Base Study: Change From Baseline in Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) Score at Cycle 9
Timepoint [4] 0 0
Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
Secondary outcome [5] 0 0
Base Study: Change From Baseline in 36-Item Short Form Health Survey (SF-36) Score
Timepoint [5] 0 0
Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
Secondary outcome [6] 0 0
Base Study: Number of Participants Who Experienced Events Indicative of Clinical Worsening of Pulmonary Arterial Hypertension (PAH)
Timepoint [6] 0 0
Up to 24 weeks
Secondary outcome [7] 0 0
Base Study: Number of Participants Who Experienced an Improvement From Baseline in World Health Organization (WHO) Functional Class at 24 Weeks
Timepoint [7] 0 0
Baseline and 24 Weeks
Secondary outcome [8] 0 0
Base Study: Number of Participants Who Experienced One or More AEs
Timepoint [8] 0 0
Up to 24 weeks
Secondary outcome [9] 0 0
Base Study: Number of Participants Who Discontinued Study Treatment Due to an AE
Timepoint [9] 0 0
Up to 24 weeks
Secondary outcome [10] 0 0
Base Study: Change From Baseline in Body Mass Index (BMI) at Cycle 9
Timepoint [10] 0 0
Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
Secondary outcome [11] 0 0
Base Study: Change From Baseline in Systolic and Diastolic Blood Pressure at Cycle 9
Timepoint [11] 0 0
Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
Secondary outcome [12] 0 0
Base Study: Change From Baseline in Respiratory Rate at Cycle 9
Timepoint [12] 0 0
Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
Secondary outcome [13] 0 0
Base Study: Change From Baseline in QTcF Interval at Cycle 9
Timepoint [13] 0 0
Baseline and Day 1 of Cycle 9, up to 24 weeks (Each cycle was 21 days.)
Secondary outcome [14] 0 0
Base Study: Maximum Plasma Concentration (Cmax) of Sotatercept
Timepoint [14] 0 0
Day 8 of Cycle 1 (Each cycle was 21 days.)
Secondary outcome [15] 0 0
Extension Period: Change From Baseline in 6MWD (Delayed-Start Analysis)
Timepoint [15] 0 0
Baseline and the timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
Secondary outcome [16] 0 0
Extension Period: Change From Baseline in 6MWD (Placebo-Crossed Analysis)
Timepoint [16] 0 0
Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
Secondary outcome [17] 0 0
Extension Period: Number of Participants Who Experienced an Improvement From Baseline in WHO Functional Class (Delayed-Start Analysis)
Timepoint [17] 0 0
Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24
Secondary outcome [18] 0 0
Extension Period: Change From Baseline in WHO Functional Class (Placebo-Crossed Analysis)
Timepoint [18] 0 0
Baseline and timepoint at which third right heart catheterization was performed, which occurred between Month 18 and Month 24

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,New South WhalesQLD
Recruitment hospital [1] 0 0
St. Vincent's Hospital Sydney - Darlinghurst
Recruitment hospital [2] 0 0
Westmead Hospital - Westmead
Recruitment hospital [3] 0 0
John Hunter Hospital - New Lambton
Recruitment hospital [4] 0 0
Prince Charles Hospital - Chermside
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
2145 - Westmead
Recruitment postcode(s) [3] 0 0
2305 - New Lambton
Recruitment postcode(s) [4] 0 0
4032 - Chermside
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
Florida
Country [5] 0 0
United States of America
State/province [5] 0 0
Kansas
Country [6] 0 0
United States of America
State/province [6] 0 0
Michigan
Country [7] 0 0
United States of America
State/province [7] 0 0
Ohio
Country [8] 0 0
United States of America
State/province [8] 0 0
South Carolina
Country [9] 0 0
United States of America
State/province [9] 0 0
Texas
Country [10] 0 0
Brazil
State/province [10] 0 0
Minas Gerais
Country [11] 0 0
Brazil
State/province [11] 0 0
Riogrande Do Sul
Country [12] 0 0
Brazil
State/province [12] 0 0
Santa Catarina
Country [13] 0 0
Brazil
State/province [13] 0 0
Cerqueira César
Country [14] 0 0
Brazil
State/province [14] 0 0
Jardim Botânico
Country [15] 0 0
Brazil
State/province [15] 0 0
Sao Paulo
Country [16] 0 0
France
State/province [16] 0 0
Hérault
Country [17] 0 0
France
State/province [17] 0 0
La Tronche
Country [18] 0 0
France
State/province [18] 0 0
Le Kremlin-Bicêtre
Country [19] 0 0
France
State/province [19] 0 0
Saint-Étienne
Country [20] 0 0
Germany
State/province [20] 0 0
Niedersachsen
Country [21] 0 0
Germany
State/province [21] 0 0
Sachsen-Anhalt
Country [22] 0 0
Germany
State/province [22] 0 0
Sachsen
Country [23] 0 0
Germany
State/province [23] 0 0
Dresden
Country [24] 0 0
Israel
State/province [24] 0 0
Ashkelon
Country [25] 0 0
Israel
State/province [25] 0 0
Haifa
Country [26] 0 0
Israel
State/province [26] 0 0
Kefar Sava
Country [27] 0 0
Israel
State/province [27] 0 0
Petach-Tikva
Country [28] 0 0
Israel
State/province [28] 0 0
Ramat Gan
Country [29] 0 0
Spain
State/province [29] 0 0
Cantabria
Country [30] 0 0
Spain
State/province [30] 0 0
Madrid
Country [31] 0 0
Spain
State/province [31] 0 0
Barcelona
Country [32] 0 0
United Kingdom
State/province [32] 0 0
Clydebank
Country [33] 0 0
United Kingdom
State/province [33] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
When will data be available (start and end dates)?
Available to whom?
Available for what types of analyses?
How or where can data be obtained?
IPD available at link: http://engagezone.msd.com/ds_documentation.php


What supporting documents are/will be available?

Results publications and other study-related documents

TypeCitations or Other Details
Journal Humbert M, McLaughlin V, Gibbs JSR, Gomberg-Maitla... [More Details]