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

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ClinicalTrials.gov Identifier: NCT03496207
Recruitment Status : Active, not recruiting
First Posted : April 12, 2018
Last Update Posted : May 5, 2021
Sponsor:
Information provided by (Responsible Party):
Acceleron Pharma Inc.

Tracking Information
First Submitted Date  ICMJE March 29, 2018
First Posted Date  ICMJE April 12, 2018
Last Update Posted Date May 5, 2021
Actual Study Start Date  ICMJE June 27, 2018
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 22, 2021)
  • 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) ]
  • 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. ]
  • 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. ]
  • Extension Period - Safety and tolerability assessments based on AEs, clinical laboratory values, and vital signs [ Time Frame: Through study completion up to 24 months. ]
Original Primary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
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 double-blind treatment period (Study Day 168) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 22, 2021)
  • 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) ]
  • 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) ]
  • 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) ]
  • 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.
  • 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.
  • 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) ]
  • 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) ]
  • 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) ]
  • Assessment of vital signs - weight [ Time Frame: From initiation of treatment (Study Day 1) to end of placebo-controlled treatment period (Study Day 168) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
  • 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) ]
Original Secondary Outcome Measures  ICMJE
 (submitted: April 11, 2018)
  • Change from baseline in 6-Minute Walk Distance (6MWD) [ Time Frame: From initiation of treatment (Study Day 1) to end of double-blind treatment period (Study Day 168) ]
  • Change from baseline in amino-terminal brain natriuretic propeptide (NT-proBNP) [ Time Frame: From initiation of treatment (Study Day 1) to end of double-blind treatment period (Study Day 168) ]
  • 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 double-blind treatment period (Study Day 168) ]
  • 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 double-blind 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.
  • 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 double-blind 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH)
Official Title  ICMJE 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)
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Pulmonary Arterial Hypertension
Intervention  ICMJE
  • Drug: Placebo
    Placebo
  • 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
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    Placebo SC every 21 days plus SOC for 24 weeks
    Intervention: Drug: Placebo
  • Experimental: Sotatercept 0.3 mg/kg
    Sotatercept, 0.3 mg/kg SC every 21 days plus SOC for 24 weeks
    Intervention: Drug: Sotatercept
  • Experimental: Sotatercept 0.7 mg/kg
    Sotatercept, 0.7 mg/kg SC every 21 days plus SOC for 24 weeks
    Intervention: Drug: Sotatercept
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: February 22, 2021)
106
Original Estimated Enrollment  ICMJE
 (submitted: April 11, 2018)
90
Estimated Study Completion Date  ICMJE May 16, 2022
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Australia,   Brazil,   France,   Germany,   Israel,   Spain,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03496207
Other Study ID Numbers  ICMJE A011-09
2017-004738-27 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Acceleron Pharma Inc.
Study Sponsor  ICMJE Acceleron Pharma Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Acceleron Pharma Inc.
Verification Date May 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP