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

• Register: ClinicalTrials.gov
• Last refreshed on: 23 January 2023
• Main ID: NCT03496207
• Date of registration: 29/03/2018
• Prospective Registration: Yes
• Primary sponsor: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
• Public title: A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH) PULSAR
• 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)
• Date of first enrolment: June 13, 2018
• Target sample size: 106
• Recruitment status: Completed
• URL: https://clinicaltrials.gov/show/NCT03496207
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 2

Countries of recruitment

Australia, Brazil, France, Germany, Israel, Spain, United Kingdom, United States

Contacts

• Name: Medical Director
• Affiliation: Merck Sharp & Dohme LLC

Key inclusion & exclusion 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 in


Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Pulmonary Arterial Hypertension

Intervention(s)

Drug: Sotatercept

Drug: Placebo

Primary Outcome(s)

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.]

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 - Safety and tolerability assessments based on AEs, clinical laboratory values, and vital signs [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.]

Secondary Outcome(s)

Assessment of vital signs - weight [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)]

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)]

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 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)]

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)]

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)]

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)]

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)]

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)]

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)]

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)]

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)]

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)]

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)]

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)]

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)]

Secondary ID(s)

A011-09

2017-004738-27

Source(s) of Monetary Support

Please refer to primary and secondary sponsors