A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (PAH)
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Placebo; Sotatercept; SOC
Intervention description: Placebo; 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.; 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.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 106.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PAH

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.
    

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