A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Sotatercept; SOC
Intervention description: Sotatercept injection; SOC therapy refers to combination therapy consisting of drugs from two or more of the following drug classes: an endothelin-receptor antagonist (ERA), a phosphodiesterase 5 (PDE5) inhibitor, a soluble guanylate cyclase stimulator, and/or a prostacyclin analogue or receptor agonist.
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 21.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: PAH

Summary:

      This study evaluates the effect of sotatercept (ACE-011) in adults with pulmonary arterial
      hypertension (PAH). Each eligible participant will receive standard of care (SOC) plus
      sotatercept (ACE-011) for a 24-week treatment period, followed by an 18-month extension
      period, and an 8-week follow-up period.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age ≥ 18 years

          2. Documented findings on RHC at any time prior to Screening consistent with a diagnosis
             of World Health Organization (WHO) pulmonary hypertension Group 1: PAH of any of the
             following subtypes:

               -  Idiopathic PAH

               -  Heritable PAH

               -  Drug- or toxin-induced PAH

               -  PAH associated with connective tissue disease

               -  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 III

          4. Screening RHC documenting a minimum PVR of ≥ 4 Wood units

          5. Pulmonary function tests within 6 months prior to Screening as follows:

               1. Total lung capacity > 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 per investigator
                  interpretation or

               2. Forced expiratory volume (first second) (FEV1)/forced vital capacity (FVC) > 70%
                  predicted

               3. For subjects with a history of lobectomy or pneumonectomy, and for whom there are
                  no population-based normalization methods, assessment based on residual lung
                  volume will be permitted to assess eligibility.

          6. Ventilation-perfusion (VQ) scan (or, if unavailable, a negative CT pulmonary angiogram
             [CTPA] or pulmonary angiography result), any time prior to Screening or conducted
             during Screening Period with normal or low probability result

          7. 6MWD ≥ 100 and ≤ 550 meters repeated twice during Screening Period and both values
             within 15% of each other, calculated from the highest value

          8. Combination PAH therapy at stable (per investigator) dose levels for at least 90 days
             prior to Cycle 1 Day 1 (C1D1)

        Exclusion Criteria:

        Participants will be excluded from the study if they meet any of the following criteria:

          1. Started or stopped receiving any general supportive therapy for pulmonary hypertension
             (e.g., diuretics, oxygen, anticoagulants, digoxin) within 60 days prior to C1D1 (Cycle
             1 Day 1)

          2. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine,
             vasopressin) within 30 days prior to 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. History of portal hypertension or chronic liver disease, defined as mild to severe
             hepatic impairment (Child-Pugh Classes A to C)

          6. History of human immunodeficiency virus infection-associated PAH

          7. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536)

          8. Uncontrolled systemic hypertension as evidenced by sitting systolic BP > 160 mm Hg or
             sitting diastolic BP > 100 mm Hg during Screening after a period of rest

          9. Systolic BP < 90 mm Hg during Screening or at baseline

         10. History of known pericardial constriction

         11. Electrocardiogram (ECG) with QTcF > 480 msec during Screening or C1D1

         12. History of personal or family history of long QTc syndrome or sudden cardiac death

         13. History of restrictive or constrictive cardiomyopathy

         14. Left ventricular ejection fraction < 45% on echocardiogram performed within 6 months
             of Screening OR pulmonary capillary wedge pressure (PCWP) > 15 mm Hg on RHC during
             baseline evaluation

         15. Any current symptomatic coronary disease (myocardial infarction, percutaneous coronary
             intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain in
             the past 6 months prior to Screening)

         16. Acutely decompensated heart failure within 30 days prior to C1D1, as per investigator
             assessment

         17. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular
             disease