A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (MK-7962-003/A011-11)(STELLAR)
Condition: Pulmonary Arterial Hypertension
MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension
Intervention: Sotatercept; Placebo; Background PAH Therapy
Intervention description: Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy.; Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy.; Background PAH 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 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Participants will be randomized to one of two treatment arms to receive either sotatercept (0.7 mg/kg) by subcutaneous administration once every 3 weeks, or placebo. All participants will be on concurrent, stable background PAH therapy. Randomization will be stratified by baseline WHO Functional Class (Class II or III) and by background PAH therapy (mono/double or triple therapy)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking description: Study participants, care providers. Investigators and outcomes assessor will be masked to the study intervention until the final participant completes the 24-week efficacy assessment.
Enrollment: 324.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Pulmonary Hypertension

Summary:

      The objectives of this study are to evaluate the efficacy and safety of sotatercept (MK-7962)
      treatment (plus background pulmonary arterial hypertension (PAH) therapy) versus placebo
      (plus background PAH therapy) at 24 weeks in adults with PAH. The primary hypothesis of the
      study is that the participants receiving sotatercept will have improved 6-minute walk
      distance (6MWD) at 24 weeks compared to participants receiving placebo.
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Age ≥ 18 years

          -  Documented diagnostic right heart catheterization (RHC) at any time prior to screening
             confirming the diagnosis of World Health Organization (WHO) pulmonary arterial
             hypertension (PAH) Group 1 in any of the following subtypes:

               -  Idiopathic PAH

               -  Heritable PAH

               -  Drug/toxin-induced PAH

               -  PAH associated with connective tissue disease

               -  PAH associated with simple, congenital systemic to pulmonary shunts at least 1
                  year following repair

          -  Symptomatic PAH classified as WHO Functional Class (FC) II or III

          -  Baseline RHC performed during the Screening Period documenting a minimum pulmonary
             vascular resistance (PVR) of ≥ 5 Wood units (WU) and a pulmonary capillary wedge
             pressure (PCWP) or left ventricular end-diastolic pressure of ≤ 15 mmHg.

          -  On stable doses of background PAH therapy and diuretics (i.e., patient-specific dose
             goal for each therapy already achieved) for at least 90 days prior to screening; for
             infusion prostacyclins, dose adjustment within 10% of optimal dose is allowed per
             medical practice.

          -  6-Minute Walk Distance (6MWD) ≥ 150 and ≤ 500 m repeated twice at screening (measured
             at least 4 hours apart, but no longer than 1 week), and both values are within 15% of
             each other (calculated from the highest value)

          -  Females of childbearing potential must:

               -  Have 2 negative urine or serum pregnancy tests as verified by the investigator
                  prior to starting study therapy; she must agree to ongoing urine or serum
                  pregnancy testing during the study and until 8 weeks after the last dose of the
                  study drug

               -  If sexually active, have used, and agree to use, highly effective contraception
                  without interruption, for at least 28 days prior to starting the investigational
                  product, during the study (including dose interruptions), and for 16 weeks (112
                  days) after discontinuation of study treatment

               -  Refrain from breastfeeding a child or donating blood, eggs, or ovum for the
                  duration of the study and for at least 16 weeks (112 days) after the last dose of
                  study treatment

               -  Male participants must:

               -  Agree to use a condom, defined as a male latex condom or nonlatex condom NOT made
                  out of natural (animal) membrane (e.g., polyurethane), during sexual contact with
                  a pregnant female or a female of childbearing potential while participating in
                  the study, during dose interruptions and for at least 16 weeks (112 days)
                  following investigational product discontinuation, even if he has undergone a
                  successful vasectomy

               -  Refrain from donating blood or sperm for the duration of the study and for 16
                  weeks (112 days) after the last dose of study treatment

               -  Ability to adhere to study visit schedule and understand and comply with all
                  protocol requirements

               -  Ability to understand and provide written informed consent

        Key Exclusion Criteria:

          -  Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5

          -  Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus
             (HIV)-associated PAH and PAH associated with portal hypertension. Exclusions in PAH
             Group I should also include schistosomiasis associate PAH and pulmonary veno occlusive
             disease

          -  Hemoglobin (Hgb) at screening above gender-specific upper limit of normal (ULN), per
             local laboratory test

          -  Baseline platelet count < 50,000/mm^3 (< 50.0 x 109/L) at screening

          -  Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure >
             160 mmHg or sitting diastolic blood pressure > 100 mmHg during screening visit after a
             period of rest

          -  Baseline systolic blood pressure < 90 mmHg at screening

          -  Pregnant or breastfeeding women

          -  Any of the following clinical laboratory values at the screening visit:

               -  Estimated glomerular filtration rate (eGFR) < 30 mL/min/m2 (as defined by the
                  Modification of Diet in Renal Disease [MDRD] equation)

               -  Serum alanine aminotransferase, aspartate aminotransferase, or total bilirubin
                  levels > 3 × ULN (bilirubin criterion waived if there is a documented history of
                  Gilbert's syndrome)

          -  Currently enrolled in or have completed any other investigational product study within
             30 days for small molecule drugs or within 5 half-lives for biologics prior to the
             date of signed informed consent

          -  Prior exposure to sotatercept (ACE-011) or luspatercept (ACE 536) and/or excipients or
             known allergic reaction to either one

          -  History of full pneumonectomy

          -  Pulmonary function test (PFT) values of forced vital capacity (FVC) < 60% predicted at
             the screening visit or within 6 months prior to the screening visit. If PFT is not
             available, a chest CT scan showing more than mild interstitial lung disease (ILD) at
             the screening visit or 1 year prior to it

          -  Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days
             prior to the screening visit 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)

          -  History of more than mild obstructive sleep apnea that is untreated

          -  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)

          -  History of restrictive, constrictive or congestive cardiomyopathy

          -  History of atrial septostomy within 180 days prior to the screening visit

          -  Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 500 ms during
             the screening period

          -  Personal or family history of long QT syndrome (LQTS) or sudden cardiac death

          -  Left ventricular ejection fraction < 45% on historical echocardiogram within 6 months
             prior to the screening visit

          -  Any symptomatic coronary disease events (prior myocardial infarction, percutaneous
             coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest
             pain) within 6 months prior to the screening visit. Note: Anginal pain can be ignored
             as an exclusion criterion if coronary angiography shows no obstructions

          -  Cerebrovascular accident within 3 months prior to the screening visit

          -  Acutely decompensated heart failure within 30 days prior to the screening visit, as
             per investigator assessment

          -  Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular
             disease

          -  Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine,
             vasopressin) within 30 days prior to the screening visit