Table 1 Patient inclusion and exclusion criteria

Inclusion criteria

• ≥ 18 to ≤ 80 years of age

• BMI ≤ 35.9 kg m^–2*

• Diagnosis of documented and RHC–confirmed PAH in any of the following:

  • Idiopathic, primary, or familial PAH

    OR

  • PAH associated with connective tissue diseases

    OR

  • PAH associated with: HIV; simple, congenital systemic–to–pulmonary shunts ≥ 1-year post–surgical repair; exposure to drugs, chemicals, and toxins

• The patient must have had ventilation/perfusion scan, computerized tomography angiogram, or pulmonary arteriogram that rules out chronic thromboembolic pulmonary hypertension

• Previous PAH diagnosis with the following conditions:

  • Stable PAH without significant adjustments of disease–specific background PAH therapy ≥ 3 months before the CPET procedure

    AND

  • If on corticosteroids, has been receiving a stable dose of ≤ 20 mg per day of prednisone (or equivalent dose of other corticosteroid) for ≥ 30 days before the baseline CPET

• PFT within 6 months before commencement of screening, or during the screening period for this study, that fulfills the following:

  • FEV₁ ≥ 60% predicted

  • FVC ≥ 60% predicted

  • FEV₁/FVC ≥ 60%

• RHC performed and documented before screening that is consistent with the diagnosis of PAH, meeting all the following criteria:

  • mPAP ≥ 20 mmHg (at rest)

    AND

  • PCWP or LVEDP of ≤ 12 mmHg if PVR is ≥ 300 to < 500 dyn·s cm^– 5, or PCWP or LVEDP ≤ 15 mmHg if PVR is ≥ 500 dyn·s cm^–5 and, if PCWP is not available, then mLAP or LVEDP ≤ 15 mmHg or ≤ 12 mmHg in the absence of left atrial obstruction

    AND

  • PVR > 3 Wood units or > 240 dyn·s cm^–5

• WHO/NYHA functional class II–IV symptomatology

• On stable^† PAH disease–specific background therapy of ≤ three oral therapies and/or inhaled therapy

• Able to walk ≥ 150 m on the 6MWT^‡

• Has a VE/VCO₂ slope ≥ 36 during the baseline CPET^§

• Maximal effort on the baseline CPET must reach a peak RER of ≥ 1.0

• If the patient is taking the following concomitant medications, which may affect PAH, the patient must be on a stable therapeutic dose for ≥ 1 month before the screening, and the dosage must be maintained throughout the study:

  • Vasodilators

  • Digoxin

  • L–arginine supplement

  • Anticoagulants (anticoagulation status should be maintained/stable in the therapeutic range for ≥ 1 month before the screening)

Exclusion criteria

• Baseline systemic hypotension, defined as MAP < 50 mmHg or SBP < 90 mmHg at screening

• History of chronic uncontrolled asthma

• Patients who are unable or may find it difficult to use an inhaler device

• Requirement for intravenous inotropes within 30 days before the baseline CPET procedure

• Use of parenteral PAH medications

• Use of ricioguat as background PAH therapy ≤ 1 month before initiating screening or during the study through the end of visit 4

• Use of oral, topical, or inhaled nitrates within 2 weeks before the baseline CPET procedure

• Has history of or current uncontrolled systemic hypertension as evidenced by sitting SBP > 175 mmHg or sitting DBP > 110 mmHg at screening

• Portopulmonary hypertension, portal hypertension, or chronic liver disease determined to be Child–Pugh B or C

• Evidence or history of left–sided heart disease and/or clinically significant cardiac disease

• History of atrial septostomy

• History of known uncorrected right–to–left shunt; clinically relevant, persistent patent foramen ovale; or known Eisenmenger’s physiology

• Paroxysmal or uncontrolled atrial fibrillation

• Chronic renal insufficiency

• Serum alanine aminotransferase or aspartate aminotransferase that is ≥ 3x the upper limit of the normal range

• Platelets < 50,000 µL^–1 at screening

• Hemoglobin concentration < 9 g dL^–1 at screening