Table 3.

Inclusion and exclusion criteria.

Inclusion criteria

1. Willing and able to sign a written informed consent before any study‐related procedures and able to understand and follow instructions; return to the study unit for specified study visits; and able to participate in the study for the entire period. 2. Male or females aged 18–80 years. 3. BMI of 18–40 kg/m2 at screening; if BMI is >35 kg/m2, subject chest circumference should be <65 inches (165 cm). 4. Subjects with PAH belonging to one of the following subgroups of NICE Clinical Classification of PAH category: a. Idiopathic PAH b. Heritable PAH c. Drug or toxin‐induced (anorexigen or methamphetamine use) d. PAH associated with connective tissue disease 5. Subjects with PAH who are symptomatic and have reduced exercise capacity due primarily to their PAH diagnosis, having been assessed by qualified individual, that is, physician, physician assistant, or nurse practitioner to be in NYHA/WHO functional class II or III and having a REVEAL 2.0 score of 6–10. 6. PAH therapy at stable doses of standard‐of‐care therapies for at least 90 days before screening. 7. Subject has most recent (within the last 36 months) hemodynamic assessment of PAH by RHC demonstrating a persistent resting mPAP ≥25 mmHg and resting mean pulmonary vascular resistance (PVR) ≥5 Wood Units with pulmonary capillary wedge pressure ≤15 mmHg. 8. Subject is willing to undergo CardioMEMS PA Sensor implantation and RHC before randomization or has had the CardioMEMS PA Sensor implanted previously. 9. 6MWD ≥150 and <550 m at screening 10. Female subjects of childbearing potential must be willing and able to practice effective contraception during the study and continuing contraception for 30 days after their last dose of study drug. Female subjects of non‐childbearing potential are defined as being surgically sterilized by bilateral tubal ligation, bilateral oophorectomy, or hysterectomy. A female subject 45–60 years of age, who is post‐menopausal for at least 1 year, and has a follicle‐stimulating hormone level confirmation indicating post‐menopausal status will be considered of non‐childbearing potential. Female subjects >60 years of age are considered post‐menopausal and of non‐childbearing potential.

Exclusion criteria 1. Pulmonary hypertension category 2–5. 2. Adult congenital heart disease (ACHD). 3. Concomitant medical or psychiatric disorder, condition, history, or any other condition that in the opinion of the Investigator would either put the subject at risk or impair the subject's ability to participate in or complete the requirements of the study or confound the objectives of the study. 4. A concomitant medical disorder that is expected to limit the subject's life‐expectancy to ≤1 year. 5. REVEAL 2.0 score of ≤5 or ≥11. 6. Heart failure with preserved ejection fraction defined as >50% ejection fraction (with signs and symptoms of heart failure) or left atrial volume >34 mL/m2. 7. Subject is not able to have CardioMEMS HF System implanted due to: a. An active, ongoing infection defined as being febrile, an elevated white blood cell count, on intravenous antibiotics, and/or positive cultures (blood, sputum, or urine). b. History of current or recurrent (≥2 episodes within 5 years before consent) pulmonary emboli and/or deep vein thromboses. c. Cannot tolerate RHC. d. PA branch inner diameter <7 mm in a descending branch within the left or right lower lung lobe (target implant vessel). e. Unable to take dual antiplatelet or anticoagulation therapy for 1 month after CardioMEMS implantation. 8. Likely to undergo lung transplantation within the next 6 months. 9. Untreated, moderate to severe obstructive sleep apnea. 10. Evidence of significant chronic thromboembolic disorder as determined by the Investigator or recent pulmonary embolism within 6 months before screening. 11. Uncontrolled hypertension (˃160/100 mmHg, confirmed by duplicate seated readings) at two or more historical visits within 3 months before screening. 12. Sustained systolic blood pressure <95 mmHg and/or diastolic blood pressure <50 mmHg (confirmed by duplicate seated readings) on at least three consecutive occasions (self‐monitored or office) before or at screening, or overt symptomatic hypotension. 13. Sustained resting heart rate >120 beats per minute (confirmed by duplicate assessments of office vital signs) or consecutive ECG assessments on at least three consecutive occasions before or at screening. 14. A history of a bleeding disorder. 15. Thrombocytopenia (platelets <150,000/mm3). 16. Known porphyria, mitochondrial disease, or urea cycle disease. 17. A history of chronic pancreatic disease. 18. Pregnant or lactating. 19. A positive result from serology testing at screening for HIV, HBsAg, HCV; but if the subject has a historical diagnosis (before screening) of being positive for HIV, HBsAg, or HCV must be clinically stable and if on therapy, be on stable therapy for ≥3 months before screening. A subject should not have active COVID‐19; however, those with previous COVID‐19 are permitted. 20. Participation in another investigational drug study within 30 days before screening or participating in a non‐medication study which, in the opinion of the Investigator, would interfere with the study compliance or outcome assessments. 21. Subject is on regular treatment with VPA, other antiseizure medications, or other prohibited medications that cannot be discontinued at the screening visit. 22. Regular anticoagulation or DAPT that cannot be discontinued at the screening visit; however, during the baseline period following CardioMEMS implantation, DAPT is allowed according to clinical practice for up to 4 weeks. 23. More than mild mitral or aortic valve disease, LVEF <50%, or left ventricular regional wall motion abnormality suggestive of active coronary artery disease on two‐dimensional‐echocardiogram at screening. 24. Subject has a forced expiratory volume in 1 s (FEV1)/forced vital capacity <70% (absolute), FEV1 ≤50% or total lung capacity (TLC) <70% predicted on pulmonary function testing (PFT); for potential subjects with TLC 60%–69% predicted, non‐contrasted computerized tomography (CT) scan must be performed to exclude subjects with more than mild interstitial lung disease. PFTs should have been obtained within 3 years before screening. 25. Clinically significant renal dysfunction (eGFR of <30 mL/min/1.73 m2) as calculated by Modification of Diet in Renal Disease (MDRD) at screening. 26. Significant liver dysfunction as measured by any one of the following at screening (including subjects with acute or chronic hepatitis as well as subjects with own or family history of serious hepatitis, especially drug related): a. ALT >2.0 × ULN. b. AST >2.0 × ULN. c. Serum bilirubin ≥1.6 mg/dL or >2.0 × ULN. 27. A known history of substance abuse including alcohol abuse within the 1 year before screening that in the opinion of the Investigator would impair the subject's ability to participate in or complete the requirements of the study. 28. Any major surgical procedure or trauma within 30 days before screening or planned surgical procedure during the study period. 29. Any inpatient hospitalization (defined as >23 h) within 30 days before screening. 30. Enrollment within 90 days before screening or plans to enroll during the study into a cardiopulmonary rehabilitation program. 31. Known hypersensitivity to study drug or any of the excipients of the drug formulation.

Abbreviations: 6MWD, 6‐minute walk distance; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; DAPT, dual antiplatelet therapy; eGFR, estimated glomerular filtration rate; HBsAg, hepatitis B surface antigen; HCV, hepatitis C; HIV, human immunodeficiency virus; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary artery pressure; NICE, National Institute of Health and Care Excellence; NYHA, New York Heart Association; PA, pulmonary artery; PAH, pulmonary arterial hypertension; PVR, pulmonary vascular resistance; RHC, right heart catheterization; ULN, upper limit of normal; VPA, valproic acid; WHO, World Health Organization.