Inclusion Criteria:

• Male and female patients must be at least 18 years of age at the time of signing the informed consent:
  • Male patients and female partners must agree to use contraception starting 4 weeks prior to the first dose of IP, during the treatment period, and for at least 100 days after the last dose of IP. Male patients must refrain from donating sperm during this period;
  • Female patients of childbearing potential must agree to use contraception starting at Screening, during the treatment period, and for at least 4 weeks after the last dose of IP.
• Body mass index (BMI) ≥ 18 kg/m^2 and ≤ 40 kg/m^2.
• Patients with symptomatic PAH belonging to one of the following 2018 Clinical Group 1 Sub-types:
  • Idiopathic PAH;
  • Heritable PAH;
  • Drug- or toxin- induced.
• PAH associated with:
  • Connective tissue disease.
• Congenital systemic to pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus) repaired at least one year prior to Screening.
• Human Immunodeficiency Virus (HIV) infection - if diagnosed with HIV, must have stable disease status defined as follows:
  • stable treatment with HIV medications for at least 8 weeks prior to Screening;
  • no active opportunistic infection during the Screening Period;
  • no hospitalizations due to HIV for at least 4 weeks prior to Screening.
• WHO FC II or III.
• Confirmed diagnosis of PAH and meet all the following hemodynamic criteria by means of a screening RHC completed prior to randomization:
  • mPAP of ≥ 20 mmHg;
  • PVR ≥ 350 dyne•sec/cm^5;
  • Pulmonary capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of ≤ 12 mmHg if PVR ≥ 400 and < 500 dyne•sec/cm^5, or PCWP/LVEDP ≤ 15 mmHg if PVR ≥ 500 dyne•sec/cm^5;
  • 6MWD of 100 to 550 meters at Screening.
• Currently on a stable treatment regimen with one or more treatments approved for PAH. Stable therapy is defined as receiving the same medication(s) for ≥ 12 weeks prior to the screening RHC and at a stable dose level for each for ≥ 8 weeks prior to the  screening RHC. Any instances where doses of a medication have been missed prior to RHC must be discussed with the Medical Monitor prior to performing the RHC.
• Meet all of the following criteria determined by pulmonary function tests completed no more than 24 weeks prior to Screening (performed with or without bronchodilation):
  • Forced expiratory volume in one second (FEV1) ≥ 60% of predicted normal; and
  • Total lung capacity (TLC) ≥ 70% of predicted normal or FVC ≥ 70% predicted if TLC is not available; For subjects with CTD associated PAH, if TLC is ≥ 60% of predicted but < 70% of predicted of if FVC ≥ 60% or predicted but < 70% of predicted, high resolution computed tomography [HRCT] obtained within 6 months of screening may be utilized to demonstrate limited interstitial lung disease.
• If participating in an exercise program for pulmonary rehabilitation, the program must have been initiated ≥ 12 weeks prior to Screening, and patient must agree to maintain the current level of rehabilitation for the first 24 weeks of IP. If not participating in an exercise training program for pulmonary rehabilitation, must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 24 weeks of IP.
• Willing and able to give written informed consent and to comply with the requirements of the study for its duration. 

Exclusion Criteria:

• Women of childbearing potential who are pregnant, planning to become pregnant, or lactating or female/male patients unwilling to use effective contraception.
• WHO Pulmonary Hypertension (PH) Group 1 PAH associated with portal hypertension or schistosomiasis; PH due to left heart disease (WHO PH Group 2), lung diseases and/or hypoxia (WHO PH Group 3), chronic thromboembolic pulmonary hypertension (WHO PH Group 4), or PH with unclear multifactorial mechanisms (WHO PH Group 5).
• PAH associated with significant venous or capillary involvement (PCWP > 15 mmHg), pulmonary capillary hemangiomatosis, portal hypertension, or unrepaired congenital heart defects (CHD)
• Three or more of the following risk factors for left ventricular disease:
  • BMI > 30 kg/m^2;
  • Diagnosis of essential hypertension that is actively treated;
  • Diabetes mellitus;
  • History of significant coronary artery disease (e.g., chronic stable angina, history of coronary intervention within the last 3 months, or a stenosis > 70% at coronary angiography);
  • Atrial fibrillation;
  • Left atrial volume index > 41 mL/m^2.
• Known genetic hypertrophic cardiomyopathy.
• Known cardiac sarcoidosis or amyloidosis.
• The patient has a history of, or currently has, a constrictive cardiomyopathy.
• Known history of any LVEF < 40% by echocardiogram within 3 years of randomization (Note: a transient decline in LVEF below 40% that occurred and recovered more than 6 months before the start of Screening and was associated with an acute intercurrent condition [e.g., atrial fibrillation] is allowed).
• Hemodynamically significant valvular heart disease as determined by the Investigator, including:
  • greater than mild aortic and/or mitral stenosis; and/or
  • severe mitral and/or aortic regurgitation (> Grade 3).
• Severe arthritis, musculoskeletal problems, or morbid obesity that, in the opinion of the Investigator, is the cause of the patient’s functional limitation and would affect the patient’s ability to perform or complete the 6MWT.
• Planned major surgery within the next 3 months, including lung transplantation, major abdominal or major intestinal surgery
• End stage renal disease defined as receiving peritoneal dialysis, hemodialysis, or status after renal transplantation; or severe liver disease defined as Child-Pugh Class C, with or without cirrhosis
• Known congenital long QT syndrome (LQTS) or known family history of LQTS
• Depression that is currently rated as severe (defined as a score of ≥ 16 on the QIDS-C and/or Hospital Anxiety and Depression Scale [HADS] Depression and/or Anxiety score ≥ 15), recent suicidal behavior (either preparatory acts/behavior, aborted attempt, interrupted attempt, or actual attempt in the past 3 months per the Screening Columbia Suicide Severity Rating Scale [C-SSRS], or active suicidal ideation with intent to act (defined as C-SSRS category score of 4 or 5 in the past month).
• Patients with (during Screening):
  • Severe hypertension (SBP > 180 mmHg and/or Diastolic Blood Pressure [DBP] > 110 mmHg), and patients with severe hypotension (SBP < 90 mmHg and/or DBP < 50 mmHg);
  • Hypertension or hypotension considered not controlled in line with clinical standards.
• Clinically significant electrolyte abnormality (e.g., hypokalemia, hypomagnesemia, or hypocalcemia) in the judgement of the Investigator.
• Current or prior history within the last 5 years of neoplasm (except for treated basal cell or squamous small cell carcinoma of the skin with no evidence of recurrence)
• Any concurrent clinically significant medical condition/disorder which in the Investigator’s opinion would interfere with the patient’s ability to comply with or complete the study or could affect the interpretation of the efficacy and safety variables.
• Use of any of the following medications or supplements within 30 days prior to Screening: 
  • Monoamine oxidase inhibitors (MAOIs);
  • Hydroxytryptophan (5-HTP) or L-tryptophan;
  • Telotristat ethyl.
• Patients currently taking one or more drugs known to prolong the QT interval and which are clearly associated with a known risk of Torsades de Pointe.
• Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m^2 at Screening as determined by central laboratory.
• 12-Lead electrocardiogram (ECG) results at Screening demonstrating QTcF interval > 450 ms for males or > 470 ms for females.
• Elevated alanine transaminase (ALT), aspartate transaminase (AST)), or total bilirubin (TBL) > 2 x upper limit of normal (ULN).
• Any ECG or clinical laboratory abnormality which precludes safe participation in the study in the opinion of the Investigator.
• History of active substance abuse disorder (including alcohol) within the past 2 years which, in the option of the Investigator, would limit the ability of the patient to provide adequate informed consent or to comply with study requirements.
• Use of any investigational drug within 30 days or 5 half-lives (whichever is longer) prior to Screening, or 90 days if an investigational drug for PAH, unless local health authority guidelines mandate a longer period, or in consultation with the medical monitor, will not interfere with the safety or efficacy of the study.
• Any history of hypersensitivity to rodatristat ethyl, any of its components, or any components in the placebo preparation (refer to Rodatristat Ethyl IB, 2021).
• Patient is deprived of their liberty by a judicial or administrative decision, or is receiving psychiatric care, and is admitted to a health or social institution.
• Patient is subject to legal protection or is unable to express consent.

Eligibility last updated 5/9/22.  Questions regarding updates should be directed to the study team contact.