Clinical Trials

Inclusion Criteria:

• Male or female adults (between 18 and 75 years) at the Screening Visit within 28 days prior to Day 1.
• Subjects with a diagnosis of PAH belong to one of the subgroups of the NICE classification of Group 1:
  • I/HPAH, PAH-CTD;
  • PAH due to drugs and toxins (having been in the care of the Investigator for at least one year with no relapses of drug or toxin/chemical abuse);
  • HIV associated or d. PAH due to repaired congenital heart disease (at least 1 year since repair).
• World Health Organization (WHO) Functional Class II, III or IV symptoms.
• Meets all of the following hemodynamic criteria by means of an RHC at Screening:
  • mPAP ≥ 25 mmHg, PVR > 400 dynes.sec/cm^5 and PCWP ≤ 15 mmHg. For the Intermediate and Phase 3 Parts.
• On a stable background of at least two PAH medications. Parenteral and oral prostacyclins (including prostanoids and prostacyclin receptor antagonists) are permitted. Subjects should have been stable on their PAH medications for at least 90 days. Stability of parenteral prostacyclins means a change of no more than 10% in the previous 12 weeks.
• A history of ventilation/perfusion (V/Q) scan, pulmonary arteriogram, or CT angiogram negative for chronic thromboembolic pulmonary hypertension (CTEPH) at the time of their Group 1 PAH diagnosis.
• Must meet all of the following criteria for pulmonary function (spirometry) tests completed no more than 24 weeks before the Screening Visit: FEV1 ≥ 60% of predicted normal and FEV1:FVC ratio ≥ 0.60.
• Must have a resting arterial oxygen saturation (SaO2) ≥ 90%, with or without supplemental oxygen, as measured by pulse oximetry at the Screening Visit.
• Must be able to walk a distance of at least 100 m but no more than 475 m during the screening 6-minute walk test. In addition, the subject must be able to demonstrate a stable baseline for the 6-minute walk tests between the Screening and Randomization Visits.
• Able to understand the study procedures and be willing to comply with the study restrictions. Willing and able to sign a written informed consent prior to all study-related procedures.
• Female subjects of childbearing potential must agree to use an acceptable form of contraception for at least 28 days prior to when they will receive the first dose of study drug, and for at least 30 days after completing or discontinuing study treatment.
• Evidence of negative test for SARS-CoV-2, by PCR, at the Screening Visit; Subjects with a previous COVID-19 infection may be included provided the PCR test is negative for SARS-CoV-2 and they do not have chronic symptoms as a result of COVID-19. COVID19 testing may be performed at local lab, per site/local guidelines, or via the study Central Lab. Subjects who have been fully vaccinated against SARS-CoV-2 may be enrolled without need for PCR testing.
• Has not enrolled in an exercise training program for pulmonary rehabilitation within 12 weeks prior to the Screening Visit and must agree not to enroll in an exercise training program for pulmonary rehabilitation during the Screening Period and the first 24 weeks of the study.
• If currently enrolled in an exercise training program for pulmonary rehabilitation for more than 12 weeks at the time of the Screening Visit, must agree to maintain their current level of rehabilitation for the first 24 weeks of the study.

Exclusion Criteria:

• Taking warfarin (or any vitamin K antagonists), DOACs or dual antiplatelet therapy within 2 weeks prior to Day 1/Randomization. (DSMB and Sponsor will decide whether to allow warfarin in Phase 3 Part of the study.
• PH belonging to Groups 2 to 5 of the 2018 NICE classification.
• A history of LVEF ≤ 40% on echocardiogram within 6 months of screening, or clinically significant ischemic, mitral or aortic valve disease, or constrictive heart disease in the opinion of the Investigator
• Evidence of ≥ 3 of the following left ventricular disease/dysfunction risk factors:
  • Body mass index (BMI) ≥ 30 at the Screening Visit; or
  • History of essential hypertension;
  • Diabetes mellitus – any type.
• Historical evidence of significant coronary artery disease (CAD) established by any one of the following:
  • History of myocardial infarction;
  • History of PCI;
  • Angiographic evidence of CAD (> 50% stenosis in at least on vessel), by angiography;
  • Positive stress test with imaging;
  • Previous coronary artery surgery;
  • History of chronic stable angina or unstable angina.
• Taking inhaled prostacyclins within the past 3 months prior to the Screening Visit 6. History of chronic uncontrolled asthma (subjects taking corticosteroids will be allowed into the study.
• History of any illness or condition that, in the opinion of the Investigator could confound the results of the study or pose an additional risk to the subject through their participation in the study.
• Inability to use or may have potential difficulties using an inhaler device during each dosing period.
• Participating in a clinical study (e.g., attending follow-up visits) or who have received an investigational drug (new chemical entity) in the past 30 days prior to the Screening Visit. Involvement in strictly observational studies (Registries) is allowed provided this is approved by the Contract Research Organization (CRO) Medical Monitor.
• Donated blood, plasma, or platelets in the month prior to screening or who have made donations on more than two occasions within the 12 months preceding the first dose administration of study drug or have had a loss of ≥ 400 mL of blood within 2 months prior to Day 1/Randomization.
• Deficient thrombocyte function, thrombocytopenia < 50 x10^9 /L (50 x 10^3 /μL) at the Screening Visit.
• Uncontrolled systemic arterial hypertension, systolic > 180 mm Hg or diastolic >110 mm Hg at the Screening Visit or Day 1/Randomization Visit.
• QTcF > 450 msec for males and > 470 msec for females at the Screening Visit in the absence of right bundle branch block.
• History of Long QT Syndrome or Torsade de Pointes.
• Hemoglobin < 80 g/L (8 g/dL) at the Screening Visit.
• Serum ALT or AST lab value that is > 3 x ULN at the Screening Visit.
• Severe renal impairment (eGFR < 30 mL/min/1.73m 2 at the Screening Visit based on the CKD-EPI equation).
• Severe hepatic impairment (Child-Pugh Class C with or without cirrhosis) at the Screening Visit.
• Known deficiencies of blood coagulation, inherited, or acquired blood coagulation disorders, factor XII, factor XIII; decreased generation of coagulation factors due to acute or chronic liver diseases, inefficient coagulation; e.g., due to autoantibodies against coagulation factors such as in lupus anticoagulant, DIC etc.
• Evidence or history of major bleeding or intracranial hemorrhage.
• History of elevated intracranial pressure.
• Significant history or drug allergy as determined by the Investigator.
• Known or suspected drug hypersensitivity to any component of the trial drug (lactose intolerant subjects are allowed into the study).
• Clinically relevant history or current psychological abnormality (including alcohol abuse), psychiatric or neurological illness or autonomic neuropathy, which in the opinion of the Investigator could jeopardize or would compromise the subject’s ability to participate in the trial.
• Recent major surgical intervention which in the opinion of the Investigator would compromise the subject’s ability to participate in the trial. Pregnant or breast-feeding females.
• Receiving the SARS-CoV-2 vaccination from 1 week prior to the Screening Visit and through 4 weeks post-Day1/Randomization.
• Post COVID-19 chronic symptoms (“Long Haulers”) at Screening.

Eligibility last updated 2/18/22. Questions regarding updates should be directed to the study team contact.