Clinical Drug Experience Knowledgebase

Criteria

Inclusion Criteria

Subjects must meet all of the following criteria:

Male or female, aged 18 to 75 years inclusive

WHO Group 1 PAH related to one of the following conditions:

Idiopathic
Heritable
Drugs or toxins-induced
Associated with connective tissue disease
Associated with congenital heart disease if subjects underwent surgical correction more than 12 months before Screening
Symptoms due to PAH are consistent with WHO functional class II- III
Have not taken endothelin receptor antagonists (ERAs) within 3 months before Randomization
Has been taking at least one oral PAH targeted drug that has been approved by local guidelines for at least 3 months before Screening with stable dosage and the disease did not worsen during this period per Investigator's judgment

Right heart catheterization (RHC) result meets below criteria when Screening:

Mean pulmonary arterial pressure (PAP) ≥25 mmHg
Pulmonary vascular resistance (PVR) >3 Woods units
PA wedge pressure (PAWP) ≤15 mmHg

If a subject has undergone RHC within 3 months before Screening, the waveform results will serve as baseline data only if they meet the entry criteria and the RHC at Screening will not be repeated. In case PAWP cannot be well measured during RHC, left ventricular end diastolic pressure will be tested by left heart catheterization.

Has a six-minute walk test (6MWT) with distance between 150 to 450 meters at Screening
The dosage of digitalis drugs or L-arginine supplementation must be stable for at least 1 month before Screening, if applicable.
No new use of an IV diuretic, cardiotonic (positive inotropic agents), or vasoactive drug within 30 days before Screening
Both male and female subjects agree to use 2 medically acceptable methods of contraception (Appendix 4) throughout the entire study period from informed consent signing to 90 days after last dose, if the possibility of conception exists. Medically acceptable methods of contraception include oral, implantable, or injectable contraceptives (starting 2 months before dosing); diaphragm with vaginal spermicide; intrauterine device; condom and partner using vaginal spermicide; and surgical sterilization (6 months after surgery). Women who are surgically sterile or those who are postmenopausal for at least 2 years are not considered to be of childbearing potential. Eligible male and female subjects must agree not to participate in a conception process (i.e. active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 90 days after the last dose of study drug.
Body weight no less than 40 kg at Screening
Able to understand and willing to sign the Informed Consent Form (ICF) and comply with the study procedures.

Exclusion Criteria

Subjects who me et any of the following criteria will not be allowed to participate in this study:

Diagnosed with WHO Group II, III, IV, V of PH
Use of calcium channel blockers within 1 month prior to Screening
Systolic blood pressure (SBP) >160 mmHg or diastolic blood pressure (DBP) >100 mmHg at Screening
SBP <90 mmHg at Screening
Pulmonary function test: FEV1 <60% of predicted, TLC <60% of predicted, DLCO <60% of predicted
History of pulmonary embolism as judged by the Investigator
Uncontrolled sleep apnea at the discretion of the Investigator
Limited full participation in the 6MWT due to arthritic, neuromuscular, vascular or other diseases unrelated to PAH
History of acute cardiovascular and/or cerebrovascular events within 6 months before Screening

Echocardiogram (ECHO) demonstrating at least one of the following at Screening:

LVEF <50%
Mean end-diastolic left ventricular septal and posterior wall thickness of >12 mm
Left atrial (LA) area on apical 4 chamber view >20 cm2
LA volume >55 mL
LA volume index >34 mL/m2
Significant valvular heart disease including moderate or severe mitral or aortic stenosis with an aortic valve area <1.0 cm2 or mitral valve area <1.5 cm2, greater than moderate aortic or mitral regurgitation, greater than moderate tricuspid or pulmonic stenosis
Restrictive, dilated or hypertrophic cardiomyopathy or constrictive pericarditis
Using non-oral prostacyclin when Screening

Laboratory parameters during Screening:

Baseline aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥2 times the upper limit of normal (ULN) or total bilirubin ≥1.5 times ULN

Estimated glomerular filtration rate (eGFR) <60 mL/min by Cockcroft-Gault formula

Online calculation available from https://www.kidney.org/professionals/KDOQI/gfr_calculatorCoc

Cockcroft-Gault formula (1973):

Male: CCr=((l40-Age) × Weight)/(72×SCr)

Female: CCr={((l40-Age) × Weight)/(72×SCr)}× 0.85

CCr (creatinine clearance rate) = mL/min

Age = year

Weight = Kg

SCr (serum creatinine) = mg/dL

Hemoglobin concentration ≤100 g/L at Screening
QTc interval by Fridericia's criteria (QTcF) ≥500 msec at Screening
Malignancy within 5 years before Screening visit (with the exception of localized non-metastatic basal cell carcinoma of the skin, non-metastatic carcinoma of the prostate or in-situ carcinoma of the cervix excised with curative results)
Alcohol or drug abuse within 1 year before Screening
A psychiatric, addictive or other disorder that compromises the ability to give informed consent for participating in this study
History of organ transplantation
Pregnant or nursing females
History of HIV
Positive hepatitis B surface antigen (HBsAg), hepatitis C antibody (HCV-Ab), or HIV antibody (HIV-ab)
Enrolled in another interventional study within 30 days before Screening
Any condition that, in the opinion of the Investigator, prevents a potential subject from safely participating in the study
Start a new exercise program or participate in any unusually strenuous physical exertion within 6 weeks prior to Screening.