high lung blood pressure pulmonary arterial hypertension (PAH)
Conditions
Interventions
Titration period: Subject will start taking the study medication at a dose of
50 micrograms (mcg) once daily for a week. The dose will be increased by 50 mcg
every week, up to a maximum daily dose o
Sponsors
United Therapeutics Corporation
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: Each subject must meet ALL of the following inclusion criteria to be eligible for enrollment into the study: 1. At least 18 years of age 2. Evidence of a personally signed and dated Informed Consent Form indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures. 3. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures. 4. Primary diagnosis of symptomatic PAH classified by one of the following subgroups: a. Idiopathic pulmonary arterial hypertension; b. Heritable pulmonary arterial hypertension; c. Drug or toxin induced based on prior exposure to drugs, chemicals, or toxins, such as fenfluramine derivatives, other anorexigens, toxic rapeseed oil, or L-tryptophan. d. PAH associated with: Connective tissue disease (CTD), HIV infection; Congenital systemic-pulmonary intracardiac shunt (must have undergone surgical correction or repair with a closure device at least 1 year prior to Screening and have no, or a clinically insignificant, shunt fraction [1.0 =20 mmHg (at rest) b. PAWP 2.00 Wood units (>=160 dynes/sec/cm5). 6. Has WHO/NYHA functional class II to IV symptoms. 7. If on PAH-specific background oral therapy, subject is on stable therapy with either an endothelin receptor antagonist (ERA) and/or a PDE5-I or a soluble guanylate cyclase (sGC) stimulator. Subjects must have access to locally available standard of care treatment in accordance with national guidelines a. Stable is defined as no change in dose or regimen within 30 days prior to Baseline and for the duration of the study. b. Subjects may be on either a PDE5 inhibitor or an sGC at stable dose (but not both). c. If the subject's disease-specific PAH therapy does not include a PDE-5 inhibitor, the use of PDE5-I for erectile dysfunction, up to 3 doses per week, is permitted. 8. Has a 6MWD of >=150 meters. 9. If the subject is taking concomitant medications that may affect the clinical manifestations of PAH (e.g., calcium channel blockers, diuretics, digoxin, or L-arginine supplementation, beta blockers, angiotensinconverting enzyme inhibitors, or angiotensin II receptor blockers), the subject must be on a stable dose for at least 30 days prior to the Baseline Visit and the dosage mainta, beta blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor blockers), the subject must be on a stable dose for at least 30 days prior to the Baseline Visit and the dosage maintained throughout the study. The exception is that the dose of diuretics must be stable for at least the 10 days prior to Baseline. 10. Both male and female subjects agree to use a highly effective method of birth control throughout the entire study period from informed consent through the 30-Day Follow-up Vis
Exclusion criteria
Exclusion criteria: Subjects must not meet ANY of the following exclusion criteria to be eligible for enrollment into the study, unless otherwise indicated: 1. For subjects with known HIV-associated PAH, a cluster designation 4 T-cell count =30 kg/m2 b. History of systemic hypertension c. Diabetes mellitus - any type d. Historical evidence of significant coronary artery disease established by any 1 of the following: History of myocardial infarction or percutaneous coronary intervention or angiographic evidence of coronary artery disease (>50% stenosis in at least 1 coronary artery); Positive stress test with imaging; Previous coronary artery bypass graft; angina e. Recurrent or persistent atrial fibrillation. 3. Has evidence of more than mild lung disease on PFTs performed within 180 days prior to, or during Screening. Subjects with any of the following criteria will be excluded: a. Forced expiratory volume in 1 second 450 msec and female subjects with a QTcF >470 msec on ECG recorded at Screening and analyzed by the central ECG laboratory. Subjects with evidence of intraventricular conduction delay (IVCD). In the presence of IVCD, subjects, defined as a QRS interval greater than 110 msec, will be excluded if the QTcF is >500 msec for both males and females. 7. Severe chronic liver disease (i.e., Child-Pugh Class C), portal hypertension, cirrhosis or complications of cirrhosis/portal hypertension (e.g., history of variceal hemorrhage, encephalopathy). 8. Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). 9. Subjects with alanine aminotransferase or aspartate aminotransferase >=3 times the upper limit of normal (ULN) or total bilirubin >=2 × ULN at Screening. 10. Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or requiring dialysis at Screening. 11. Hemoglobin concentration 6 months or within 90 days prior to Baseline. Subject is not eligible if treatment was stopped for a safety or tolerability issue related to systemic prostacyclin adverse effects at any time. If a subject discontinued for other reasons, the subject may be eligible if the subject has been off therapy and stable (i.e., no change in WHO/NYHA FC or change in PAHspecific background oral therapy) for at least 90 days prior to Baseline. 14. Subject has pulmonary veno-occlusive disease. 15. Malignancy diagnosed and/or treated within 5 years prior to
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| The primary endpoint is the time (in days) from randomization to the first adjudicated protocol-defined worsening event. Subjects without a protocol-defined worsening event will be censored at date of last contact, 7 days after last study dose, interim analysis data cut date, or end of study date, whichever is the earliest. | — |
Secondary
| Measure | Time frame |
|---|---|
| The secondary objectives of the study are: To evaluate the effects of ralinepag from Baseline to Week 28 on: •N-terminal pro b-type natriuretic peptide (NT-proBNP) •6 minute walk distance (6MWD) •WHO/ New York Heart Association (NYHA) functional class •Shift and proportion of subjects who attain all three of the following:o NT-proBNP 440 meters oWHO/NYHA functional class I or II •Reveal risk score •Clinical improvement as defined by the absence of clinical worsening and fulfillment of at least 2 of the 3 following criteria: oIncrease in 6MWD by >=10% or >=30 m oImprovement to or maintenance of WHO FC I or II oDecrease in NT-proBNP by at least 30% •Health-related quality of life (HRQoL) measures •Time to first all-cause hospitalization •Time to all-cause mortality •Heart rate recovery (HRR) following completion of the 6MWT •To evaluate the safety and tolerability of ralinepag in subjects with PAH | — |
Countries
Netherlands
Outcome results
None listed