pulmonary arterial hypertension (PAH) MedDRA version: 20.0 Level: LLT Classification code 10077731 Term: Pulmonary hypertension WHO functional class I System Organ Class: 100000004855
Conditions
Sponsors
United Therapeutics Corporation
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Each subject must meet ALL of the following inclusion criteria to be eligible for enrollment into the study: 1) Evidence of a personally signed and dated Informed Consent Form (ICF) indicating that the subject has been informed of all pertinent aspects of the study prior to initiation of any study-related procedures. 2) At least 18 years of age at the time of consent. 3) Primary diagnosis of PAH classified by one of the following subgroups: a. Idiopathic pulmonary arterial hypertension b. Heritable pulmonary arterial hypertension c. Drugs or toxins 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: i. Connective tissue disease ii. Human immunodeficiency virus (HIV) infection iii. 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=pulmonary-systemic flow ratio =1.5) 4. Has had a diagnostic right heart catheterization (RHC) performed at or within 3 years before Screening (or during Screening if one is not available) that is consistent with the diagnosis of PAH, meeting all the following criteria: a) Pulmonary artery pressure mean >20 mmHg (at rest) b) PAWP =15 mmHg (If PAWP cannot be reliably attained, then left ventricular end diastolic pressure [LVEDP] =15 mmHg) c) Pulmonary vascular resistance (PVR) =2 Wood units or >160 dynes/sec/cm5 If more than 1 RHC was performed within 3 years of Screening, the most recent RHC that includes parameters sufficient to evaluate the above criteria must be used for this assessment. 5) Has WHO/NYHA FC II to III symptoms at Baseline. 6) Must be on a stable dose(s) of PAH-specific oral therapy, defined as no change in dose or regimen for at least 90 days prior to randomization. Allowable PAH-specific therapy is an ERA and/or PDE5-I or a sGC stimulator. Subjects may be on a stable dose of either a PDE5-I or a sGC stimulator, not both. a) If the subject’s disease-specific PAH therapy does not include a PDE5-I, the use of PDE5-I as needed for erectile dysfunction (ED), up to 3 doses per week, is permitted. The subject should not have taken a dose within 48 hours of Baseline. 7) Has a 6MWD of =150 meters during Screening. 8) Removed in Amendment2. 9) Has a peak VO2 of =9 to <18 mL/min/kg during the Screening CPET, as assessed by the CPET core laboratory. 10) If the subject is taking concomitant medications that may affect the clinical manifestations of PAH (ie, calcium channel blockers, digoxin, diuretics, beta blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, or L-arginine suplements), the subject must be on a stable dose for at least 30 days prior to the randomization. The exception is that the dose of diuretics should remain stable for at least the 10 days prior to randomization. 11. Both male and female subjects agree to use a highly effective method of birth control throughout the entire study period from informed consent through to the Week 28 Visit/28-day Follow-up Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process (ie, actively attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 30 days after the final dose of study drug. Eligi
Exclusion criteria
Exclusion criteria: Subjects must not meet ANY of the following exclusion criteria to be eligible for enrollment into the study: 1) For subjects with known HIV-associated PAH, a cluster designation 4 (CD4+) T-cell count 50% stenosis in at least 1 coronary artery) ii) Positive stress test or cardiac ischemia with imaging iii) Previous coronary artery bypass graft iv) Angina e) Recurrent or persistent atrial fibrillation 3) Removed in Amendment 1. 4) Symptomatic coronary artery disease and/or myocardial infarction within past 6 months. 5) Current symptomatic aortic or mitral valve disease. 6) Has evidence of more than mild lung disease on pulmonary function tests performed within 1 year prior to, or during, Screening. Subjects with any of the following criteria will be excluded (BOTH measurements must be performed): a. Forced expiratory volume in 1 second) (FEV1) 450 msec and female subjects with QTcF >470 msec on electrocardiogram (ECG) recorded at Screening. Subjects with evidence of intraventricular conduction delay (defined as a QRS interval >110msec) will be excluded if QTcF is >500 msec for both males and females. 13) Severe chronic liver disease (ie, Child-Pugh C), portal hypertension, cirrhosis, or complications of cirrhosis/portal hypertension (eg, history of variceal hemorrhage, encephalopathy). 14) Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV). 15) Subjects with alanine aminotransferase or aspartate aminotransferase =3 times the upper limit of normal or total bilirubin = 2 times the upper limit of normal at Screening. 16) Chronic renal insufficiency as defined by estimated glomerular filtration rate <30 or requiring dialysis at Screening. 17) Hemoglobin concentration <9 g/dL at Screening. 18) Subjects treated with an intravenous (IV), SC, inhaled or oral prostacyclin pathway agent (eg, epoprostenol, treprostinil, iloprost, beraprost or selexipag) for PAH within 90 days of randomization (use in vasoreactive testing is permitted). Subject is not eligible if previous prostacyclin therapy was stopped for a safety or tolerability issue related to systemic prostacyclin adverse effects. 19) Combined with Exclusion Criteria #18 20) Subject has pulmonary veno-occlusive disease. 21) Malignancy diagnosed and/or treated within 3 years of Screening, with the exception of localized non-metastatic basal cell or squa
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the effects of ralinepag therapy on exercise capacity as assessed by change in peak oxygen consumption (VO2) derived from cardiopulmonary exercise testing (CPET) after 28 weeks of treatment;Secondary Objective: To evaluate the effects of ralinepag on: 1. NT-proBNP 2. VE/VCO2 slope 3. WHO/New York Heart Association (NYHA) Functional Class (FC) 4. Health-related quality of life (HRQoL) measured by the Short Form (36) Health Survey (SF-36) 5. Time to first all-cause nonelective hospitalization 6. Safety and tolerability Note: Other protocol defined exploratory objectives may apply.;Primary end point(s): The primary endpoint of the study is the change from Baseline in peak VO2 after 28 weeks of treatment with study drug.;Timepoint(s) of evaluation of this end point: Through the study. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The following secondary endpoints will be analyzed in hierarchical order: • Change from Baseline at Week 28 in NT-proBNP: NT-proBNP with log transformation will be analyzed in the ITT population using mixed-effect model repeated measures (MMRM) analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline NT-proBNP as a covariate • Change from Baseline at Week 28 in VE/VCO2 slope: VE/VCO2 slope will be analyzed in the mITT population and repeated in the ITT population using ANCOVA with a model that includes treatment and the stratification factors as factors and Baseline VE/VCO2 slope as a covariate. • Change in SF-36 scores from Baseline to Week 28: the component and domain scores will be analyzed in the ITT population using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline component/domain score as a covariate. • Time to first all-cause nonelective hospitalization in randomized subjects during the study period will be analyzed in the ITT population using Cox proportional hazard regression model that includes treatment and the stratification factors.;Timepoint(s) of evaluation of this end point: Throughout the study. | — |
Countries
Argentina, Australia, Austria, Belgium, Brazil, Canada, Germany, Italy, Poland, Portugal, Spain, United Kingdom, United States
Contacts
Public ContactRegulatory Department
United Therapeutics Corporation
Outcome results
None listed