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. 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 (IPAH); b. Heritable pulmonary arterial hypertension (HPAH); 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: Connective tissue disease (CTD), HIV infection; Congenital systemic-pulmonary shunt (must have undergone surgical correction at least 1 year prior to Screening and have no, or a clinically insignificant, shunt fraction [1.0 =pulmonary-systemic flow ratio (Qp/Qs) =1.5]) in the opinion of the Investigator. 5. Has had a right heart catheterization (RHC) performed at or within 3 years of Screening (RHC will be performed during Screening if not available) that is consistent with the diagnosis of PAH, meeting all of the following criteria: a. Mean pulmonary arterial pressure (mPAP) =20 mmHg (at rest) b. PAWP =15 mmHg (if PAWP cannot be reliably attained, then left ventricular end diastolic pressure [LVEDP] =15 mmHg) c. PVR >3.00 Wood units (=240 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 may be naïve to PAH-specific treatments; however, 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 as needed for erectile dysfunction, up to 3 doses per week, is permitted. The subject should not have taken a dose within 48-hours of any Baseline or study related efficacy assessment. 8. Has a 6MWD of =150 meters. 9. If the subject is taking concomitant medications that may affect PAH (e.g., calcium channel blockers, digoxin, or L-arginine supplementation), 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. 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 Visit, if the possibility of conception exists. Eligible male and female subjects must also agree not to participate in a conception process (i.e., actively attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization) during the study and for 30 days after the last dose of IMP. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects
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 (CD4+) T-cell count 50% stenosis in at least 1 coronary artery); Positive stress test with imaging; Previous coronary artery bypass graft; Stable angina e. Any chronic 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 (FEV1) 450 msec and female subjects with a QTcF >470 msec on ECG measured at Screening or Baseline in subjects without evidence of intraventricular conduction delay (IVCD). In the presence of IVCD, subjects will be excluded if the QTcF >500 msec for both males and females. 7. Severe chronic liver disease (i.e., Child-Pugh 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 (ALT) or aspartate aminotransferase (AST) =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 <9 g/dL at Screening. 12. Subjects treated with an IV or SC prostacyclin pathway agent (e.g., epoprostenol, treprostinil, or iloprost) at any time prior to Baseline (use in vasoreactive testing is permitted). 13. Subjects treated with an inhaled or oral prostacyclin pathway agent (iloprost, treprostinil, beraprost, or selexipag) that was stopped for a safety or tolerability issue. If a subject discontinued for other reasons, the subject is 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 90 days prior to Baseline. 14. Subject has pulmonary veno-occlusive disease. 15. Malignancy diagnosed and/or treated within 5 years prior to Screening, with the exception of localized non-metastatic basal cell or squamous cell carcinoma of the skin or in-situ carcinoma of the cervix excised with curative intent. 16. Subject tests positive for amphetamine, cocaine, methamphetamine, methylenedioxymethamphetamine or phencyclidine in urine drug screen performed at Screening, or has a recent history (6 months) of alcohol or drug abuse. 17. Initiation of a cardio-pulmonary r
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primary objective of this study is: To demonstrate the effect of ralinepag on the time to first adjudicated protocol-defined clinical worsening event in subjects with PAH.;Secondary Objective: The secondary objectives of the study are: 1) 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 o WHO/NYHA functional class I or II • Health-related quality of life (HRQoL) measures • Heart rate recovery (HRR) following completion of the 6-minute walk test (6MWT) 2) To evaluate the time to all-cause hospitalization 3) To evaluate the time to all-cause mortality 4) To evaluate the safety and tolerability of ralinepag in subjects with PAH;Primary end point(s): The primary endpoint is the time (in days) from randomization to the first adjudicated protocol-defined worsening event. Subjects without a protocol-defined clinical worsening event will be censored at date of last contact, 7 days after last study dose, or end of study date, whichever is the earliest. ;Timepoint(s) of evaluation of this end point: Throughout the study | — |
Secondary
| Measure | Time frame |
|---|---|
| Timepoint(s) of evaluation of this end point: Throughout the study; secondary endpoints will be assessed as the change from baseline to Week 28, except for time to all-cause hospitalization and time to all-cause mortality.;Secondary end point(s): • NT-proBNP with log transformation will be analyzed using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline NT-proBNP as a covariate. Least squares means, standard errors (SE), and 95% CIs for the treatments and their difference will be presented together with the p-value. • 6MWD will be analyzed using MMRM analysis with treatment measured >12 hours post dose, the stratification factors (less 6MWD stratum), week, and treatment-by-week interaction as factors and baseline 6MWD as a covariate. Least squares means, SEs, and 95% CIs for the treatments and their difference will be presented together with the p-value. • WHO/NYHA functional class will be analyzed using using CMH method adjusted for baseline WHO/NYHA functional class and using modified ridit scores to compute the test statistic and p-value for the between treatment comparison. • Time to first all-cause hospitalization will be analyzed using Cox regression with a model that includes treatment and the stratification factors. The hazard ratio for treatment together with its 95% CI and p-value will be presented. • Time to all-cause mortality will be analyzed using Cox regression with a model that includes treatment and the stratification factors. The hazard ratio for treatment together with its 95% CI and p-value will be presented. • HRR following completion of 6MWT will be analyzed using MMRM analysis with treatment, the stratification factors, week, and treatment-by-week interaction as factors and baseline HRR as a covariate. Least squares means, SEs, and 95% CIs for the treatments and their difference will be presented together with the p-value. • The proportion of subjects who achieve all | — |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Canada, Chile, China, Croatia, Denmark, European Union, Germany, Greece, Hungary, Israel, Korea, Republic of, Mexico, Netherlands, Portugal, Serbia, Singapore, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States
Contacts
Public ContactRegulatory Department
United Therapeutics Corporation
Outcome results
None listed