Evaluation of Ralinepag Efficacy and Safety in Pulmonary Arterial Hypertension: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial
- Trial ID
- 2023-509304-16-00
- Protocol
- ROR-PH-301
- Sponsor
- United Therapeutics Corp.
Trial statistics
Diseases & Conditions
Objectives
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 pulmonary arterial hypertension (PAH). This is clinically relevant as it aims to assess the potential of ralinepag to delay disease progression, which is critical in managing PAH, a condition characterized by high morbidity and mortality.
Secondary objectives include evaluating the effects of ralinepag from baseline to week 28 on several parameters:
- 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: NT-proBNP <300 pg/mL, 6MWD >440 meters, WHO/NYHA functional class I or II
- REVEAL risk score
- Clinical improvement defined by the absence of clinical worsening and fulfillment of at least 2 of the 3 following criteria: increase in 6MWD by ≥10% or ≥30 m, improvement to or maintenance of WHO FC I or II, decrease 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
Participants
The clinical trial involves a total of **575 participants** diagnosed with **pulmonary arterial hypertension (PAH)**. The study population includes both male and female subjects, aged 18 years and older, who are capable of adhering to the study's requirements. Participants were selected based on their primary diagnosis of symptomatic PAH, which may be idiopathic, heritable, drug or toxin-induced, or associated with conditions such as connective tissue disease, HIV infection, or congenital systemic pulmonary intracardiac shunt. The trial includes individuals who have undergone right heart catheterization consistent with PAH diagnosis and exhibit WHO/NYHA functional class II to IV symptoms. Participants are required to be on stable PAH-specific background oral therapy, if applicable, and maintain stable doses of any concomitant medications that may affect PAH manifestations. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial population includes vulnerable groups, ensuring comprehensive representation of the PAH patient demographic.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **ralinepag** in improving treatment outcomes for patients with **pulmonary arterial hypertension** (PAH). This is a Phase 3, randomized, double-blind, placebo-controlled study. The trial aims to demonstrate the effect of ralinepag on the time to the first adjudicated protocol-defined clinical worsening event in subjects with PAH. The study is expected to last until June 2025, with participant recruitment having commenced in July 2019.
Participants will be involved in the study for a maximum treatment period of 48 weeks. The trial includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor progress and safety, and an end-of-study visit to assess final outcomes. The inclusion criteria require participants to be at least 18 years old, have a primary diagnosis of symptomatic PAH, and meet specific hemodynamic criteria confirmed by right heart catheterization. Participants must also be on stable PAH-specific background oral therapy if applicable.
Study visits are structured to ensure comprehensive monitoring and data collection. The screening visit will involve informed consent, medical history review, and baseline assessments. Follow-up visits will occur at regular intervals to evaluate treatment efficacy and safety, including assessments of 6-minute walk distance (6MWD), WHO/NYHA functional class, and NT-proBNP levels. The end-of-study visit will include a final evaluation of the primary and secondary endpoints.
Participants may be withdrawn from the study if they experience significant adverse events, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The primary endpoint is the time from randomization to the first adjudicated protocol-defined worsening event. Secondary endpoints include changes in NT-proBNP levels, 6MWD, WHO/NYHA functional class, and time to first all-cause hospitalization or mortality. The study employs a mixed model for repeated measures (MMRM) and Cox regression analysis to evaluate these outcomes.
Treatment
The clinical trial involves the administration of **Ralinepag**, a **prolonged-release tablet** developed by United Therapeutics Corporation. Ralinepag is chemically synthesized and is administered orally. The active substance in Ralinepag is also known by its chemical name, 2-((trans-4-((((4-chlorophenyl)(phenyl)carbamoyl)oxy)methyl)cyclohexyl)methoxy)acetic acid, and is identified by the sponsor product code APD811. The maximum daily dose of Ralinepag is 9000 micrograms, with a total maximum dose of 12960 milligrams over a treatment period of up to 48 weeks. The trial aims to evaluate the efficacy and safety of Ralinepag in improving treatment outcomes for patients with pulmonary arterial hypertension (PAH).
In addition to the experimental medication, a **placebo** is used as a comparator in the study. The placebo is designed to mimic the appearance of Ralinepag extended-release tablets but does not contain any active pharmaceutical ingredients. The placebo is utilized to ensure the validity of the trial results by providing a control group for comparison against the effects observed in participants receiving Ralinepag. The administration route and frequency for the placebo are consistent with those of the experimental medication to maintain blinding and integrity of the study design.
Efficacy
The efficacy of **Ralinepag** in the treatment of pulmonary arterial hypertension (PAH) will be assessed through a series of predefined endpoints. The primary endpoint is the time from randomization to the first adjudicated protocol-defined clinical worsening event. This will be measured in days, and subjects without such an event will be censored at the date of last contact, 7 days after the last study dose, or the end of the study date, whichever occurs first.
Secondary endpoints include several parameters: NT-proBNP levels will be analyzed using a mixed model for repeated measures (MMRM) analysis, incorporating treatment, stratification factors, week, and treatment-by-week interaction as factors, with baseline NT-proBNP as a covariate. The 6-minute walk distance (6MWD) will also be analyzed using MMRM, with similar factors and covariates. WHO/NYHA functional class will be evaluated using the Cochran-Mantel-Haenszel (CMH) method, adjusted for baseline class. Time to first all-cause hospitalization and time to all-cause mortality will be analyzed using Cox regression models, including treatment and stratification factors.
Additional analyses will include heart rate recovery (HRR) following the 6-minute walk test (6MWT), the proportion of subjects achieving specific clinical criteria (NT-proBNP <300 pg/mL, 6MWD >440 meters, WHO/NYHA class I or II), REVEAL score, and health-related quality of life (HRQoL) measures using the SF-36. These will be analyzed using MMRM or CMH methods as appropriate, with results presented as least squares means, standard errors, 95% confidence intervals, and p-values.
Inclusion and Exclusion Criteria
Inclusion Criteria
- At least 18 years of age
- 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.
- Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
- 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 ≤pulmonary-systemic flow ratio ≤1.5] in the opinion of the Investigator.
- Has had a right heart catheterization (RHC) performed at or within 3 years prior to 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 ≤15 mmHg) c. PVR >2.00 Wood units (>160 dynes/sec/cm5).
- Has WHO/NYHA functional class II to IV symptoms.
- If on PAH-specific background oral therapy, subject is on stable therapy with either an endothelin receptor antagonist 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.
- Has a 6MWD of ≥150 m.
- If the subject is taking concomitant medications that may affect the clinical manifestations of PAH (e.g., calcium channel blockers, diuretics, digoxin, L-arginine supplementation, 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.
- 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 (ie, actively attempt to become pregnant or to impregnate, in vitro fertilization) during the study and for 30 days after the last dose of IMP. Eligible male subjects must agree not to participate in sperm donation for 90 days after the last dose of IMP.
Exclusion Criteria
- For subjects with known HIV-associated PAH, a cluster designation 4 T-cell count <200/mm3 within 90 days of Baseline.
- Subjects must not have 3 or more of the following left ventricular dysfunction risk factors: a. Body mass index ≥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.
- 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 <60% (predicted); or b. Total lung capacity (TLC) <60% (predicted)
- Has evidence of thromboembolic disease as determined by a V/Q lung scan or other local standard of care diagnostic evaluation at or after diagnosis of PAH.
- Current diagnosis of ongoing and clinically significant sleep apnea as defined by the Investigator.
- Male subjects with a corrected QT interval using Fridericia's formula (QTcF) >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.
- 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).
- Confirmed active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).
- Subjects with alanine aminotransferase or aspartate aminotransferase ≥3 times the upper limit of normal (ULN) or total bilirubin ≥2 × ULN at Screening.
- Chronic renal insufficiency as defined by serum creatinine >2.5 mg/dL or requiring dialysis at Screening.
- Hemoglobin concentration <9 g/dL at Screening.
- Subjects treated with an IV or SC prostacyclin pathway agent (e.g., epoprostenol, treprostinil, or iloprost) or activin signaling inhibitor for PAH at any time prior to Baseline (use in vasoreactive testing is permitted).
- Subjects currently on or who were treated with an inhaled or oral prostacyclin pathway agent (iloprost, treprostinil, beraprost, or selexipag) for >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.
- Subject has pulmonary veno-occlusive disease.
- 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.
- Subject tests positive for amphetamine, cocaine, methamphetamine, methylenedioxymethamphetamine or phencyclidine on thein urine drug screen performed at Screening, or has a recent history (6 months) of alcohol or drug abuse. A subject will not be excluded due to a positive drug screen caused by prescribed medications.
- Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon exercise within 90 days prior to Screening and/or planned during study participation.
- Prior participation in any study of ralinepag or participation in another interventional clinical study with medicinal products within 30 days prior to Screening. Concurrent participation in registry or observational studies is allowed, as long as the subject can fulfill all other entry criteria and comply with all study procedures.
- Any reason that, in the opinion of the Investigator or Medical Monitor, precludes the subject from participating in the study (e.g., any previous or intercurrent medical condition) that may increase the risk associated with study participation or that would confound study analysis or impair study participation or cooperation.
- Known hypersensitivity to ralinepag or any of the excipients.
- Life expectancy <12 months based on the Investigator's opinion.
- Women who are pregnant, lactating, or breast-feeding
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 19 Jul 2019 | 5 |
 Belgium | Not Recruiting | 19 Jul 2019 | 6 |
 Bulgaria | Not Recruiting | 19 Jul 2019 | 7 |
 Czechia | Not Recruiting | 19 Jul 2019 | 3 |
 Denmark | Not Recruiting | 19 Jul 2019 | 15 |
 France | Not Recruiting | 19 Jul 2019 | 20 |
 Germany | Not Recruiting | 19 Jul 2019 | 25 |
 Greece | Not Recruiting | 19 Jul 2019 | 15 |
 Hungary | Not Recruiting | 19 Jul 2019 | 8 |
 Italy | Not Recruiting | 19 Jul 2019 | 18 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo for Ralinepag extended-release tablets | Placebo | N/A | — | — | — | N/A |
Ralinepag | Test | PROLONGED-RELEASE TABLET | ORAL USE | 9000 | 48 | PRD11176291 |
Ralinepag | Test | PROLONGED-RELEASE TABLET | ORAL USE | 9000 | 48 | PRD11176287 |
Ralinepag | Test | PROLONGED-RELEASE TABLET | ORAL USE | 9000 | 48 | PRD8191893 |