A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients

• Register: ClinicalTrials.gov
• Last refreshed on: 29 April 2024
• Main ID: NCT03626688
• Date of registration: 27/07/2018
• Prospective Registration: Yes
• Primary sponsor: United Therapeutics
• Public title: A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
• Scientific title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Ralinepag When Added to PAH Standard of Care or PAH Specific Background Therapy in Subjects With WHO Group 1 PAH
• Date of first enrolment: August 30, 2018
• Target sample size: 1000
• Recruitment status: Recruiting
• URL: https://clinicaltrials.gov/ct2/show/NCT03626688
• Study type: Interventional
• Study design: Allocation: Randomized. Intervention model: Parallel Assignment. Primary purpose: Treatment. Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor).
• Phase: Phase 3

Countries of recruitment

Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Canada, Chile, China, Croatia, Czechia, Denmark, France, Germany, Greece, Hungary, Israel, Italy, Korea, Republic of, Mexico, Netherlands, Poland, Portugal, Romania, Serbia, Singapore, Spain, Sweden, Taiwan, Turkey, Ukraine, United Kingdom, United States

Contacts

• Name: United Therapeutics Global Medical Information

Key inclusion & exclusion criteria

Inclusion Criteria:

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.

5. 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.

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 phosphodiesterase type 5 inhibitor
(PDE5-I) or a soluble guanylate cyclase (sGC) stimulator.

8. Has a 6MWD of =150 meters.

9. If taking concomitant medications that may affect the clinical manifestations of PAH
(eg, calcium channel blockers, diuretics, digoxin, or L arginine supplementation, beta
blockers, angiotensin-converting enzyme inhibitors, or angiotensin II receptor
blockers), 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 to 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 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:

1. For subjects with known HIV-associated PAH, a cluster designation 4 (CD4+) T-cell
count <200/mm3 within 90 days of Baseline.

2. Must not have 3 or more left ventricular dysfunction risk factors as defined in the
study protocol.

3. Has evidence of more than mild lung disease on pulmonary function tests performed
within 180 days prior to, or during Screening.

4. Has evidence of thromboembolic disease as determined by a V/Q lung scan or local
standard of care diagnostic evaluation at or after diagnosis of PAH.

5. Current diagnosis of ongoing and clinically significant sleep apnea as defined by the
Investigator.

6. 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, 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 (ie, Child-Pugh Class C), portal hypertension, cirrhosis
or complications of cirrhosis/portal hypertension (eg, 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 <9 g/dL at Screening.

12. Subjects treated with an IV or SC prostacyclin pathway agent (eg, epoprostenol,
treprostinil, or iloprost) for PAH at any time prior to Baseline (use in vasoreactive
testing is permitted).

13. 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.

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. A subject will
not be excluded due to a positive drug screen caused by prescribed medications.

17. Initiation or discontinuation of a cardio-pulmonary rehabilitation program based upon
exercise within 90 days prior to Screening and/or planned during study participation.

18. 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.

19. Any reason that, in the opinion of the Investigator or Medical Monitor, precludes the
subject from participating in the study (eg, 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.

20. Known hypersensitivity to ralinepag or any of the excipients.

21. Life expectancy <12 months based on the Investigator's opinion.

22. Women who are pregnant, lactating or breast-feeding.



Age minimum: 18 Years
Age maximum: N/A
Gender: All

Health Condition(s) or Problem(s) studied

Hypertension, Pulmonary

Cardiovascular Diseases

PAH

Pulmonary Hypertension

Connective Tissue Diseases

Familial Primary Pulmonary Hypertension

Pulmonary Arterial Hypertension

Hypertension

Respiratory Tract Disease

Lung Diseases

Vascular Diseases

Intervention(s)

Drug: Placebo

Drug: Ralinepag

Primary Outcome(s)

Time from randomization to the first adjudicated protocol-defined clinical worsening event [Time Frame: The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study, up to 3 years]

Secondary Outcome(s)

Change from Baseline in heart rate recovery (HRR) following completion of the 6MWT [Time Frame: Baseline to Week 28]

Clinical improvement as defined by the absence of clinical worsening and fulfillment of at least 2 of the 3 of the following: increase in 6MWD =10% or =30 m, improvement to or maintenance of WHO FC I or II, and decrease in NT-proBNP by at least 30%. [Time Frame: Baseline to Week 28]

Change from Baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) [Time Frame: Baseline to Week 28]

Time to all-cause mortality [Time Frame: The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study (when the target number of adjudicated events was achieved, as defined in the study protocol).]

Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) risk score [Time Frame: Baseline to Week 28]

Change from Baseline in health-related quality of life as measured by patient-reported outcomes. [Time Frame: Baseline to Week 28]

Shift and proportion of subjects who attain all 3 of the following: NT-proBNP level <300 pg/mL, 6MWD >440 meters, and WHO/NYHA Functional Class I or II [Time Frame: Baseline to Week 28]

Time to first all-cause nonelective hospitalization [Time Frame: The study duration was event-based. This parameter was assessed from randomization until the conclusion of the study (when the target number of adjudicated events was achieved, as defined in the study protocol).]

Change from Baseline in 6-minute walk distance (6MWD) [Time Frame: Baseline to Week 28]

Change from Baseline in WHO/New York Heart Association (NYHA) Functional Class [Time Frame: Baseline to Week 28]

Safety and tolerability of ralinepag in subjects with PAH [Time Frame: Baseline to Week 28]

Secondary ID(s)

ROR-PH-301

APD811-301

Source(s) of Monetary Support

Please refer to primary and secondary sponsors