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

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ClinicalTrials.gov Identifier: NCT03626688
Recruitment Status : Recruiting
First Posted : August 13, 2018
Last Update Posted : October 8, 2021
Sponsor:
Information provided by (Responsible Party):
United Therapeutics

Brief Summary:
Study ROR-PH-301, ADVANCE OUTCOMES, is designed to assess the efficacy and safety of ralinepag when added to pulmonary arterial hypertension (PAH) standard of care or PAH-specific background therapy in subjects with World Health Organization (WHO) Group 1 PAH.

Condition or disease Intervention/treatment Phase
PAH Pulmonary Hypertension Pulmonary Arterial Hypertension Hypertension Connective Tissue Diseases Familial Primary Pulmonary Hypertension Vascular Diseases Cardiovascular Diseases Hypertension, Pulmonary Lung Diseases Respiratory Tract Disease Drug: Ralinepag Drug: Placebo Phase 3

Detailed Description:
Study ROR-PH-301 is a multicenter, randomized, double-blind, placebo-controlled study. Subjects who meet entry criteria will be randomly allocated 1:1 to receive ralinepag or placebo, in addition to their standard of care or PAH-specific background therapy, as applicable. The primary endpoint is the time (in days) from randomization to the first adjudicated protocol-defined clinical worsening event. All primary endpoint events will be adjudicated by an independent Clinical Event Committee (CEC) in a blinded fashion. Subjects who have a confirmed primary endpoint event adjudicated by the CEC at any time during the study and all subjects on treatment at the conclusion of the study (after the target number of events is achieved) will have the option to enroll in an open-label extension (OLE) study. Subjects who do not choose to participate in the OLE study will discontinue study drug, and should remain in the study for long-term follow-up of survival status and will receive standard of care PAH treatment, at the discretion of the treating physician.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 700 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : August 30, 2018
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: Ralinepag
Ralinepag once daily extended-release tablets (oral) 50, 250, and 400 mcg titrated to the highest tolerated dose.
Drug: Ralinepag
Active
Other Name: APD811

Placebo Comparator: Placebo
Matching placebo tablets (oral)
Drug: Placebo
Placebo




Primary Outcome Measures :
  1. 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 ]
    Clinical worsening events are defined as death, nonelective hospital admission for worsening PAH (further defined in clinical study protocol), initiation of parenteral or inhaled prostacyclin pathway agent for treatment of worsening PAH, disease progression (further defined in clinical study protocol), or unsatisfactory long-term clinical response (further defined in clinical study protocol).


Secondary Outcome Measures :
  1. Change from Baseline in N-terminal pro-brain natriuretic peptide (NT-proBNP) [ Time Frame: Baseline to Week 28 ]
    NT-proBNP was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.

  2. Change from Baseline in 6-minute walk distance (6MWD) [ Time Frame: Baseline to Week 28 ]
    6MWD was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.

  3. Change from Baseline in WHO/New York Heart Association (NYHA) Functional Class [ Time Frame: Baseline to Week 28 ]
    The severity of PAH was graded according to the functional status of the subject and assessed at every visit.

  4. 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 ]
    Data from NT-proBNP, 6MWD, and WHO/NYHA functional class assessment were compiled as a composite endpoint at visits through Week 28.

  5. Change from Baseline in health-related quality of life as measured by patient-reported outcomes. [ Time Frame: Baseline to Week 28 ]
    Quality of life was assessed using patient-reported outcomes at Baseline (prior to starting study drug) and Week 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.

  6. 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). ]
    All nonelective hopsitalizations during the study period were collected.

  7. 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). ]
    All deaths during the study period were collected.

  8. Change from Baseline in heart rate recovery (HRR) following completion of the 6MWT [ Time Frame: Baseline to Week 28 ]
    HRR was measured at Baseline (prior to starting study drug) and Week 4, 8, 12, and 16, then every 12 weeks thereafter including the End of Study/Early Termination Visit.

  9. Safety and tolerability of ralinepag in subjects with PAH [ Time Frame: Baseline to Week 28 ]
    Safety and tolerability were assessed by adverse events.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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. Subjects may be naïve to PAH-specific treatment.
  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) 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03626688


Contacts
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Contact: United Therapeutics Global Medical Information 919-485-8350 clinicaltrials@unither.com

Locations
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Sponsors and Collaborators
United Therapeutics
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Responsible Party: United Therapeutics
ClinicalTrials.gov Identifier: NCT03626688    
Other Study ID Numbers: ROR-PH-301
APD811-301 ( Other Identifier: Arena Pharmaceuticals )
First Posted: August 13, 2018    Key Record Dates
Last Update Posted: October 8, 2021
Last Verified: October 2021

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by United Therapeutics:
Prostacyclin
Connective Tissue Disease-Associated
6 Minute Walk Test
6 Minute Walk Distance
Pulmonary Vascular Resistance
Right Ventricular Function
Additional relevant MeSH terms:
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Lung Diseases
Hypertension, Pulmonary
Pulmonary Arterial Hypertension
Respiratory Tract Diseases
Familial Primary Pulmonary Hypertension
Hypertension
Cardiovascular Diseases
Vascular Diseases
Connective Tissue Diseases