Long-term Safety and Efficacy of Ralinepag in Pulmonary Arterial Hypertension

An Open-label Extension Study of Ralinepag in Patients With Pulmonary Arterial Hypertension

This study was an open-label extension study to determine the long-term safety and tolerability of ralinepag in subjects with World Health Organization (WHO) Group 1 pulmonary arterial hypertension (PAH) who have completed Study APD811-003, or who were assigned to receive placebo and were discontinued due to clinical worsening.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Ralinepag

Detailed Description

This study was an open-label extension study to determine the long-term safety and tolerability of ralinepag in subjects with WHO Group 1 PAH who completed Study APD811-003. Subjects who completed Study APD811-003 and met eligibility criteria for Study APD811-007 were enrolled. Additionally, placebo-treated subjects who discontinued study drug treatment due to clinical worsening in Study APD811-003 were permitted to enroll in Study APD811-007, upon approval of the medical monitor, provided that all end of study procedures including right heart catheterization (RHC) were performed per the study protocol. The Week 25 Visit in Study APD811-003 served as the Baseline Visit for Study APD811-007.

All subjects enrolled in Study APD811-007 received open-label treatment with ralinepag. The starting dose and titration schedule were individually determined and in accordance with the starting dose and titration schedule optimized from Study APD811-003. Adjustments in the dose and titration schedule were made according to subject tolerability.

After an individual subject completed Study APD811-003 and that subject's database was locked, subject unblinding occurred. Subjects on active treatment (ralinepag) remained on their current dose and had onsite clinical assessments performed every 3 months until the subject was discontinued from the study.

Subjects in the placebo treatment group underwent a dose titration period until a stable, maximum tolerated dose (MTD) was reached (up to 9 weeks), followed by a treatment period after the MTD was determined during which monthly onsite clinic assessments were performed for the first 3 months and then every 3 months until the subject was discontinued from the study or the study was terminated. Dose reductions could be made at any time for safety reasons. Incremental dose increases were also allowed during the Treatment Period at the discretion of the Investigator (as clinically indicated) and according to the stepwise titration scheme.

Subjects were assessed for clinical worsening during each clinic visit. If clinical worsening was confirmed, the Investigator could have opted to either continue treatment with ralinepag at the current dose, increase the dose of ralinepag, interrupt treatment, or discontinue the subject at his/her discretion.

In addition, attempts were made to contact all subjects at the time of Study APD811-007 termination to assess their vital (mortality) status. After the last subject enrolled in Study APD811-007 completed approximately 6 months of the study, a cumulative all-subject data analysis was performed for all subjects who entered the study. Subjects continued to have visits to the clinic every 3 months until the Sponsor discontinued the study. At the time of the Sponsor's decision to discontinue the study, all ongoing subjects completed an End of Study Visit. A 28-day Follow-up Visit was conducted to ensure appropriate subject safety. Subjects who remained on ralinepag were eligible to transition into the Phase 3 open-label extension study (ROR-PH-303) prior to APD811-007 study termination. For those subjects that did not enroll in Study ROR-PH-303, a 28-day Follow-up Visit was conducted to evaluate ongoing subject safety, including survival status.

• Study Type: Interventional
• Enrollment (Actual): 45
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Murdoch, Australia, 6150
    • Fiona Stanley Hospital
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St. Vincent's Hospital
  • Queensland
    • Chermside, Queensland, Australia, 4032
      • The Prince Charles Hospital
  • Tasmania
    • Hobart, Tasmania, Australia, 7001
      • Royal Hobart Hospital
  • Victoria
    • Fitzroy, Victoria, Australia, 3065
      • St Vincent's Hospital
• Bulgaria
  • Sofia, Bulgaria, 1000
    • Multiprofile Hospital for Active Treatment "National Heart Hospital" EAD, Clinic of Cardiology
  • Sofia, Bulgaria, 1303
    • Multiprofile Hospital for Active Treatment " St. Anna", Sofia AD, Cardiology Clinic
• Czechia
  • Olomouc, Czechia, 77900
    • Department of Internal Medicine I - Cardiology, University Hospital Olomouc
  • Prague, Czechia, 12808
    • Second Internal Clinic - Clinic of Cardiology and Angiology, 1st Faculty of Medicine, Charles University in Prague, General University Hospital in Prague
• Hungary
  • Budapest, Hungary, 1051
    • Gottsegen Gyorgy Orszagos Kardiológiai lntézet - National Institute of Cardiology, Department of Adult Cardiology
  • Budapest, Hungary, 1051
    • Semmelweis University, Department of Pulmonology - Semmelweis Egyetem Pulmonológiai Klinika
  • Budapest, Hungary, 1051
    • University of Szeged Faculty of Medicine, 2nd Department of Medicine and Cardiology Center, Albert Szent-Györyi Clinical Center - SZTE ÁOK Szent-Györgyi A lbert Klinikai Központ I I. sz. Belgyógyászati Klini ka és Kard ilógiai Központ
  • Budapest, Hungary, 105
    • University of Pecs, Medical School, Heart Institute - Pécsi Tudományegyetem, Klinikai Központ, Szívgyógyászati Klinika
  • Debrecen, Hungary, 4032
    • University of Derecen Clinical Research Center Cardiology and Cardiac Surgery Department - Debreceni Egyetem Klinikai Kozpont Kardiologiai es Szivsebeszeti Klinika
• Poland
  • Krakow, Poland, 31-202
    • John Paul II Hospital in Cracov Department of Cardiac and Vascular Diseases - Krakowski Szpital Specjalistyczny im. Jana Pawła II, Oddział Kliniczny Chorób Serca i Naczyń
  • Kraków, Poland, 15-276
    • Medical University of Bialystok Clinical Hospital Cardiology Clinic - Uniwersytecki Szpital Kliniczny, Klinika Kardiologii z Oddziałem Intensywnego Nadzoru Kardiologicznego
  • Lodz, Poland, 90-647
    • Biegański Provincial Specialist Hospital Department of Cardiology - Wojewódzki Szpital Specjalistyczny im. dr Wł. Biegańskiego w Lodzi, Oddział Kardiologiczny
• Romania
  • Bucharest, Romania, 022322
    • "Prof. Dr. C.C. Iliescu" Institute of Cardiovascular Diseases, Department of Clinic Cardiology III - Institutul de Urgenţă pentru Boli Cardiovasculare "Prof. Dr. C.C. Iliescu", Secţia Clinica Cardiologie fIJ
  • Bucharest, Romania, 050159
    • "Marius Nasta" Institute of Pneumoftiziology, Department of Pneumoftiziology IV - Institutul de Pneumoftiziologie "Marius Nasta", Sectia Clinica Pneumoftiziologie IV
  • Timisoara, Romania, 300310
    • "Dr. Victor Babes" Clinic Hospital for Infesctious Diseases and Pneumoftiziology, Department of Clinic Pneumology II
• Serbia
  • Belgrade, Serbia, 11000
    • Clinical Centre of Serbia (CCS), Cardiology Clinic - Klinicki Centar SrЬije, Klinika za kardiologiju
  • Belgrade, Serbia, 11080
    • Кlinicko-bolnicki Centar Zemun, Кlinika za internu medicinu, Sluzba za kardiologiju
  • Sremska Kamenica, Serbia, 21204
    • Institut za plucne bolesti Vojvodine Sremska Kamenica, Klinika za urgcntnu pulmologiju, Odeljcnje intenzivne nege - Institute of Pulmonary Diseases of Vojvodina Sremska Kamenica (IPDVSK), The Clinic for Urgent Pulmonology, ICU - Intensive Care Unit
• Slovakia
  • Bratislava, Slovakia, 833 48
    • Department of Heart Failure and Transplantation, National Institute of Cardiovascular Diseases - Oddelenie zlyhávania a transplantácie srdca, Národný ústav srdcových a cievnych chorôb, a.s.
  • Košice, Slovakia, 4011
    • Cardiology department, East Slovak Institute for Cardiovascular Diseases - Kardiologické oddelenie Klinika kardiológie , Východoslovenský ústav srdcových a cievnych chorôb, a.s
• Spain
  • Barcelona, Spain, 08036
    • Clinic Hospital of Barcelona, Department of Pneumology
  • Barcelona, Spain, 08036
    • General University Hospital Vall d'Hebron, Department of Pneumology
  • Madrid, Spain, 28041
    • Hospital 12th of October, Department of Cardiology
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35249
      • University of Alabama at Birmingham
  • California
    • Beverly Hills, California, United States, 90211
      • Cedars-Sinai Medical Center
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA
    • Sacramento, California, United States, 95817
      • University of California Davis Medical Center
    • Torrance, California, United States, 90502
      • Harbor-UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Cardiac and Vascular Center, Anschutz Inpatient Pavilion
  • Florida
    • Weston, Florida, United States, 33331
      • Cleveland Clinic Florida
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa Hospitals and Clinics
  • Maine
    • Portland, Maine, United States, 04106
      • Chest Medicine Associates
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland Medical Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University Medical Center General Clinical Research Unit (GCRU)
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
  • Ohio
    • Cincinnati, Ohio, United States, 45219
      • UC Health
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Case Medical Center
    • Columbus, Ohio, United States, 43221
      • The Ohio State University Wexner Medical Center - Martha Morehouse Medical Pavilion
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15229
      • UPMC, Presbyterian
  • Texas
    • Dallas, Texas, United States, 75390
      • UT Southwestern Medical Center
    • Houston, Texas, United States, 77030
      • Memorial Hermann Hospital - Texas Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Evidence of a personally signed and dated informed consent document.
• Was willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures and was deemed an appropriate candidate for participation in a long-term extension study.
• Female subjects were nonpregnant, nonlactating, surgically sterile or postmenopausal, or agreed to use an accepted method of birth control for at least 3 months prior to the first dose, during, and for at least 30 days after the last dose of study drug.
• Male subjects were either surgically sterile or agreed to use a condom with spermicide when sexually active with a female partner who was not using an acceptable method of birth control during the study and for 30 days after the last dose of study drug.
• Male and female subjects agreed not to participate in a conception process during the study and for 30 days after the last dose of study drug.
• Fulfilled all eligibility criteria for Study APD811-003 and completed the study as planned.

Subjects who were assigned to placebo in Study APD811-003 and experienced clinical worsening in that study could enroll in Study APD811-007 after completing all end of study procedures per protocol, including RHC, for Study APD811-003 and had their data locked.

Exclusion Criteria:

• Subjects who enrolled in Study APD811-003 and were withdrawn from study drug treatment due to any adverse event (AE), serious adverse event (SAE), or subjects who did not complete Study APD811003, with the exception made for placebo-treated subjects who experienced a clinical worsening event.
• Female •subjects who wished to become pregnant.
• Systolic blood pressure <90 mmHg at Baseline.
• Other severe acute or chronic medical or laboratory abnormalities that could have increased the risk associated with study participation or investigational product administration or interfered with the interpretation of study results and, in the judgment of the investigator, would have made the subject inappropriate for entry into this study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral Ralinepag; Ralinepag immediate-release (IR) capsules of 10, 20, 30, 40, and 100 mcg or extended-release (XR) tablets of 50, 250, and 400 mcg for oral administration.	Drug: Ralinepag; Active; Other Names: APD811

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Pulmonary Vascular Resistance	Pulmonary vascular resistance was collected by right heart catheterization (RHC).	At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.
Change From Baseline in Cardiac Output	Cardiac output was collected by right heart catheterization (RHC).	At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.
Change From Baseline in Cardiac Index	Cardiac index was collected by right heart catheterization (RHC).	At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.
Change From Baseline in Mean Pulmonary Arterial Pressure	Mean pulmonary arterial pressure was collected by right heart catheterization (RHC).	At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time From Randomization to the First Protocol-defined Clinical Worsening Event	Clinical worsening events were defined as death, or onset of a treatment-emergent adverse event (AE) with a fatal outcome occurring ≤14 days after treatment discontinuation; hospitalization for worsening PAH, heart-lung or lung transplant, or atrial septostomy; necessity of addition (or dose change) of any prostacyclin/prostacyclin analogue, phosphodiesterase type 5 inhibitor (PDE5-I) or soluble guanylate cyclase (sGC), or endothelin receptor antagonist (ERA); and the combined occurrence of a decrease in 6-Minute Walk Distance (6MWD) by at least 20% from Baseline, confirmed on two 6-Minute Walk Tests (6MWTs) on different days; worsening in WHO/New York Heart Association (NYHA) Functional Class (FC) from Baseline; and appearance of or worsening of signs/symptoms of right heart failure that did not respond to optimized oral diuretic therapy.	From Baseline to 28 days following discontinuation of study drug, up to 235 weeks.
Change From Baseline in 6MWD	6MWD was measured at Baseline (prior to starting study drug) and every 3 months thereafter including the End of Study Visit.	From Baseline to discontinuation of study drug, up to 235 weeks
Change From Baseline in WHO/NYHA FC	WHO/NYHA FC was measured at Baseline (prior to starting study drug) and every 3 months thereafter including at the End of Study and 28-Day Follow-up Visits. FC recorded as I, II, III, or IV based on the following: I: PH but without limitation of physical activity; physical activity without undue dyspnea or fatigue, chest pain or near syncope. II: PH with slight limitation of physical activity; physical activity causes undue dyspnea or fatigue, chest pain or near syncope. III: PH with marked limitation of physical activity; less than ordinary activity causes undue dyspnea or fatigue, chest pain or near syncope. IV: PH with inability to carry out any physical activity without symptoms. Signs of right heart failure. Dyspnea and/or fatigue at rest. Discomfort is increased by any physical activity.	From Baseline to 28 days following discontinuation of study drug, up to 235 weeks

Collaborators and Investigators

• Sponsor: United Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): July 8, 2015
• Primary Completion (Actual): March 29, 2021
• Study Completion (Actual): March 29, 2021

Study Registration Dates

• First Submitted: October 25, 2014
• First Submitted That Met QC Criteria: October 29, 2014
• First Posted (Estimate): October 31, 2014

Study Record Updates

• Last Update Posted (Actual): December 22, 2021
• Last Update Submitted That Met QC Criteria: November 23, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: APD811-007

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No