Long-term Safety and Efficacy of Ralinepag in Pulmonary Arterial Hypertension
- Registration Number
- NCT02279745
- Lead Sponsor
- United Therapeutics
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 45
- 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.
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Oral Ralinepag 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.
- Primary Outcome Measures
Name Time Method Change From Baseline in Pulmonary Vascular Resistance At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2. Pulmonary vascular resistance was collected by right heart catheterization (RHC).
Change From Baseline in Cardiac Output At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2. Cardiac output was collected by right heart catheterization (RHC).
Change From Baseline in Mean Pulmonary Arterial Pressure At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2. Mean pulmonary arterial pressure was collected by right heart catheterization (RHC).
Change From Baseline in Cardiac Index At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2. Cardiac index was collected by right heart catheterization (RHC).
- Secondary Outcome Measures
Name Time Method Time From Randomization to the First Protocol-defined Clinical Worsening Event From Baseline to 28 days following discontinuation of study drug, up to 235 weeks. 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.
Change From Baseline in 6MWD From Baseline to discontinuation of study drug, up to 235 weeks 6MWD was measured at Baseline (prior to starting study drug) and every 3 months thereafter including the End of Study Visit.
Change From Baseline in WHO/NYHA FC From Baseline to 28 days following discontinuation of study drug, up to 235 weeks 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.
Trial Locations
- Locations (46)
David Geffen School of Medicine at UCLA
🇺🇸Los Angeles, California, United States
St Vincent's Hospital
🇦🇺Fitzroy, Victoria, Australia
Multiprofile Hospital for Active Treatment "National Heart Hospital" EAD, Clinic of Cardiology
🇧🇬Sofia, Bulgaria
University of Michigan Health System
🇺🇸Ann Arbor, Michigan, United States
University of Pecs, Medical School, Heart Institute - Pécsi Tudományegyetem, Klinikai Központ, Szívgyógyászati Klinika
🇭🇺Budapest, Hungary
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
🇵🇱Krakow, Poland
"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
UC Health
🇺🇸Cincinnati, Ohio, United States
Memorial Hermann Hospital - Texas Medical Center
🇺🇸Houston, Texas, United States
Cedars-Sinai Medical Center
🇺🇸Beverly Hills, California, United States
University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States
Harbor-UCLA Medical Center
🇺🇸Torrance, California, United States
University of Colorado Cardiac and Vascular Center, Anschutz Inpatient Pavilion
🇺🇸Aurora, Colorado, United States
University of California Davis Medical Center
🇺🇸Sacramento, California, United States
Cleveland Clinic Florida
🇺🇸Weston, Florida, United States
Chest Medicine Associates
🇺🇸Portland, Maine, United States
University of Iowa Hospitals and Clinics
🇺🇸Iowa City, Iowa, United States
University of Maryland Medical Center
🇺🇸Baltimore, Maryland, United States
Boston University Medical Center General Clinical Research Unit (GCRU)
🇺🇸Boston, Massachusetts, United States
The Ohio State University Wexner Medical Center - Martha Morehouse Medical Pavilion
🇺🇸Columbus, Ohio, United States
University Hospitals Case Medical Center
🇺🇸Cleveland, Ohio, United States
UPMC, Presbyterian
🇺🇸Pittsburgh, Pennsylvania, United States
UT Southwestern Medical Center
🇺🇸Dallas, Texas, United States
St. Vincent's Hospital
🇦🇺Darlinghurst, New South Wales, Australia
The Prince Charles Hospital
🇦🇺Chermside, Queensland, Australia
Royal Hobart Hospital
🇦🇺Hobart, Tasmania, Australia
Fiona Stanley Hospital
🇦🇺Murdoch, Australia
Department of Internal Medicine I - Cardiology, University Hospital Olomouc
🇨🇿Olomouc, Czechia
Multiprofile Hospital for Active Treatment " St. Anna", Sofia AD, Cardiology Clinic
🇧🇬Sofia, Bulgaria
Second Internal Clinic - Clinic of Cardiology and Angiology, 1st Faculty of Medicine, Charles University in Prague, General University Hospital in Prague
🇨🇿Prague, Czechia
Gottsegen Gyorgy Orszagos Kardiológiai lntézet - National Institute of Cardiology, Department of Adult Cardiology
🇭🇺Budapest, Hungary
Semmelweis University, Department of Pulmonology - Semmelweis Egyetem Pulmonológiai Klinika
🇭🇺Budapest, Hungary
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
University of Derecen Clinical Research Center Cardiology and Cardiac Surgery Department - Debreceni Egyetem Klinikai Kozpont Kardiologiai es Szivsebeszeti Klinika
🇭🇺Debrecen, Hungary
Biegański Provincial Specialist Hospital Department of Cardiology - Wojewódzki Szpital Specjalistyczny im. dr Wł. Biegańskiego w Lodzi, Oddział Kardiologiczny
🇵🇱Lodz, Poland
Medical University of Bialystok Clinical Hospital Cardiology Clinic - Uniwersytecki Szpital Kliniczny, Klinika Kardiologii z Oddziałem Intensywnego Nadzoru Kardiologicznego
🇵🇱Kraków, Poland
"Marius Nasta" Institute of Pneumoftiziology, Department of Pneumoftiziology IV - Institutul de Pneumoftiziologie "Marius Nasta", Sectia Clinica Pneumoftiziologie IV
🇷🇴Bucharest, Romania
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
🇷🇸Sremska Kamenica, Serbia
Clinical Centre of Serbia (CCS), Cardiology Clinic - Klinicki Centar SrЬije, Klinika za kardiologiju
🇷🇸Belgrade, Serbia
Кlinicko-bolnicki Centar Zemun, Кlinika za internu medicinu, Sluzba za kardiologiju
🇷🇸Belgrade, Serbia
"Dr. Victor Babes" Clinic Hospital for Infesctious Diseases and Pneumoftiziology, Department of Clinic Pneumology II
🇷🇴Timisoara, Romania
Cardiology department, East Slovak Institute for Cardiovascular Diseases - Kardiologické oddelenie Klinika kardiológie , Východoslovenský ústav srdcových a cievnych chorôb, a.s
🇸🇰Košice, Slovakia
Department of Heart Failure and Transplantation, National Institute of Cardiovascular Diseases - Oddelenie zlyhávania a transplantácie srdca, Národný ústav srdcových a cievnych chorôb, a.s.
🇸🇰Bratislava, Slovakia
Hospital 12th of October, Department of Cardiology
🇪🇸Madrid, Spain
Clinic Hospital of Barcelona, Department of Pneumology
🇪🇸Barcelona, Spain
General University Hospital Vall d'Hebron, Department of Pneumology
🇪🇸Barcelona, Spain