Clinical trial NCT02279745: Long-term Safety and Efficacy of Ralinepag in Pulmonary Arterial Hypertension
Official title: An Open-label Extension Study of Ralinepag in Patients With Pulmonary Arterial Hypertension
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: United Therapeutics
Sponsor class: INDUSTRY
First posted: 2014-10-31
Enrollment: 45
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in Pulmonary Vascular Resistance
timeFrame: At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.
measure: Change From Baseline in Cardiac Output
timeFrame: At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.
measure: Change From Baseline in Cardiac Index
timeFrame: At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.
measure: Change From Baseline in Mean Pulmonary Arterial Pressure
timeFrame: At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.
Secondary outcomes:
measure: Time From Randomization to the First Protocol-defined Clinical Worsening Event
timeFrame: From Baseline to 28 days following discontinuation of study drug, up to 235 weeks.
measure: Change From Baseline in 6MWD
timeFrame: From Baseline to discontinuation of study drug, up to 235 weeks
measure: Change From Baseline in WHO/NYHA FC
timeFrame: From Baseline to 28 days following discontinuation of study drug, up to 235 weeks
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Beverly Hills
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA
state: California
city: Sacramento
country: United States
facility: University of California Davis Medical Center
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cardiac and Vascular Center, Anschutz Inpatient Pavilion
state: Colorado
city: Weston
country: United States
facility: Cleveland Clinic Florida
state: Florida
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Portland
country: United States
facility: Chest Medicine Associates
state: Maine
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Boston
country: United States
facility: Boston University Medical Center General Clinical Research Unit (GCRU)
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan Health System
state: Michigan
city: Cincinnati
country: United States
facility: UC Health
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals Case Medical Center
state: Ohio
city: Columbus
country: United States
facility: The Ohio State University Wexner Medical Center - Martha Morehouse Medical Pavilion
state: Ohio
city: Pittsburgh
country: United States
facility: UPMC, Presbyterian
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Memorial Hermann Hospital - Texas Medical Center
state: Texas
city: Darlinghurst
country: Australia
facility: St. Vincent's Hospital
state: New South Wales
city: Chermside
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Hobart
country: Australia
facility: Royal Hobart Hospital
state: Tasmania
city: Fitzroy
country: Australia
facility: St Vincent's Hospital
state: Victoria
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
city: Sofia
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment "National Heart Hospital" EAD, Clinic of Cardiology
city: Sofia
country: Bulgaria
facility: Multiprofile Hospital for Active Treatment " St. Anna", Sofia AD, Cardiology Clinic
city: Olomouc
country: Czechia
facility: Department of Internal Medicine I - Cardiology, University Hospital Olomouc
city: Prague
country: Czechia
facility: Second Internal Clinic - Clinic of Cardiology and Angiology, 1st Faculty of Medicine, Charles University in Prague, General University Hospital in Prague
city: Budapest
country: Hungary
facility: Gottsegen Gyorgy Orszagos Kardiológiai lntézet - National Institute of Cardiology, Department of Adult Cardiology
city: Budapest
country: Hungary
facility: Semmelweis University, Department of Pulmonology - Semmelweis Egyetem Pulmonológiai Klinika
city: Budapest
country: Hungary
facility: 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
city: Budapest
country: Hungary
facility: University of Pecs, Medical School, Heart Institute - Pécsi Tudományegyetem, Klinikai Központ, Szívgyógyászati Klinika
city: Debrecen
country: Hungary
facility: University of Derecen Clinical Research Center Cardiology and Cardiac Surgery Department - Debreceni Egyetem Klinikai Kozpont Kardiologiai es Szivsebeszeti Klinika
city: Krakow
country: Poland
facility: 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
city: Kraków
country: Poland
facility: Medical University of Bialystok Clinical Hospital Cardiology Clinic - Uniwersytecki Szpital Kliniczny, Klinika Kardiologii z Oddziałem Intensywnego Nadzoru Kardiologicznego
city: Lodz
country: Poland
facility: Biegański Provincial Specialist Hospital Department of Cardiology - Wojewódzki Szpital Specjalistyczny im. dr Wł. Biegańskiego w Lodzi, Oddział Kardiologiczny
city: Bucharest
country: Romania
facility: "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
city: Bucharest
country: Romania
facility: "Marius Nasta" Institute of Pneumoftiziology, Department of Pneumoftiziology IV - Institutul de Pneumoftiziologie "Marius Nasta", Sectia Clinica Pneumoftiziologie IV
city: Timisoara
country: Romania
facility: "Dr. Victor Babes" Clinic Hospital for Infesctious Diseases and Pneumoftiziology, Department of Clinic Pneumology II
city: Belgrade
country: Serbia
facility: Clinical Centre of Serbia (CCS), Cardiology Clinic - Klinicki Centar SrЬije, Klinika za kardiologiju
city: Belgrade
country: Serbia
facility: Кlinicko-bolnicki Centar Zemun, Кlinika za internu medicinu, Sluzba za kardiologiju
city: Sremska Kamenica
country: Serbia
facility: 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
city: Bratislava
country: Slovakia
facility: Department of Heart Failure and Transplantation, National Institute of Cardiovascular Diseases - Oddelenie zlyhávania a transplantácie srdca, Národný ústav srdcových a cievnych chorôb, a.s.
city: Košice
country: Slovakia
facility: Cardiology department, East Slovak Institute for Cardiovascular Diseases - Kardiologické oddelenie Klinika kardiológie , Východoslovenský ústav srdcových a cievnych chorôb, a.s
city: Barcelona
country: Spain
facility: Clinic Hospital of Barcelona, Department of Pneumology
city: Barcelona
country: Spain
facility: General University Hospital Vall d'Hebron, Department of Pneumology
city: Madrid
country: Spain
facility: Hospital 12th of October, Department of Cardiology
Study officials:
References: