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

Pulmonary Arterial Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02279745
• Other study ID #: APD811-007
• Status: Completed
• Phase: Phase 2
• Start date: July 8, 2015
• Est. completion date: March 29, 2021

Study information

• Verified date: November 2021
• Source: United Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 45
• Est. completion date: March 29, 2021
• Est. primary completion date: March 29, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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.

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Ralinepag
Active

Locations

Country	Name	City	State
Australia	The Prince Charles Hospital	Chermside	Queensland
Australia	St. Vincent's Hospital	Darlinghurst	New South Wales
Australia	St Vincent's Hospital	Fitzroy	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Fiona Stanley Hospital	Murdoch
Bulgaria	Multiprofile Hospital for Active Treatment " St. Anna", Sofia AD, Cardiology Clinic	Sofia
Bulgaria	Multiprofile Hospital for Active Treatment "National Heart Hospital" EAD, Clinic of Cardiology	Sofia
Czechia	Department of Internal Medicine I - Cardiology, University Hospital Olomouc	Olomouc
Czechia	Second Internal Clinic - Clinic of Cardiology and Angiology, 1st Faculty of Medicine, Charles University in Prague, General University Hospital in Prague	Prague
Hungary	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 Pecs, Medical School, Heart Institute - Pécsi Tudományegyetem, Klinikai Központ, Szívgyógyászati 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
Poland	John Paul II Hospital in Cracov Department of Cardiac and Vascular Diseases - Krakowski Szpital Specjalistyczny im. Jana Pawla II, Oddzial Kliniczny Chorób Serca i Naczyn	Krakow
Poland	Medical University of Bialystok Clinical Hospital Cardiology Clinic - Uniwersytecki Szpital Kliniczny, Klinika Kardiologii z Oddzialem Intensywnego Nadzoru Kardiologicznego	Kraków
Poland	Bieganski Provincial Specialist Hospital Department of Cardiology - Wojewódzki Szpital Specjalistyczny im. dr Wl. Bieganskiego w Lodzi, Oddzial Kardiologiczny	Lodz
Romania	"Marius Nasta" Institute of Pneumoftiziology, Department of Pneumoftiziology IV - Institutul de Pneumoftiziologie "Marius Nasta", Sectia Clinica Pneumoftiziologie IV	Bucharest
Romania	"Prof. Dr. C.C. Iliescu" Institute of Cardiovascular Diseases, Department of Clinic Cardiology III - Institutul de Urgenta pentru Boli Cardiovasculare "Prof. Dr. C.C. Iliescu", Sectia Clinica Cardiologie fIJ	Bucharest
Romania	"Dr. Victor Babes" Clinic Hospital for Infesctious Diseases and Pneumoftiziology, Department of Clinic Pneumology II	Timisoara
Serbia	?linicko-bolnicki Centar Zemun, ?linika za internu medicinu, Sluzba za kardiologiju	Belgrade
Serbia	Clinical Centre of Serbia (CCS), Cardiology Clinic - Klinicki Centar Sr?ije, Klinika za kardiologiju	Belgrade
Serbia	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
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	Cardiology department, East Slovak Institute for Cardiovascular Diseases - Kardiologické oddelenie Klinika kardiológie , Východoslovenský ústav srdcových a cievnych chorôb, a.s	Košice
Spain	Clinic Hospital of Barcelona, Department of Pneumology	Barcelona
Spain	General University Hospital Vall d'Hebron, Department of Pneumology	Barcelona
Spain	Hospital 12th of October, Department of Cardiology	Madrid
United States	University of Michigan Health System	Ann Arbor	Michigan
United States	University of Colorado Cardiac and Vascular Center, Anschutz Inpatient Pavilion	Aurora	Colorado
United States	University of Maryland Medical Center	Baltimore	Maryland
United States	Cedars-Sinai Medical Center	Beverly Hills	California
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston University Medical Center General Clinical Research Unit (GCRU)	Boston	Massachusetts
United States	UC Health	Cincinnati	Ohio
United States	University Hospitals Case Medical Center	Cleveland	Ohio
United States	The Ohio State University Wexner Medical Center - Martha Morehouse Medical Pavilion	Columbus	Ohio
United States	UT Southwestern Medical Center	Dallas	Texas
United States	Memorial Hermann Hospital - Texas Medical Center	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	David Geffen School of Medicine at UCLA	Los Angeles	California
United States	UPMC, Presbyterian	Pittsburgh	Pennsylvania
United States	Chest Medicine Associates	Portland	Maine
United States	University of California Davis Medical Center	Sacramento	California
United States	Harbor-UCLA Medical Center	Torrance	California
United States	Cleveland Clinic Florida	Weston	Florida

Sponsors (1)

Lead Sponsor	Collaborator
United Therapeutics

Countries where clinical trial is conducted

United States,  Australia,  Bulgaria,  Czechia,  Hungary,  Poland,  Romania,  Serbia,  Slovakia,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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.
Primary	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.
Primary	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	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.
Secondary	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
Secondary	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