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

• Sponsor: United Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02279745
• Collaborator: (none)
• Enrollment: 45
• Locations: 46
• Arm: 1
• Actual Duration (Months): 68.7
• Patients Per Site: 1
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: Ralinepag	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Extension Study of Ralinepag in Patients With Pulmonary Arterial Hypertension
• Actual Study Start Date: Jul 8, 2015
• Actual Primary Completion Date: Mar 29, 2021
• Actual Study Completion Date: Mar 29, 2021

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. 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).

2. 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).

3. 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).

4. 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).

Secondary Outcome Measures

1. 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.

2. 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.

3. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35249
2	Cedars-Sinai Medical Center	Beverly Hills	California	United States	90211
3	David Geffen School of Medicine at UCLA	Los Angeles	California	United States	90095
4	University of California Davis Medical Center	Sacramento	California	United States	95817
5	Harbor-UCLA Medical Center	Torrance	California	United States	90502
6	University of Colorado Cardiac and Vascular Center, Anschutz Inpatient Pavilion	Aurora	Colorado	United States	80045
7	Cleveland Clinic Florida	Weston	Florida	United States	33331
8	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
9	Chest Medicine Associates	Portland	Maine	United States	04106
10	University of Maryland Medical Center	Baltimore	Maryland	United States	21201
11	Boston University Medical Center General Clinical Research Unit (GCRU)	Boston	Massachusetts	United States	02118
12	University of Michigan Health System	Ann Arbor	Michigan	United States	48109
13	UC Health	Cincinnati	Ohio	United States	45219
14	University Hospitals Case Medical Center	Cleveland	Ohio	United States	44106
15	The Ohio State University Wexner Medical Center - Martha Morehouse Medical Pavilion	Columbus	Ohio	United States	43221
16	UPMC, Presbyterian	Pittsburgh	Pennsylvania	United States	15229
17	UT Southwestern Medical Center	Dallas	Texas	United States	75390
18	Memorial Hermann Hospital - Texas Medical Center	Houston	Texas	United States	77030
19	St. Vincent's Hospital	Darlinghurst	New South Wales	Australia	2010
20	The Prince Charles Hospital	Chermside	Queensland	Australia	4032
21	Royal Hobart Hospital	Hobart	Tasmania	Australia	7001
22	St Vincent's Hospital	Fitzroy	Victoria	Australia	3065
23	Fiona Stanley Hospital	Murdoch		Australia	6150
24	Multiprofile Hospital for Active Treatment "National Heart Hospital" EAD, Clinic of Cardiology	Sofia		Bulgaria	1000
25	Multiprofile Hospital for Active Treatment " St. Anna", Sofia AD, Cardiology Clinic	Sofia		Bulgaria	1303
26	Department of Internal Medicine I - Cardiology, University Hospital Olomouc	Olomouc		Czechia	77900
27	Second Internal Clinic - Clinic of Cardiology and Angiology, 1st Faculty of Medicine, Charles University in Prague, General University Hospital in Prague	Prague		Czechia	12808
28	Gottsegen Gyorgy Orszagos Kardiológiai lntézet - National Institute of Cardiology, Department of Adult Cardiology	Budapest		Hungary	1051
29	Semmelweis University, Department of Pulmonology - Semmelweis Egyetem Pulmonológiai Klinika	Budapest		Hungary	1051
30	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	1051
31	University of Pecs, Medical School, Heart Institute - Pécsi Tudományegyetem, Klinikai Központ, Szívgyógyászati Klinika	Budapest		Hungary	105
32	University of Derecen Clinical Research Center Cardiology and Cardiac Surgery Department - Debreceni Egyetem Klinikai Kozpont Kardiologiai es Szivsebeszeti Klinika	Debrecen		Hungary	4032
33	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	31-202
34	Medical University of Bialystok Clinical Hospital Cardiology Clinic - Uniwersytecki Szpital Kliniczny, Klinika Kardiologii z Oddziałem Intensywnego Nadzoru Kardiologicznego	Kraków		Poland	15-276
35	Biegański Provincial Specialist Hospital Department of Cardiology - Wojewódzki Szpital Specjalistyczny im. dr Wł. Biegańskiego w Lodzi, Oddział Kardiologiczny	Lodz		Poland	90-647
36	"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	022322
37	"Marius Nasta" Institute of Pneumoftiziology, Department of Pneumoftiziology IV - Institutul de Pneumoftiziologie "Marius Nasta", Sectia Clinica Pneumoftiziologie IV	Bucharest		Romania	050159
38	"Dr. Victor Babes" Clinic Hospital for Infesctious Diseases and Pneumoftiziology, Department of Clinic Pneumology II	Timisoara		Romania	300310
39	Clinical Centre of Serbia (CCS), Cardiology Clinic - Klinicki Centar SrЬije, Klinika za kardiologiju	Belgrade		Serbia	11000
40	Кlinicko-bolnicki Centar Zemun, Кlinika za internu medicinu, Sluzba za kardiologiju	Belgrade		Serbia	11080
41	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	21204
42	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	833 48
43	Cardiology department, East Slovak Institute for Cardiovascular Diseases - Kardiologické oddelenie Klinika kardiológie , Východoslovenský ústav srdcových a cievnych chorôb, a.s	Košice		Slovakia	4011
44	Clinic Hospital of Barcelona, Department of Pneumology	Barcelona		Spain	08036
45	General University Hospital Vall d'Hebron, Department of Pneumology	Barcelona		Spain	08036
46	Hospital 12th of October, Department of Cardiology	Madrid		Spain	28041

Sponsors and Collaborators

• United Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - May 15, 2019
• Statistical Analysis Plan - Jan 12, 2021

More Information

Publications

None provided.

• Responsible Party: United Therapeutics
• ClinicalTrials.gov Identifier: NCT02279745
• Other Study ID Numbers: APD811-007
• First Posted: Oct 31, 2014
• Last Update Posted: Dec 22, 2021
• Last Verified: Nov 1, 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension

Study Results

Participant Flow

Arm/Group Title	Oral Ralinepag
Arm/Group Description	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 were provided. The starting dose and titration schedule were determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003. Subjects in the placebo treatment group in Study APD811-003 underwent a dose titration period (up to 9 weeks) with ralinepag until a stable maximum tolerated dose (MTD) was reached. Ralinepag: Active
Period Title: Overall Study
STARTED	45
COMPLETED	25
NOT COMPLETED	20

Baseline Characteristics

Arm/Group Title	Oral Ralinepag
Arm/Group Description	Ralinepag IR capsules of 10, 20, 30, 40, and 100 mcg or XR tablets of 50, 250, and 400 mcg for oral administration were provided. The starting dose and titration schedule were determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003. Subjects in the placebo treatment group in Study APD811-003 underwent a dose titration period (up to 9 weeks) with ralinepag until a stable MTD was reached. Ralinepag: Active
Overall Participants	45
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	39 86.7%
>=65 years	6 13.3%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	51.0
Sex: Female, Male (Count of Participants)
Female	39 86.7%
Male	6 13.3%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 2.2%
Not Hispanic or Latino	44 97.8%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 2.2%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 2.2%
White	42 93.3%
More than one race	0 0%
Unknown or Not Reported	1 2.2%
Time Since Pulmonary Arterial Hypertension (PAH) Diagnosis (years) [Median (Full Range) ]
Median (Full Range) [years]	2.30
Etiology of PAH (Count of Participants)
Idiopathic PAH	23 51.1%
Heritable PAH	4 8.9%
Drug or Toxin Induced PAH	2 4.4%
PAH Associated with Other Disease	16 35.6%
6-Minute Walk Distance (6MWD) at Baseline (meters) [Median (Full Range) ]
Median (Full Range) [meters]	425.0
World Health Organization (WHO) Functional Class at Baseline (Count of Participants)
I	3 6.7%
II	32 71.1%
III	10 22.2%
N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) at Baseline (pg/mL) [Median (Full Range) ]
Median (Full Range) [pg/mL]	357.60

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Pulmonary Vascular Resistance
Description	Pulmonary vascular resistance was collected by right heart catheterization (RHC).
Time Frame	At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.

Outcome Measure Data

Analysis Population Description

The number of subjects varied at post-baseline assessments due to the timing of the assessments relative to the subjects' time on study drug.

Arm/Group Title	Oral Ralinepag
Arm/Group Description	Ralinepag IR capsules of 10, 20, 30, 40, and 100 mcg or XR tablets of 50, 250, and 400 mcg for oral administration were provided. The starting dose and titration schedule were determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003. Subjects in the placebo treatment group in Study APD811-003 underwent a dose titration period (up to 9 weeks) with ralinepag until a stable MTD was reached. Ralinepag: Active
Measure Participants	31
Median (Full Range) [dynes.sec/cm5]	-52.2

2. Secondary Outcome

Title	Time From Randomization to the First Protocol-defined Clinical Worsening Event
Description	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.
Time Frame	From Baseline to 28 days following discontinuation of study drug, up to 235 weeks.

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Oral Ralinepag
Arm/Group Description	Ralinepag IR capsules of 10, 20, 30, 40, and 100 mcg or XR tablets of 50, 250, and 400 mcg for oral administration were provided. The starting dose and titration schedule were determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003. Subjects in the placebo treatment group in Study APD811-003 underwent a dose titration period (up to 9 weeks) with ralinepag until a stable MTD was reached. Ralinepag: Active
Measure Participants	45
Median (Full Range) [weeks]	56.50

3. Secondary Outcome

Title	Change From Baseline in 6MWD
Description	6MWD was measured at Baseline (prior to starting study drug) and every 3 months thereafter including the End of Study Visit.
Time Frame	From Baseline to discontinuation of study drug, up to 235 weeks

Outcome Measure Data

Analysis Population Description

The number of subjects varied from month to month based on total study population at the time of each visit.

Arm/Group Title	Oral Ralinepag
Arm/Group Description	Ralinepag IR capsules of 10, 20, 30, 40, and 100 mcg or XR tablets of 50, 250, and 400 mcg for oral administration were provided. The starting dose and titration schedule were determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003. Subjects in the placebo treatment group in Study APD811-003 underwent a dose titration period (up to 9 weeks) with ralinepag until a stable MTD was reached. Ralinepag: Active
Measure Participants	45
Month 3	20.9
Month 6	17.6
Month 9	22.8
Month 12	28.5
Month 15	16.2
Month 18	16.0
Month 21	32.0
Month 24	41.0
Month 27	38.5
Month 30	21.0
Month 33	17.0
Month 36	47.0
Month 39	24.0
Month 42	53.0
Month 45	20.5
Month 48	1.0
Month 51	-120
End of Study (Time of Discontinuation of Study by Sponsor)	37.0

4. Secondary Outcome

Title	Change From Baseline in WHO/NYHA FC
Description	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.
Time Frame	From Baseline to 28 days following discontinuation of study drug, up to 235 weeks

Outcome Measure Data

Analysis Population Description

The number of subjects varied from month to month based on total study population at the time of each visit.

Arm/Group Title	Oral Ralinepag
Arm/Group Description	Ralinepag IR capsules of 10, 20, 30, 40, and 100 mcg or XR tablets of 50, 250, and 400 mcg for oral administration were provided. The starting dose and titration schedule were determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003. Subjects in the placebo treatment group in Study APD811-003 underwent a dose titration period (up to 9 weeks) with ralinepag until a stable MTD was reached. Ralinepag: Active
Measure Participants	45
Improved	1 2.2%
No Change	43 95.6%
Deteriorated	0 0%
Improved	2 4.4%
No Change	37 82.2%
Deteriorated	3 6.7%
Improved	1 2.2%
No Change	36 80%
Deteriorated	3 6.7%
Improved	0 0%
No Change	37 82.2%
Deteriorated	2 4.4%
Improved	0 0%
No Change	33 73.3%
Deteriorated	3 6.7%
Improved	2 4.4%
No Change	31 68.9%
Deteriorated	1 2.2%
Improved	0 0%
No Change	30 66.7%
Deteriorated	4 8.9%
Improved	2 4.4%
No Change	28 62.2%
Deteriorated	3 6.7%
Improved	2 4.4%
No Change	28 62.2%
Deteriorated	2 4.4%
Improved	2 4.4%
No Change	23 51.1%
Deteriorated	4 8.9%
Improved	1 2.2%
No Change	21 46.7%
Deteriorated	3 6.7%
Improved	1 2.2%
No Change	13 28.9%
Deteriorated	2 4.4%
Improved	1 2.2%
No Change	11 24.4%
Deteriorated	1 2.2%
Improved	0 0%
No Change	10 22.2%
Deteriorated	1 2.2%
Improved	1 2.2%
No Change	6 13.3%
Deteriorated	1 2.2%
Improved	1 2.2%
No Change	4 8.9%
Deteriorated	0 0%
Improved	0 0%
No Change	2 4.4%
Deteriorated	0 0%
Improved	2 4.4%
No Change	29 64.4%
Deteriorated	4 8.9%

5. Primary Outcome

Title	Change From Baseline in Cardiac Output
Description	Cardiac output was collected by right heart catheterization (RHC).
Time Frame	At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.

Outcome Measure Data

Analysis Population Description

The number of subjects varied at post-baseline assessments due to the timing of the assessments relative to the subjects' time on study drug.

Arm/Group Title	Oral Ralinepag
Arm/Group Description	Ralinepag IR capsules of 10, 20, 30, 40, and 100 mcg or XR tablets of 50, 250, and 400 mcg for oral administration were provided. The starting dose and titration schedule were determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003. Subjects in the placebo treatment group in Study APD811-003 underwent a dose titration period (up to 9 weeks) with ralinepag until a stable MTD was reached. Ralinepag: Active
Measure Participants	31
Median (Full Range) [L/min]	-0.0

6. Primary Outcome

Title	Change From Baseline in Cardiac Index
Description	Cardiac index was collected by right heart catheterization (RHC).
Time Frame	At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.

Outcome Measure Data

Analysis Population Description

The number of subjects varied at post-baseline assessments due to the timing of the assessments relative to the subjects' time on study drug.

Arm/Group Title	Oral Ralinepag
Arm/Group Description	Ralinepag IR capsules of 10, 20, 30, 40, and 100 mcg or XR tablets of 50, 250, and 400 mcg for oral administration were provided. The starting dose and titration schedule were determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003. Subjects in the placebo treatment group in Study APD811-003 underwent a dose titration period (up to 9 weeks) with ralinepag until a stable MTD was reached. Ralinepag: Active
Measure Participants	31
Median (Full Range) [L/min/m2]	0.0

7. Primary Outcome

Title	Change From Baseline in Mean Pulmonary Arterial Pressure
Description	Mean pulmonary arterial pressure was collected by right heart catheterization (RHC).
Time Frame	At 1 or 2 years after the subject enrolled into the study, pending their last RHC prior to Protocol Amendment 2.

Outcome Measure Data

Analysis Population Description

The number of subjects varied at post-baseline assessments due to the timing of the assessments relative to the subjects' time on study drug.

Arm/Group Title	Oral Ralinepag
Arm/Group Description	Ralinepag IR capsules of 10, 20, 30, 40, and 100 mcg or XR tablets of 50, 250, and 400 mcg for oral administration were provided. The starting dose and titration schedule were determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003. Subjects in the placebo treatment group in Study APD811-003 underwent a dose titration period (up to 9 weeks) with ralinepag until a stable MTD was reached. Ralinepag: Active
Measure Participants	31
Median (Full Range) [mmHg]	-2.0

Adverse Events

Time Frame	AEs were recorded for each subject throughout the course of the study from Baseline to 28 days following discontinuation of study drug (up to 235 weeks).
Adverse Event Reporting Description	Monitoring of AEs was continued up to 30 days after cessation of study drug administration. If an AE was not resolved or stabilized within 30 days, the Sponsor in consultation with the Investigator decided whether to continue to monitor the AE or close out the event in the database if no further follow-up was necessary. Serious adverse events (SAEs) were monitored until resolution or stabilization.
Arm/Group Title	Oral Ralinepag
Arm/Group Description	Ralinepag IR capsules of 10, 20, 30, 40, and 100 mcg or XR tablets of 50, 250, and 400 mcg for oral administration were provided. The starting dose and titration schedule were determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003. Subjects in the placebo treatment group in Study APD811-003 underwent a dose titration period (up to 9 weeks) with ralinepag until a stable MTD was reached. Ralinepag: Active There was only 1 active dose group in this open-label study (oral ralinepag). Subjects included in this study received ralinepag and completed previous Study APD811-003, or received placebo and discontinued Study APD811-003 due to clinical worsening. All subjects enrolled in Study APD811-007 received open-label treatment with oral ralinepag IR or XR formulations. The starting dose and titration schedule were individually determined in accordance with the starting dose and titration schedule optimized during Study APD811 003. Adjustments in the dose and titration schedule were made according to subject tolerability.
All Cause Mortality
	Oral Ralinepag
	Affected / at Risk (%)	# Events
Total	8/45 (17.8%)
Serious Adverse Events
	Oral Ralinepag
	Affected / at Risk (%)	# Events
Total	21/45 (46.7%)
Blood and lymphatic system disorders
Anaemia	2/45 (4.4%)	2
Cardiac disorders
Right ventricular failure	6/45 (13.3%)	7
Cardiac arrest	2/45 (4.4%)	2
Arrhythmia supraventricular	1/45 (2.2%)	1
Atrial fibrillation	1/45 (2.2%)	1
Cardiac failure	2/45 (4.4%)	2
Cardiac failure congestive	1/45 (2.2%)	1
Cardiopulmonary failure	1/45 (2.2%)	1
Atrial flutter	1/45 (2.2%)	1
Gastrointestinal disorders
Haematemesis	2/45 (4.4%)	2
Abdominal distension	1/45 (2.2%)	1
Abdominal pain	1/45 (2.2%)	1
Oesophageal varices haemorrhage	1/45 (2.2%)	2
Varices oesophageal	1/45 (2.2%)	1
General disorders
Asthenia	1/45 (2.2%)	1
Chest pain	1/45 (2.2%)	1
Drug withdrawal syndrome	1/45 (2.2%)	1
Multiple organ dysfunction syndrome	1/45 (2.2%)	1
Non-cardiac chest pain	1/45 (2.2%)	1
Infections and infestations
Brain abscess	1/45 (2.2%)	1
COVID-19	1/45 (2.2%)	1
COVID-19 pneumonia	1/45 (2.2%)	1
Clostridium difficile infection	1/45 (2.2%)	1
Device related sepsis	1/45 (2.2%)	1
Gastroenteritis viral	1/45 (2.2%)	1
Pneumonia	2/45 (4.4%)	3
Injury, poisoning and procedural complications
Foot fracture	1/45 (2.2%)	1
Head injury	1/45 (2.2%)	1
Metabolism and nutrition disorders
Hyponatraemia	1/45 (2.2%)	1
Musculoskeletal and connective tissue disorders
Myositis	1/45 (2.2%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Benign breast neoplasm	1/45 (2.2%)	1
Breast cancer in situ	1/45 (2.2%)	1
Nervous system disorders
Epilepsy	1/45 (2.2%)	2
Syncope	1/45 (2.2%)	1
Renal and urinary disorders
Acute kidney injury	1/45 (2.2%)	1
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/45 (2.2%)	1
Haemoptysis	1/45 (2.2%)	1
Pleural effusion	1/45 (2.2%)	1
Pneumonia aspiration	1/45 (2.2%)	1
Pulmonary infarction	1/45 (2.2%)	1
Pulmonary arterial hypertension	2/45 (4.4%)	2
Vascular disorders
Hypotension	1/45 (2.2%)	1
Deep vein thrombosis	1/45 (2.2%)	1
Other (Not Including Serious) Adverse Events
	Oral Ralinepag
	Affected / at Risk (%)	# Events
Total	45/45 (100%)
Blood and lymphatic system disorders
Anaemia	8/45 (17.8%)	12
Cardiac disorders
Palpitations	5/45 (11.1%)	5
Right ventricular failure	6/45 (13.3%)	8
Cardiac failure	4/45 (8.9%)	4
Gastrointestinal disorders
Diarrhoea	17/45 (37.8%)	27
Nausea	14/45 (31.1%)	25
Vomiting	5/45 (11.1%)	7
Abdominal pain	3/45 (6.7%)	4
General disorders
Fatigue	7/45 (15.6%)	8
Oedema peripheral	4/45 (8.9%)	4
Non-cardiac chest pain	3/45 (6.7%)	3
Infections and infestations
Influenza	3/45 (6.7%)	3
Pneumonia	4/45 (8.9%)	5
Bronchitis	3/45 (6.7%)	3
Lower respiratory tract infection	4/45 (8.9%)	6
Urinary tract infection	4/45 (8.9%)	7
Respiratory tract infection	3/45 (6.7%)	3
Upper respiratory tract infection	5/45 (11.1%)	6
Investigations
N-terminal prohormone brain natriuretic peptide increased	6/45 (13.3%)	10
Metabolism and nutrition disorders
Hyperkalaemia	3/45 (6.7%)	3
Hypokalaemia	3/45 (6.7%)	3
Iron deficiency	5/45 (11.1%)	5
Musculoskeletal and connective tissue disorders
Pain in jaw	15/45 (33.3%)	20
Myalgia	12/45 (26.7%)	23
Arthralgia	7/45 (15.6%)	8
Pain in extremity	7/45 (15.6%)	13
Back pain	3/45 (6.7%)	3
Muscle spasms	5/45 (11.1%)	6
Nervous system disorders
Headache	29/45 (64.4%)	60
Dizziness	8/45 (17.8%)	15
Syncope	3/45 (6.7%)	5
Presyncope	3/45 (6.7%)	3
Psychiatric disorders
Anxiety	3/45 (6.7%)	3
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	4/45 (8.9%)	4
Dyspnoea	4/45 (8.9%)	4
Pulmonary arterial hypertension	3/45 (6.7%)	3
Skin and subcutaneous tissue disorders
Pruritus	4/45 (8.9%)	4
Vascular disorders
Flushing	12/45 (26.7%)	16
Hypotension	6/45 (13.3%)	6

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.