Safety and Efficacy of APD811 in Pulmonary Arterial Hypertension

• Sponsor: United Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02279160
• Collaborator: (none)
• Enrollment: 61
• Locations: 35
• Arms: 2
• Duration (Months): 30
• Patients Per Site: 1.7
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The study was conducted as a placebo-controlled, randomized, 22-week double-blind study which included a dose titration period. An additional transition period occurred for those patients who elected to enroll into the open-label extension study, APD811-007. A total of 61 patients with PAH were enrolled.

Condition or Disease	Intervention/Treatment	Phase
Pulmonary Arterial Hypertension	Drug: APD811; Drug: Placebo	Phase 2

Detailed Description

Study APD811-003 was a 22-week, randomized, double-blind, parallel-group, placebo-controlled study in subjects with symptomatic WHO Group 1 PAH. The study consisted of a dose titration period of up to 9 weeks, a 13-week maintenance period, and a follow-up visit that was to occur approximately 3 weeks after the end of the maintenance period (Week 25). The transition period of 3 weeks (±1 week) was to occur for those subjects who elected to enroll into the open-label extension (OLE) Study APD811-007.

Approximately 60 subjects with PAH were planned to be enrolled (61 actual). After screening, eligible subjects were randomized 2:1 to ralinepag (APD811) or to placebo. Randomization was stratified by baseline WHO/NYHA functional class (II versus III or IV). Subjects randomized to active therapy were given ralinepag at a starting dose of 0.01 mg BID. Subjects randomized to the placebo arm received matching placebo capsules to preserve the blind. Subjects were instructed to take the study drug (ralinepag or placebo) with food. Dosage was then uptitrated, as tolerated, over the course of the 9-week dose-titration period to a maximum dose of 0.3 mg BID. Although doses could be reduced based on tolerability, the final dosage reached was required to be stable during the 13-week treatment period prior to evaluation at Week 22.

Subjects could receive concomitant oral disease-specific PAH therapy consisting of an ERA and/or an agent acting on the nitric oxide pathway, a PDE-5 inhibitor or a sGC stimulator, provided the dose had remained stable for at least 3 months prior to the start of screening. It was recommended that subjects continue the same dose and regimen of these medications for the duration of the study. With the exception of prostanoids, the use of other supporting therapies, which may affect PAH, was also permitted.

During the study, assessments of efficacy were performed including PVR and other hemodynamic parameters as determined by RHC, the 6MWT, assessment of clinical worsening, BNP and NT-proBNP levels, WHO/NYHA functional class assessment of PAH. Safety assessments included standard evaluations of AEs, clinical laboratory values, vital signs, and ECG measurements.

At the end of the maintenance period, subjects who did not choose to participate in the OLE study were to discontinue study drug (ralinepag or placebo). All subjects that chose to continue in the OLE study were to remain on study drug until the follow-up visit at Week 25. This visit served as the baseline visit for the OLE study if the subject was eligible and chose to participate.

Study Design

• Study Type: Interventional
• Actual Enrollment: 61 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Parallel-group, Placebo-controlled Phase 2 Trial of Ralinepag, an Oral IP Receptor Agonist, in Patients With Pulmonary Arterial Hypertension
• Study Start Date: Dec 1, 2014
• Actual Primary Completion Date: Jun 1, 2017
• Actual Study Completion Date: Jun 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: APD811 Multiple dose titration to maximum tolerated dose.	Drug: APD811; Other Names: Ralinepag
Placebo Comparator: Placebo Multiple dose titration to maximum tolerated dose.	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Change From Baseline in Pulmonary Vascular Resistance (PVR) [Baseline and 22 Weeks]

   Measurements of PVR from right heart catheterization were obtained prior to Day 1 of the dose titration period and at the end of the maintenance period (Week 22), approximately 4 hours after the last dose of study drug.

2. Change From Baseline in 6-minute Walk Distance (6MWD) in Patients With PAH [Baseline and 22 Weeks]

   The 6MWT was conducted according to the modified guidelines issued by the American Thoracic Society prior to Day 1 of the dose titration period and at the end of the maintenance period (Week 22).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Males or females aged 18-75 years, inclusive

• Symptomatic WHO Group 1 PAH classified by one of the following subgroups:

• Idiopathic pulmonary arterial hypertension (IPAH);

• Heritable pulmonary arterial hypertension (HPAH);

• Drugs and toxins induced;

• Associated pulmonary arterial hypertension (APAH); specifically connective tissue diseases, HIV infection and congenital heart disease.

• Has had the diagnosis of PAH confirmed by cardiac catheterization

• Has WHO/NYHA functional class II- IV symptomatology

• Previously diagnosed with PAH and on stable oral disease-specific PAH therapy with either an ERA and/or an agent acting on the nitric oxide pathway, i.e. a PDE5 inhibitor or a soluble guanylate cyclase stimulator. Stable is defined as no change in dose within 3 months of the start of Screening and for the duration of the study

• Has 6MWT distances of 100-500 m, and within 15% of each other on 2 consecutive tests done on different days at Screening

• Has pulmonary function tests (PFTs) within 6 months prior to the start of Screening with no evidence of significant parenchymal lung disease

• Has a ventilation-perfusion (V/Q) lung scan or pulmonary angiogram within 5 years prior to Screening and concomitant with or following diagnosis of PAH that shows no evidence of thromboembolic disease

• If on vasodilators (including calcium channel blockers), digoxin, spironolactone, or L-Arginine supplementation; the patient must be on a stable dose for at least 1 month prior to the start of Screening

Exclusion Criteria:

• Newly diagnosed with PAH and on no disease-specific PAH therapy

• Previous participation in any clinical study with an investigational drug, biologic, or device within 2 months prior to the Screening visit

• Acutely decompensated heart failure within 1 month prior to start of Screening

• Systolic blood pressure <90 mm Hg at Screening

• Evidence or history of left-sided heart disease and/or clinically significant cardiac disease

• Use or chronic administration (defined as >30 days) of a prostacyclin or prostacyclin analogue within 3 months of Screening

• Any previous use of a prostacyclin or prostacyclin analogue that was stopped for safety or tolerability issues associated with pharmacology/mechanism of action

• Other severe acute or chronic medical or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient 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	35233
2	Cedars-Sinai Medical Center	Los Angeles	California	United States	90048
3	UC Davis Medical Center	Sacramento	California	United States	95817
4	UCLA Medical Center	Torrance	California	United States	90502
5	University of Iowa Hospitals and Clinics	Iowa City	Iowa	United States	52242
6	University of Maryland	Baltimore	Maryland	United States	21201
7	Boston University Medical Center	Boston	Massachusetts	United States	02118
8	University of Cincinnati	Cincinnati	Ohio	United States	45267
9	Ohio State University Medical Center	Columbus	Ohio	United States	43221
10	University of Pittsburg Medical Center	Pittsburgh	Pennsylvania	United States	15229
11	UT Southwestern	Dallas	Texas	United States	75390
12	University of Texas, Houston Center for Clinical and Translational Sciences	Houston	Texas	United States	77030
13	The Prince Charles Hospital	Chermside		Australia	4032
14	St Vincent's Hospital	Darlinghurst		Australia	2010
15	St Vincent's Hospital	Fitzroy		Australia	3065
16	Royal Hobart Hospital	Hobart		Australia	7000
17	Fiona Stanley Hospital	Murdoch		Australia	6150
18	"Многопрофилната болница за активно лечение "Национална кардиологична болница "" ЕАД	Sofia		Bulgaria	1309
19	Многопрофилна болница за активно лечение "Света Анна" София АД, Клиника по кардиология	Sofia		Bulgaria	1750
20	II. interní klinika - klinika kardiologie a angiologie, 1. lékařská fakulta, Univerzita Karlova v Praze a Všeobecná fakultní nemocnice v Praze	Prague		Czechia	12808
21	Gottsegen György Országos Kardiologiai Intézet, Felnőtt Kardiológia	Budapest		Hungary	1096
22	Semmelweis Egyetem Pulmonológiai Klinika	Budapest		Hungary	1125
23	Pécsi Tudományegyetem Klinikai Központ, Szívgyógyászati Klinika	Pecs		Hungary	7624
24	Uniwersytecki Szpital Kliniczny w Białymstoku	Bialystok		Poland	15-276
25	Krakowski Szpital Specjalistyczny im. Jana Pawła II w Krakowie	Krakow		Poland	31-202
26	Wojewódzki Szpital Specjalistyczny im. W. Biegańskiego w Łodzi	Lodz		Poland	91-347
27	Institutul de Urgență pentru Boli Cardiovasculare, Secția Clinică Cardiologie III	Bucharest		Romania	022322
28	Institutul de Pneumoftiziologie "Marius Nasta", Secția Clinică Pneumoftiziologie IV	Bucharest		Romania	050159
29	Spitalul Clinic de Boli Infectioase si Pneumoftiziologie, Sectia Clinica Pneumologie II	Timisoara		Romania	300310
30	Klinički Centar Srbije (KCS), Klinika za kardiologiju	Belgrade		Serbia	11000
31	Kliničko-bolnički centar (KBC) Zemun,Klinika za internu medicinu,Sluzba kardiologije	Belgrade		Serbia	11080
32	Institut za plućne bolesti Vojvodine Sremska Kamenica (IPBVSK),	Sremska Kamenica		Serbia	21204
33	Hospital Universitari General Vall d'Hebron, Servicio de Neumología	Barcelona		Spain	08035
34	Hospital Clinic de Barcelona, Departamento de Pneumologia	Barcelona		Spain	11000
35	Hospital 12 de Octubre, Departamento de Cardiologia	Madrid		Spain	28041

Sponsors and Collaborators

• United Therapeutics

Investigators

• Study Director: Derek Solum, PhD, United Therapeutics

Study Documents (Full-Text)

• Study Protocol - Aug 15, 2014
• Statistical Analysis Plan - Jun 22, 2017

More Information

Publications

None provided.

• Responsible Party: United Therapeutics
• ClinicalTrials.gov Identifier: NCT02279160
• Other Study ID Numbers: APD811-003
• First Posted: Oct 30, 2014
• Last Update Posted: Jul 14, 2020
• Last Verified: Jun 1, 2020

• Additional relevant MeSH terms: Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension; Hypertension

Study Results

Participant Flow

Arm/Group Title	APD811	Placebo
Arm/Group Description	Multiple dose titration to maximum tolerated dose. APD811	Multiple dose titration to maximum tolerated dose. Placebo
Period Title: Overall Study
STARTED	40	21
COMPLETED	34	19
NOT COMPLETED	6	2

Baseline Characteristics

Arm/Group Title	APD811	Placebo	Total
Arm/Group Description	Multiple dose titration to maximum tolerated dose. APD811	Multiple dose titration to maximum tolerated dose. Placebo	Total of all reporting groups
Overall Participants	40	21	61
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	39 97.5%	18 85.7%	57 93.4%
>=65 years	1 2.5%	3 14.3%	4 6.6%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	46.5	60	51
Sex: Female, Male (Count of Participants)
Female	33 82.5%	20 95.2%	53 86.9%
Male	7 17.5%	1 4.8%	8 13.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 5%	2 9.5%	4 6.6%
Not Hispanic or Latino	38 95%	19 90.5%	57 93.4%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 2.5%	0 0%	1 1.6%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	1 2.5%	0 0%	1 1.6%
White	38 95%	19 90.5%	57 93.4%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	2 9.5%	2 3.3%
Region of Enrollment (participants) [Number]
Australia	6 15%	4 19%	10 16.4%
Bulgaria	2 5%	0 0%	2 3.3%
Czechia	3 7.5%	1 4.8%	4 6.6%
Hungary	0 0%	3 14.3%	3 4.9%
Poland	1 2.5%	3 14.3%	4 6.6%
Romania	3 7.5%	3 14.3%	6 9.8%
Serbia	8 20%	3 14.3%	11 18%
Spain	7 17.5%	2 9.5%	9 14.8%
United States	10 25%	2 9.5%	12 19.7%
Weight (kg) [Median (Full Range) ]
Median (Full Range) [kg]	73.5	68	72.5
Height (cm) [Median (Full Range) ]
Median (Full Range) [cm]	160.5	162	161
BMI (kg/m^2) [Median (Full Range) ]
Median (Full Range) [kg/m^2]	27.18	25.68	27.13
Duration of PAH (Years) (years) [Median (Full Range) ]
Median (Full Range) [years]	2.22	1.76	2
PAH Treatment (Count of Participants)
Monotherapy (ERA or PDE5-Inhibitor)	14 35%	11 52.4%	25 41%
Combination Therapy (ERA + PDE5-Inhibitor/sGCS)	26 65%	10 47.6%	36 59%
PAH Classification (Count of Participants)
Idiopathic PAH	21 52.5%	11 52.4%	32 52.5%
Heritable PAH	4 10%	1 4.8%	5 8.2%
Drugs or Toxin Induced	4 10%	0 0%	4 6.6%
Associated PAH	11 27.5%	9 42.9%	20 32.8%
Baseline WHO/NYHA Functional Class (Count of Participants)
Class I	0 0%	0 0%	0 0%
Class II	22 55%	12 57.1%	34 55.7%
Class III	17 42.5%	9 42.9%	26 42.6%
Class IV	1 2.5%	0 0%	1 1.6%
Baseline Pulmonary Vascular Resistance (dyn*sec/cm^-5) [Median (Full Range) ]
Median (Full Range) [dyn*sec/cm^-5]	704.6	479.7	575.7
Baseline 6MWD (meters) [Median (Full Range) ]
Median (Full Range) [meters]	405	367	400

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in Pulmonary Vascular Resistance (PVR)
Description	Measurements of PVR from right heart catheterization were obtained prior to Day 1 of the dose titration period and at the end of the maintenance period (Week 22), approximately 4 hours after the last dose of study drug.
Time Frame	Baseline and 22 Weeks

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Population

Arm/Group Title	APD811	Placebo
Arm/Group Description	Multiple dose titration to maximum tolerated dose. APD811	Multiple dose titration to maximum tolerated dose. Placebo
Measure Participants	40	21
Geometric Mean (Standard Deviation) [dyn*sec/cm^5]	514.6 (1.85)	512.0 (1.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD811, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0220
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Multiple imputation
	Estimated Value	0.742
	Confidence Interval	(2-Sided) 95%; 0.575 to 0.958
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline in 6-minute Walk Distance (6MWD) in Patients With PAH
Description	The 6MWT was conducted according to the modified guidelines issued by the American Thoracic Society prior to Day 1 of the dose titration period and at the end of the maintenance period (Week 22).
Time Frame	Baseline and 22 Weeks

Outcome Measure Data

Analysis Population Description

Modified Intent-to-Treat Population

Arm/Group Title	APD811	Placebo
Arm/Group Description	Multiple dose titration to maximum tolerated dose. APD811	Multiple dose titration to maximum tolerated dose. Placebo
Measure Participants	38	21
Least Squares Mean (Standard Error) [meters]	36.2 (11.79)	29.4 (16.16)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	APD811, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9002
	Comments
	Method	Stratified Wilcoxon
	Comments
Method of Estimation	Estimation Parameter	Hodges-Lehmann estimate
	Estimated Value	0.0
	Confidence Interval	(2-Sided) 95%; -28.0 to 30.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse events were assessed from the time the subject provided informed consent through the duration of the study (up to 22 weeks).
Adverse Event Reporting Description	Adverse events were elicited at the time indicated in the schedule by asking the question: "Since you were last asked, have you felt unwell or different from usual in any way?" Any adverse or unexpected events, signs and symptoms were fully recorded on the Adverse Event form including details of intensity, onset, duration, outcome and relationship to the drug as determined by the PI.
Arm/Group Title	APD811		Placebo
Arm/Group Description	Multiple dose titration to maximum tolerated dose. APD811		Multiple dose titration to maximum tolerated dose. Placebo
All Cause Mortality
	APD811		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		2/21 (9.5%)
Serious Adverse Events
	APD811		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/40 (10%)		6/21 (28.6%)
Cardiac disorders
Bradycardia	1/40 (2.5%)		0/21 (0%)
Cardiac arrest	1/40 (2.5%)		0/21 (0%)
Cardio-respiratory arrest	0/40 (0%)		1/21 (4.8%)
Myocardial infarction	0/40 (0%)		1/21 (4.8%)
Gastrointestinal disorders
Upper gastrointestinal haemorrhage	1/40 (2.5%)		0/21 (0%)
General disorders
Drug withdrawal syndrome	1/40 (2.5%)		0/21 (0%)
Hepatobiliary disorders
Portal vein thrombosis	1/40 (2.5%)		0/21 (0%)
Infections and infestations
Bronchitis	0/40 (0%)		1/21 (4.8%)
Injury, poisoning and procedural complications
Fall	0/40 (0%)		1/21 (4.8%)
Head injury	0/40 (0%)		1/21 (4.8%)
Investigations
Electrocardiogram QT prolonged	1/40 (2.5%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Haemarthrosis	1/40 (2.5%)		0/21 (0%)
Myositis	1/40 (2.5%)		0/21 (0%)
Nervous system disorders
Loss of consciousness	0/40 (0%)		1/21 (4.8%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	0/40 (0%)		1/21 (4.8%)
Pulmonary arterial hypertension	0/40 (0%)		1/21 (4.8%)
Skin and subcutaneous tissue disorders
Toxic skin eruption	0/40 (0%)		1/21 (4.8%)
Vascular disorders
Hypovolaemic shock	0/40 (0%)		1/21 (4.8%)
Other (Not Including Serious) Adverse Events
	APD811		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/40 (100%)		19/21 (90.5%)
Blood and lymphatic system disorders
Anaemia	3/40 (7.5%)		0/21 (0%)
Cardiac disorders
Bradycardia	2/40 (5%)		0/21 (0%)
Gastrointestinal disorders
Nausea	20/40 (50%)		5/21 (23.8%)
Diarrhoea	19/40 (47.5%)		3/21 (14.3%)
Vomiting	10/40 (25%)		3/21 (14.3%)
Abdominal Pain	7/40 (17.5%)		0/21 (0%)
Abdominal pain upper	4/40 (10%)		1/21 (4.8%)
Abdominal discomfort	2/40 (5%)		0/21 (0%)
Constipation	2/40 (5%)		0/21 (0%)
General disorders
Oedema peripheral	6/40 (15%)		1/21 (4.8%)
Asthenia	2/40 (5%)		0/21 (0%)
Infections and infestations
Urinary tract infection	4/40 (10%)		3/21 (14.3%)
Influenza	3/40 (7.5%)		0/21 (0%)
Upper respiratory tract infection	3/40 (7.5%)		2/21 (9.5%)
Investigations
Electrocardiogram QT prolonged	2/40 (5%)		0/21 (0%)
Metabolism and nutrition disorders
Arthralgia	5/40 (12.5%)		1/21 (4.8%)
Decreased appetite	3/40 (7.5%)		0/21 (0%)
Musculoskeletal and connective tissue disorders
Pain in Jaw	14/40 (35%)		3/21 (14.3%)
Myalgia	11/40 (27.5%)		1/21 (4.8%)
Pain in extremity	7/40 (17.5%)		1/21 (4.8%)
Neck pain	4/40 (10%)		0/21 (0%)
Muscle spasms	3/40 (7.5%)		2/21 (9.5%)
Musculoskeletal pain	3/40 (7.5%)		0/21 (0%)
Nervous system disorders
Headache	31/40 (77.5%)		6/21 (28.6%)
Dizziness	7/40 (17.5%)		3/21 (14.3%)
Syncope	3/40 (7.5%)		0/21 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	3/40 (7.5%)		1/21 (4.8%)
Cough	2/40 (5%)		0/21 (0%)
Vascular disorders
Flushing	13/40 (32.5%)		1/21 (4.8%)

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.