Safety and Efficacy of APD811 in Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02279160
• Other study ID #: APD811-003
• Status: Completed
• Phase: Phase 2
• Start date: December 2014
• Est. completion date: June 2017

Study information

• Verified date: June 2020
• Source: United Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 61
• Est. completion date: June 2017
• Est. primary completion date: June 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• APD811

• Placebo
Placebo

Locations

Country	Name	City	State
Australia	The Prince Charles Hospital	Chermside
Australia	St Vincent's Hospital	Darlinghurst
Australia	St Vincent's Hospital	Fitzroy
Australia	Royal Hobart Hospital	Hobart
Australia	Fiona Stanley Hospital	Murdoch
Bulgaria	"??????????????? ??????? ?? ??????? ??????? "?????????? ????????????? ??????? "" ???	Sofia
Bulgaria	????????????? ??????? ?? ??????? ??????? "????? ????" ????? ??, ??????? ?? ???????????	Sofia
Czechia	II. interní klinika - klinika kardiologie a angiologie, 1. lékarská fakulta, Univerzita Karlova v Praze a Všeobecná fakultní nemocnice v Praze	Prague
Hungary	Gottsegen György Országos Kardiologiai Intézet, Felnott Kardiológia	Budapest
Hungary	Semmelweis Egyetem Pulmonológiai Klinika	Budapest
Hungary	Pécsi Tudományegyetem Klinikai Központ, Szívgyógyászati Klinika	Pecs
Poland	Uniwersytecki Szpital Kliniczny w Bialymstoku	Bialystok
Poland	Krakowski Szpital Specjalistyczny im. Jana Pawla II w Krakowie	Krakow
Poland	Wojewódzki Szpital Specjalistyczny im. W. Bieganskiego w Lodzi	Lodz
Romania	Institutul de Pneumoftiziologie "Marius Nasta", Sec?ia Clinica Pneumoftiziologie IV	Bucharest
Romania	Institutul de Urgen?a pentru Boli Cardiovasculare, Sec?ia Clinica Cardiologie III	Bucharest
Romania	Spitalul Clinic de Boli Infectioase si Pneumoftiziologie, Sectia Clinica Pneumologie II	Timisoara
Serbia	Klinicki Centar Srbije (KCS), Klinika za kardiologiju	Belgrade
Serbia	Klinicko-bolnicki centar (KBC) Zemun,Klinika za internu medicinu,Sluzba kardiologije	Belgrade
Serbia	Institut za plucne bolesti Vojvodine Sremska Kamenica (IPBVSK),	Sremska Kamenica
Spain	Hospital Clinic de Barcelona, Departamento de Pneumologia	Barcelona
Spain	Hospital Universitari General Vall d'Hebron, Servicio de Neumología	Barcelona
Spain	Hospital 12 de Octubre, Departamento de Cardiologia	Madrid
United States	University of Maryland	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Boston University Medical Center	Boston	Massachusetts
United States	University of Cincinnati	Cincinnati	Ohio
United States	Ohio State University Medical Center	Columbus	Ohio
United States	UT Southwestern	Dallas	Texas
United States	University of Texas, Houston Center for Clinical and Translational Sciences	Houston	Texas
United States	University of Iowa Hospitals and Clinics	Iowa City	Iowa
United States	Cedars-Sinai Medical Center	Los Angeles	California
United States	University of Pittsburg Medical Center	Pittsburgh	Pennsylvania
United States	UC Davis Medical Center	Sacramento	California
United States	UCLA Medical Center	Torrance	California

Sponsors (1)

Lead Sponsor	Collaborator
United Therapeutics

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Pulmonary Vascular Resistance (PVR)	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.	Baseline and 22 Weeks
Primary	Change From Baseline in 6-minute Walk Distance (6MWD) in Patients With PAH	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).	Baseline and 22 Weeks