Clinical trial NCT02279160: Safety and Efficacy of APD811 in Pulmonary Arterial Hypertension
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: United Therapeutics
Sponsor class: INDUSTRY
First posted: 2014-10-30
Enrollment: 61
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change From Baseline in Pulmonary Vascular Resistance (PVR)
timeFrame: Baseline and 22 Weeks
measure: Change From Baseline in 6-minute Walk Distance (6MWD) in Patients With PAH
timeFrame: Baseline and 22 Weeks
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center
state: California
city: Sacramento
country: United States
facility: UC Davis Medical Center
state: California
city: Torrance
country: United States
facility: UCLA Medical Center
state: California
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Boston
country: United States
facility: Boston University Medical Center
state: Massachusetts
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburg Medical Center
state: Pennsylvania
city: Dallas
country: United States
facility: UT Southwestern
state: Texas
city: Houston
country: United States
facility: University of Texas, Houston Center for Clinical and Translational Sciences
state: Texas
city: Chermside
country: Australia
facility: The Prince Charles Hospital
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital
city: Fitzroy
country: Australia
facility: St Vincent's Hospital
city: Hobart
country: Australia
facility: Royal Hobart Hospital
city: Murdoch
country: Australia
facility: Fiona Stanley Hospital
city: Sofia
country: Bulgaria
facility: "Многопрофилната болница за активно лечение "Национална кардиологична болница "" ЕАД
city: Sofia
country: Bulgaria
facility: Многопрофилна болница за активно лечение "Света Анна" София АД, Клиника по кардиология
city: Prague
country: Czechia
facility: II. interní klinika - klinika kardiologie a angiologie, 1. lékařská fakulta, Univerzita Karlova v Praze a Všeobecná fakultní nemocnice v Praze
city: Budapest
country: Hungary
facility: Gottsegen György Országos Kardiologiai Intézet, Felnőtt Kardiológia
city: Budapest
country: Hungary
facility: Semmelweis Egyetem Pulmonológiai Klinika
city: Pecs
country: Hungary
facility: Pécsi Tudományegyetem Klinikai Központ, Szívgyógyászati Klinika
city: Bialystok
country: Poland
facility: Uniwersytecki Szpital Kliniczny w Białymstoku
city: Krakow
country: Poland
facility: Krakowski Szpital Specjalistyczny im. Jana Pawła II w Krakowie
city: Lodz
country: Poland
facility: Wojewódzki Szpital Specjalistyczny im. W. Biegańskiego w Łodzi
city: Bucharest
country: Romania
facility: Institutul de Urgență pentru Boli Cardiovasculare, Secția Clinică Cardiologie III
city: Bucharest
country: Romania
facility: Institutul de Pneumoftiziologie "Marius Nasta", Secția Clinică Pneumoftiziologie IV
city: Timisoara
country: Romania
facility: Spitalul Clinic de Boli Infectioase si Pneumoftiziologie, Sectia Clinica Pneumologie II
city: Belgrade
country: Serbia
facility: Klinički Centar Srbije (KCS), Klinika za kardiologiju
city: Belgrade
country: Serbia
facility: Kliničko-bolnički centar (KBC) Zemun,Klinika za internu medicinu,Sluzba kardiologije
city: Sremska Kamenica
country: Serbia
facility: Institut za plućne bolesti Vojvodine Sremska Kamenica (IPBVSK),
city: Barcelona
country: Spain
facility: Hospital Universitari General Vall d'Hebron, Servicio de Neumología
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona, Departamento de Pneumologia
city: Madrid
country: Spain
facility: Hospital 12 de Octubre, Departamento de Cardiologia
Study officials:
affiliation: United Therapeutics
name: Derek Solum, PhD
role: STUDY_DIRECTOR
References:
citation: Torres F, Farber H, Ristic A, McLaughlin V, Adams J, Zhang J, Klassen P, Shanahan W, Grundy J, Hoffmann I, Cabell C, Escribano Subias P, Sood N, Keogh A, D'Souza G, Rubin L. Efficacy and safety of ralinepag, a novel oral IP agonist, in PAH patients on mono or dual background therapy: results from a phase 2 randomised, parallel group, placebo-controlled trial. Eur Respir J. 2019 Oct 10;54(4):1901030. doi: 10.1183/13993003.01030-2019. Print 2019 Oct.