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Safety and Efficacy of APD811 in Pulmonary Arterial Hypertension

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02279160
Recruitment Status : Completed
First Posted : October 30, 2014
Results First Posted : July 14, 2020
Last Update Posted : July 14, 2020
Sponsor:
Information provided by (Responsible Party):
United Therapeutics

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.

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Study Type : Interventional  (Clinical Trial)
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 : December 2014
Actual Primary Completion Date : June 2017
Actual Study Completion Date : June 2017


Arm Intervention/treatment
Experimental: APD811
Multiple dose titration to maximum tolerated dose.
Drug: APD811
Other Name: Ralinepag

Placebo Comparator: Placebo
Multiple dose titration to maximum tolerated dose.
Drug: Placebo
Placebo




Primary Outcome Measures :
  1. Change From Baseline in Pulmonary Vascular Resistance (PVR) [ Time Frame: 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 [ Time Frame: 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).



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02279160


Locations
Show Show 35 study locations
Sponsors and Collaborators
United Therapeutics
Investigators
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Study Director: Derek Solum, PhD United Therapeutics
  Study Documents (Full-Text)

Documents provided by United Therapeutics:
Study Protocol  [PDF] August 15, 2014
Statistical Analysis Plan  [PDF] June 22, 2017

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: United Therapeutics
ClinicalTrials.gov Identifier: NCT02279160    
Other Study ID Numbers: APD811-003
First Posted: October 30, 2014    Key Record Dates
Results First Posted: July 14, 2020
Last Update Posted: July 14, 2020
Last Verified: June 2020
Additional relevant MeSH terms:
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Familial Primary Pulmonary Hypertension
Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases