Long Term Safety and Efficacy of Ralinepag in Pulmonary Arterial Hypertension

• Sponsor: United Therapeutics
• Information provided by (Responsible Party): United Therapeutics

Study Description

Brief Summary:

This study is an open-label extension study to determine the long-term safety and tolerability of APD811 in patients with WHO Group 1 PAH who have completed the Phase 2 study, APD811-003. Patients must have completed the APD811-003 study and must meet eligibility criteria for APD811-007.

Condition or disease	Intervention/treatment	Phase
Pulmonary Arterial Hypertension	Drug: Ralinepag	Phase 2

Detailed Description:

This study is an open-label extension study to determine the long-term safety and tolerability of APD811 in patients with WHO Group 1 PAH who have completed the Phase 2 Study APD811-003. Patients must have completed Study APD811-003 and met eligibility criteria for Study APD811-007. Additionally, placebo-treated patients who discontinue study drug treatment due to clinical worsening in Study APD811-003 will be permitted to enroll in Study APD811-007, upon approval of the medical monitor, provided that all end of study procedures including right heart catheterization are performed per protocol. The Week 25 Visit in Study APD811-003 will serve as the Baseline Visit for Study APD811-007.

All patients enrolled in Study APD811-007 will receive open-label treatment with APD811. The starting dose and titration schedule will be individually determined and in accordance with the starting dose and titration schedule optimized from Study APD811-003. Adjustments in the dose and titration schedule may be made according to patient tolerability.

After an individual patient completes Study APD811-003 and that patient's database is locked, patient unblinding will occur. Patients on active treatment (APD811) will remain on current dose and have onsite clinical assessments performed every 3 months until the patient is discontinued from the study.

Patients in the placebo treatment group will undergo a dose titration period until a stable, maximum tolerated dose (MTD) is reached (up to 9 weeks), followed by a treatment period after the MTD is determined during which monthly onsite clinic assessments will be performed for the first 3 months and then every 3 months until the patient is discontinued from the study or the study is terminated (see Table 2).

Discontinuation of the study may also occur at Sponsor's decision to terminate the study. Dose reductions may be made at any time for safety reasons.

Incremental dose increases will also be allowed during the Treatment Period at the discretion of the investigator (as clinically indicated) and according to the stepwise titration scheme. Uptitration should not occur within 6 weeks of an efficacy assessment.

Patients will be assessed for clinical worsening during each clinic visit. If clinical worsening is confirmed, the Investigator may opt to either continue treatment with APD811 at the current dose, increase the dose of APD811, interrupt treatment, or discontinue the patient at his/her discretion.

In addition, all patients will be contacted yearly following discontinuation in Study APD811-007 to assess mortality status. The mortality status follow-up contact of patients who withdraw consent will depend on local regulations or specific agreement with the subject and investigator.

After the last patient enrolled in Study APD811-007 has completed approximately 6 months of the study, a cumulative all-patient data analysis will be performed for all patients who entered the study. Patients will continue to have visits to the clinic every 3 months indefinitely to collect data until marketing approval of APD811 is granted or until the Sponsor discontinues the study. At the time of marketing approval or the Sponsor's decision to discontinue the study, all on-going patients will complete an End of Study Visit. A 28-day Follow-up Visit will be conducted to ensure appropriate subject safety.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	60 participants
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
Study Start Date :	July 2015
Estimated Primary Completion Date :	September 2019
Estimated Study Completion Date :	September 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ralinepag; Ralinepag immediate release (IR) capsules of 0.01, 0.02, 0.03, 0.04 mg, and 0.10 mg per capsule or extended release (XR) tablets of 50, 250, and 400 mcg (0.05, 0.25 and 0.4 mg) for oral administration. The starting dose and titration schedule will be determined for each subject in accordance with the starting dose and titration schedule optimized from Study APD811-003.	Drug: Ralinepag; Active; Other Name: APD811

Outcome Measures

Primary Outcome Measures :

1. Long-term safety assessed by adverse events up to 28 days following discontinuation of study drug [ Time Frame: From Baseline to 28 days following discontinuation of study drug. ]
   The number of adverse events will be computed overall and by treatment group in the parent study (Study APD811-003)

Eligibility Criteria

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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:

• Evidence of a personally signed and dated informed consent document

• Is willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures and is deemed an appropriate candidate for participation in a long-term extension study and administration of APD811

  • Fulfilled all eligibility criteria for APD811-003 and completed the study as planned
  • Patients who discontinued for clinical worsening in APD811-003 and were assigned to placebo and completed all end of study procedures including right heart catheterization (RHC) may participate after their data from the APD811-003 study is cleaned and locked

Exclusion Criteria:

• Patients who enrolled in APD811-003 and were withdrawn from study drug treatment due to any AE, SAE, or clinical worsening if assigned to APD811, or patients who did not complete the APD811 003 study for other reasons.
• Female patients who wish to become pregnant
• Systolic BP <90 mmHg at Baseline/Day 1
• 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

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United States, Maryland
University of Maryland
Baltimore, Maryland, United States, 21201
United States, Massachusetts
Boston University Medical Center
Boston, Massachusetts, United States, 02118
United States, Ohio
Ohio State University Medical Center
Columbus, Ohio, United States, 43221
United States, Texas
University of Texas, Southwestern
Dallas, Texas, United States, 75390
Australia
St Vincent's Hospital
Fitzroy, Australia, 3065
Fiona Stanley Hospital
Murdoch, Australia, 6150
Bulgaria
Multiprofile Hospital for Active Treatment " St. Anna", Sofia AD, Cardiology Clinic
Sofia, Bulgaria, 1750
Czechia
Department of Internal Medicine I - Cardiology, University Hospital Olomouc
Olomouc, Czechia, 77900
Second Internal Clinic - Clinic of Cardiology and Angiology, 1st Faculty of Medicine, Charles University in Prague, General University Hospital in Prague
Prague, Czechia, 12808
Hungary
University of Pecs, Medical School, Heart Institute
Pécs, Hungary, 7624
Poland
Medical University of Bialystok Clinical Hospital
Białystok, Poland, 15-276
Romania
"Marius Nasta" Institute of Pneumoftiziology, Department of Pneumoftiziology IV
Bucharest, Romania, 050159
"Dr. Victor Babes" Clinic Hospital for Infesctious Diseases and Pneumoftiziology, Department of Clinic Pneumology II
Timisoara, Romania, 300310
Serbia
Clinical Centre of Serbia (CCS), Cardiology Clinic
Belgrade, Serbia, 11000
Clinical Hospital Centre (CHC) Zemun, Clinic for Internal Medicine, Cardiology Department
Belgrade, Serbia, 11080
Institute of Pulmonary Diseases of Vojvodina Sremska Kamenica (IPDVSK), The Clinic for Urgent Pulmonology, ICU - Intensive Care Unit
Sremska Kamenica, Serbia, 21204
Spain
Clinic Hospital of Barcelona, Department of Pneumology
Barcelona, Spain, 11000
Hospital 12th of October, Department of Cardiology
Madrid, Spain, 28041

Sponsors and Collaborators

United Therapeutics

Investigators

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Study Director:	Isil Saib, MPH	United Therapeutics

More Information

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Responsible Party:	United Therapeutics
ClinicalTrials.gov Identifier:	NCT02279745 History of Changes
Other Study ID Numbers:	APD811-007
First Posted:	October 31, 2014
Last Update Posted:	April 23, 2019
Last Verified:	April 2019

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Additional relevant MeSH terms:

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Hypertension; Familial Primary Pulmonary Hypertension; Vascular Diseases; Cardiovascular Diseases	Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases