Safety, Tolerability, and Pharmacokinetics of Oral Treprostinil in Pediatric PAH Patients Aged 7 to 17 Years

NCT02276872 | Completed Phase 2 Results DMC

• 1 other identifier: TDE-PH-206
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 9

Brief Summary

This was a multi-center, open-label, safety, tolerability and pharmacokinetic study of oral treprostinil in pediatric subjects with stable PAH aged 7 to 17 years who were (1) transitioning from parenteral Remodulin therapy; (2) transitioning from inhaled prostacyclin therapy; or (3) not currently receiving prostacyclin therapy.

Conditions

PAH

Keywords

pediatric; treprostinil; transition; Remodulin

Outcome Measures

Primary Outcomes (1)

• Number of Participants With Successful Transition From IV/SC Remodulin to Oral Treprostinil (Cohort 1), From Inhaled Prostacyclin to Oral Treprostinil (Cohort 2), or as an add-on to Current PAH Therapy in de Novo Prostacyclin Subjects (Cohort 3).

  A successful transition was defined as a subject from Cohort 1 or Cohort 2 who was receiving oral treprostinil and no longer receiving IV/SC Remodulin or inhaled prostacyclin, respectively, at Week 4 and clinically maintained on oral treprostinil treatment through Week 24. A successful initiation of oral treprostinil for Cohort 3 was defined as a subject who was clinically maintained on oral treprostinil through Week 24.

  Up to 24 weeks

Secondary Outcomes (24)

• Cardiopulmonary Exercise Testing - Change From Baseline in Peak Oxygen Uptake (VO2) at Week 24

  Baseline and Week 24

• Cardiopulmonary Exercise Testing - Change From Baseline in Minute Ventilation (VE)/Carbon Dioxide Output (VCO2) Slope at Week 24

  Baseline and Week 24

• Cardiopulmonary Exercise Testing - Change From Baseline in Peak Watts at Week 24

  Baseline and Week 24

• Change in Symptoms of PAH From Baseline to Week 24

  Baseline and Week 24

• Change in Panama Functional Class From Baseline to Week 24

  Baseline and Week 24

Study Arms (3)

Cohort 1 (Transitioning from Parental)

EXPERIMENTAL

Transitioned from IV or SC Remodulin to oral treprostinil

Drug: oral treprostinil

Cohort 2 (Transitioning from Inhaled)

EXPERIMENTAL

Transitioned from inhaled prostacyclin to oral treprostinil

Drug: oral treprostinil

Cohort 3 (Add-on to Current PAH Therapy)

EXPERIMENTAL

Treated with oral treprostinil as a de novo add-on to current PAH therapy

Drug: oral treprostinil

Interventions

oral treprostinil DRUG

Also known as: Orenitram

Cohort 1 (Transitioning from Parental); Cohort 2 (Transitioning from Inhaled); Cohort 3 (Add-on to Current PAH Therapy)

Eligibility Criteria

• Age: 7 Years - 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Legal guardian informed consent and subject assent, if appropriate, to participate in the study was voluntarily given.
• The subject was between 7 and 17 years of age, inclusive, on the date informed consent was signed.
• Cohort 3: The subject weighed a minimum of 22 kg at Screening.
• The subject had a current diagnosis of PAH (WHO Group I) associated with:
• IPAH or HPAH
• Persistent PAH for at least 1 year following surgical repair of a congenital systemic-to-pulmonary cardiac shunt, congenital heart disease, or other congenital heart lesions with no clinically significant residual defects and condition was stabilized hemodynamically
• PAH in subjects with unrepaired restricted atrial septal defect, ventricular septal defect, or patent ductus arteriosus; subject had a resting post-ductal oxygen saturation (off oxygen) of greater than 88%.
• The subject had a current diagnosis of PAH confirmed by RHC prior to the Screening Visit with the following parameters:
• PAPm of ≥25 mmHg
• Pulmonary vascular resistance index (PVRi) of \>3 Wood Units\*m2
• Left ventricular end-diastolic pressure (LVEDP) or pulmonary capillary wedge pressure (PCWP) of ≤15 mmHg.
• Cohort 1: The subject had received IV/SC Remodulin for at least 90 days without dose change for at least 30 days prior to Baseline. The IV/SC Remodulin dose was between 25 to 75 ng/kg/min, inclusive, for the first 5 subjects in the cohort. Following safety review, the dose range was expanded to 25 to 125 ng/kg/min, inclusive, for the remaining subjects. Subjects must have received stable doses of all other PAH medications for at least 14 days prior to the baseline assessments; exception for diuretics and anticoagulants.
• Cohort 2: The subject must have received inhaled prostacyclin for at least 90 days and had been at the current stable dose without changes for at least 30 days prior to Baseline. Subjects must have received stable doses of all other PAH medications for at least 14 days prior to the baseline assessments; exception for diuretics and anticoagulants.
• All Cohorts: All subjects were optimally treated (as determined by the Investigator) with background PAH therapies (eg, phosphodiesterase type 5 inhibitor \[PDE5-I\], endothelin receptor antagonist \[ERA\], soluble guanylate cyclase \[sGC\]) for at least 90 days and had been on a stable dose without changes (except documented weight based adjustments) for at least 30 days prior to the first dose of oral treprostinil. Subjects must have received stable doses of all other PAH medications for at least 14 days prior to the first dose of oral treprostinil; exception for diuretics and anticoagulants.
• The subject was willing and able to swallow intact tablets whole without chewing, breaking, or splitting.

You may not qualify if:

• The subject had a diagnosis of large unrestrictive ventricular septal defect or patent ductus arteriosus, Eisenmenger syndrome, congenital diaphragmatic hernia, or a chronic lung disease, such as bronchopulmonary dysplasia or interstitial lung disease.
• The subject had a current disease severity of Panama FC IIIb or IV.
• The subject had previously been exposed to oral treprostinil.
• Cohort 1: The subject had previous intolerance to treprostinil or epoprostenol due to systemic adverse effects that resulted in discontinuation of therapy. This did not include site pain reactions or central venous catheter-related blood stream infections.
• Cohort 3: The subject had been previously exposed to a prostacyclin within 30 days of Screening, with the exception of vasoreactivity testing.
• The subject was pregnant or lactating.
• The subject had a current diagnosis of uncontrolled sleep apnea as defined by their physician.
• The subject had severe renal insufficiency as defined by an estimated creatinine clearance \<30 mL/min (Schwartz Formula) or the requirement for dialysis at Screening.
• The subject had moderate to severe hepatic dysfunction as defined by elevated liver function tests (aspartate aminotransferase or alanine aminotransferase) ≥3 times the upper limit of normal at Screening, or Child Pugh class B or C hepatic disease.
• The subject had clinically significant anemia as defined by a hemoglobin and/or hematocrit level \<75% of the lower limit of normal ranges according to age and gender.
• The subject had Down Syndrome.
• The subject had uncontrolled systemic hypertension as evidenced by a systolic or diastolic blood pressure greater than the 95th percentile for age, height, and gender at Screening or Baseline.
• The subject and/or legal guardian had an unstable psychiatric condition or was mentally incapable of understanding the objectives, nature, or consequences of the study, or had any condition in which the Investigator's opinion would constitute an unacceptable risk to the subject's safety.
• The subject had an active infection or any other cardiovascular, liver, renal, hematologic, gastrointestinal, immunologic, endocrine, metabolic, or central nervous system disease or condition that, in the opinion of the Investigator, might have adversely affected the safety of the subject or interfered with the interpretation of study assessments.
• Subject was actively listed for transplantation.

Sponsors & Collaborators

• United Therapeutics: lead

Study Sites (9)

Lucile Packard Children's Hospital

Palo Alto, California, 94304, United States

Location

University of California San Francisco

San Francisco, California, 94143, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Boston Children's Hospital

Boston, Massachusetts, 02115, United States

Location

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104, United States

Location

Monroe Carell Jr Children's Hospital at Vanderbilt

Nashville, Tennessee, 37232, United States

Location

Seattle Children's Hospital

Seattle, Washington, 98105, United States

Location

Children's Hospital of Wisconsin

Milwaukee, Wisconsin, 53226, United States

Location

Related Publications (2)

• Ivy DD, Feinstein JA, Yung D, Mullen MP, Kirkpatrick EC, Hirsch R, Austin ED, Fineman J, Truong U, Solum D, Deng CQ, Hopper RK. Oral treprostinil in transition or as add-on therapy in pediatric pulmonary arterial hypertension. Pulm Circ. 2019 Jul-Sep;9(3):2045894019856471. doi: 10.1177/2045894019856471.

  PMID: 31215336 BACKGROUND

• Hopper RK, Ivy DD, Yung D, Mullen MP, Hanna BD, Kirkpatrick E, Hirsch R, Austin ED, Fineman J, Solum D, Deng CQ, Feinstein JA. Pharmacokinetics of Oral Treprostinil in Children With Pulmonary Arterial Hypertension. J Cardiovasc Pharmacol. 2020 Jul;76(1):94-100. doi: 10.1097/FJC.0000000000000842.

  PMID: 32398473 BACKGROUND

MeSH Terms

Interventions

treprostinil

Results Point of Contact

• Title: Derek Solum, PhD
• Organization: United Therapeutics

dsolum@unither.com

919-425-8122

Study Officials

• Dunbar Ivy, MD

  Denver Children's Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 21, 2014
• First Posted: October 28, 2014
• Study Start: December 18, 2014
• Primary Completion: July 20, 2017
• Study Completion: July 20, 2017
• Last Updated: March 30, 2025
• Results First Posted: January 4, 2019

Record last verified: 2025-03

Locations

US (9)