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CompletedNCT02276872Updated Mar 30, 2025Results posted

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

A Phase 2 interventional study of oral treprostinil in PAH, sponsored by United Therapeutics. Completed at 9 sites in United States. Open to participants aged 7 Years to 17 Years. Per ClinicalTrials.gov, last updated 2025-03-30.

Sponsored by United Therapeutics · Phase 2, Interventional, and Treatment

Phase
Phase 2
Study type
Interventional
Enrollment
32
Allocation
Non-randomized
Ages
7 Years to 17 Years
Sex
All
01

Study 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.

Read the detailed description

Study TDE-PH-206 was a multicenter, open-label study designed to investigate the safety, tolerability, and PK of oral treprostinil administered 3 times daily (TID) or 4 times daily (QID), at the discretion of the Investigator, with food in pediatric PAH subjects aged 7 to 17 years of age (1) transitioning from continuous IV/SC Remodulin, (2) transitioning from inhaled prostacyclin, or (3) as add-on to current PAH therapies in de novo prostacyclin subjects. Eligible subjects were assigned to a cohort based upon their background therapy. All subjects received oral treprostinil provided as 0.125, 0.25, 1, or 2.5 mg extended-release tablets. Subjects in Cohort 1 began the transition from IV/SC Remodulin in the hospital with a goal of complete transition to oral treprostinil within 5 days. The initial dose of oral treprostinil for Cohort 1 was calculated from the subject's dose of IV/SC Remodulin and weight. Subjects in Cohorts 2 and 3 were initiated on 0.125 mg TID or QID oral treprostinil with dose escalations possible every 24 hours in increments of 0.125 mg TID or QID at the discretion of the Investigator during the first 4 weeks, and in increments of either 0.125 mg or 0.25 mg every 24 hours thereafter. Cross titration occurred for Cohorts 1 and 2 such that doses of IV/SC Remodulin or inhaled prostacyclin were decreased as subjects were fully transitioned to oral treprostinil.

02

Conditions studied

  • PAH

Keywords

  • pediatric
  • treprostinil
  • transition
  • Remodulin
03

In context

Lead sponsor

United Therapeutics is the lead sponsor of 81 studies on the registry; 6 are open to participants now.

Of its 17 completed or terminated interventional studies of FDA-regulated products, 14 (82%) have results posted.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
7 Years to 17 Years
Sexes eligible
All
Accepts healthy volunteers
No

Inclusion criteria

  1. Legal guardian informed consent and subject assent, if appropriate, to participate in the study was voluntarily given.
  2. The subject was between 7 and 17 years of age, inclusive, on the date informed consent was signed.
  3. Cohort 3: The subject weighed a minimum of 22 kg at Screening.

  4. The subject had a current diagnosis of PAH (WHO Group I) associated with:

    1. IPAH or HPAH
    2. 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
    3. 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%.

  5. The subject had a current diagnosis of PAH confirmed by RHC prior to the Screening Visit with the following parameters:

    1. PAPm of ≥25 mmHg
    2. Pulmonary vascular resistance index (PVRi) of >3 Wood Units*m2
    3. Left ventricular end-diastolic pressure (LVEDP) or pulmonary capillary wedge pressure (PCWP) of ≤15 mmHg.
  6. 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.
  7. 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.
  8. 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.
  9. The subject was willing and able to swallow intact tablets whole without chewing, breaking, or splitting.
  10. The subject was willing and able to comply with the dietary requirements associated with the oral treprostinil dosing regimen.
  11. The subject was on stable doses of other medical therapy for 14 days prior to the Baseline Visit with no dose adjustments, additions, or discontinuations. Dose changes of diuretics were allowed if within the usual dose adjustments prescribed for the subject. Anticoagulants could have been adjusted, but not discontinued or added, within 14 days of Baseline. Temporary discontinuation of anticoagulants when related to study-related procedures was allowed.
  12. Females of childbearing potential include any female who had experienced menarche. Females of childbearing potential must have practiced true abstinence from intercourse, had an intrauterine device, or used 2 different forms of highly effective contraception for the duration of the study and for at least 30 days after discontinuing oral treprostinil. Medically acceptable forms of effective contraception included approved hormonal contraceptives (such as birth control pills) or barrier methods (such as a condom or diaphragm) used with a spermicide. For females of childbearing potential, a negative urine pregnancy test was required at Baseline prior to oral treprostinil administration. Males participating in the study must have used a condom during intercourse for the duration of the study and for at least 48 hours after discontinuing oral treprostinil.
  13. Subjects with a history of metallic implants, prior neurosurgical clip placement, or other potential contraindications to cMRI were individually evaluated per site standard operating procedures for MRI performance.
  14. In the opinion of the Principal Investigator, the subject and/or legal guardian was able to communicate effectively with study personnel, and was considered reliable, willing, and likely to be cooperative with protocol requirements, including attending all study visits.

Exclusion criteria

Exclusion Criteria:

  1. 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.
  2. The subject had a current disease severity of Panama FC IIIb or IV.
  3. The subject had previously been exposed to oral treprostinil.
  4. 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.
  5. Cohort 1 and 2: The subject was receiving IV/SC Remodulin or Tyvaso® (as the inhaled prostacyclin) for any other disease or condition other than the treatment of PAH in accordance with the IV/SC Remodulin or Tyvaso package inserts (ie, eligible subjects must have had a WHO Group I PAH classification as defined in inclusion criterion #4).
  6. Cohort 3: The subject had been previously exposed to a prostacyclin within 30 days of Screening, with the exception of vasoreactivity testing.
  7. The subject was pregnant or lactating.
  8. The subject had a current diagnosis of uncontrolled sleep apnea as defined by their physician.
  9. 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.
  10. 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.
  11. 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.
  12. The subject had Down Syndrome.
  13. 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.
  14. 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.
  15. 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.
  16. Subject was actively listed for transplantation.
  17. The subject was receiving an investigational drug, had an investigational device in place, or had participated in an investigational drug or device study within 30 days prior to Baseline. Participation in an observational study did not disqualify a potential subject from study participation.
05

Study design

Phase
Phase 2
Primary purpose
Treatment
Allocation
Non-randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
32 participants (actual)

Study arms

  • Experimental
    Cohort 1 (Transitioning from Parental)

    Transitioned from IV or SC Remodulin to oral treprostinil

    Drug: oral treprostinil

  • Experimental
    Cohort 2 (Transitioning from Inhaled)

    Transitioned from inhaled prostacyclin to oral treprostinil

    Drug: oral treprostinil

  • Experimental
    Cohort 3 (Add-on to Current PAH Therapy)

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

    Drug: oral treprostinil

Interventions

  • Drugoral treprostinil

    Also known as: Orenitram

06

What researchers measure

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.

    Time frame: Up to 24 weeks

Secondary outcomes

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

    Cardiopulmonary Exercise Testing (CPET) was performed with progressive cycle ergometry and ventilatory expired gas analysis obtained using a metabolic cart at Baseline and Week 24/Premature Termination. CPET consisted of measuring oxygen uptake (VO2), carbon dioxide output (VCO2), minute ventilation (VE), and other variables in addition to a 12-lead ECG, blood pressure (BP) monitoring, and pulse oximetry.

    Time frame: Baseline and Week 24

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

    Cardiopulmonary Exercise Testing (CPET) was performed with progressive cycle ergometry and ventilatory expired gas analysis obtained using a metabolic cart at Baseline and Week 24/Premature Termination. CPET consisted of measuring oxygen uptake (VO2), carbon dioxide output (VCO2), minute ventilation (VE), and other variables in addition to a 12-lead ECG, blood pressure (BP) monitoring, and pulse oximetry.

    Time frame: Baseline and Week 24

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

    Cardiopulmonary Exercise Testing (CPET) was performed with progressive cycle ergometry and ventilatory expired gas analysis obtained using a metabolic cart at Baseline and Week 24/Premature Termination. CPET consisted of measuring oxygen uptake (VO2), carbon dioxide output (VCO2), minute ventilation (VE), and other variables in addition to a 12-lead ECG, blood pressure (BP) monitoring, and pulse oximetry.

    Time frame: Baseline and Week 24

  4. Change in Symptoms of PAH From Baseline to Week 24

    PAH symptoms (fatigue, dyspnea, edema, dizziness, syncope, chest pain, orthopnea) were assessed at the Baseline Visit prior to the initiation of oral treprostinil dosing and at Week 24. Scores range from 0 (for the best condition) to 3 (for the worst condition).

    Time frame: Baseline and Week 24

  5. Change in Panama Functional Class From Baseline to Week 24

    Change from Baseline in subject clinical status was recorded according to the Panama Functional Class.

    Time frame: Baseline and Week 24

  6. Change in WHO Functional Class From Baseline to Week 24

    Change from Baseline in subject clinical status was recorded according to the WHO Functional Class.

    Time frame: Baseline and Week 24

  7. Change in 6-Minute Walk Distance (6MWD) From Baseline to Week 24

    The intent of the 6MWT was to evaluate exercise capacity associated with carrying out activities of daily living. Total distance covered in a total of 6 minutes was measured. Oxygen saturation and heart rate (HR) were measured at rest prior to the 6MWT and monitored continuously during the walk. Recovery monitoring (HR and oxygen saturation) was performed and documented at Minute 0 (immediately upon stopping the 6MWT), Minute 1, Minute 2, and Minute 3 post walk.

    Time frame: Baseline and Week 24

  8. Change in Borg Dyspnea Score From Baseline to Week 24

    The Borg dyspnea score was assessed prior to and following the completion of the 6MWT at Week 24. The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the 6MWT. Scores range from 0 (for the best condition) to 10 (for the worst condition).

    Time frame: Baseline and Week 24

  9. Change in Quality of Life Assessed Via the Pediatric Quality of Life Inventory (PedsQL) Questionnaire From Baseline to Week 24

    Four subscales \[items\]: (Physical \[8\], Emotional \[5\], Social \[5\], School Functioning \[5\]). Subjects and subjects' parent(s) completed PedsQL at Week 24. Response to each item on the subscales were graded 0-4 (0=never a problem, 1=almost never a problem, 2=sometimes a problem, 3=often a problem, 4=almost always a problem). Response to each item was transformed from the 0-4 scale to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Using transformed values, mean was computed as sum of the items in each subscale over number of items answered in the same subscale. Two summary scores (Psychosocial Health Summary Score and Total Scale Score) were calculated with a range of 0-100 (higher values indicating better outcome). Psychosocial Health Summary Score was mean computed as sum of the items over the number of items answered in the Emotional, Social, and School Functioning Scales. Total Score was calculated as sum of all items over number of items answered on all the scales.

    Time frame: Baseline and Week 24

  10. Change in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-Pro BNP) From Baseline to Week 24

    Plasma NT-proBNP concentration is a useful biomarker for PAH as it is associated with changes in right heart morphology and function.

    Time frame: Baseline and Week 24

  11. Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 24

    Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

    Time frame: Baseline and Week 24

  12. Change From Baseline in Left Ventricular (LV) Stroke Volume Index at Week 24

    Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

    Time frame: Baseline and Week 24

  13. Change From Baseline in Right Ventricular (RV) Cardiac Output Index at Week 24

    Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

    Time frame: Baseline and Week 24

  14. Change From Baseline in Right Ventricular End-diastolic Volume (RVEDV) Index at Week 24

    Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

    Time frame: Baseline and Week 24

  15. Change From Baseline in Right Ventricular Ejection Fraction (RVEF) at Week 24

    Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

    Time frame: Baseline and Week 24

  16. Change From Baseline in Right Ventricular End-systolic Volume (RVESV) Index at Week 24

    Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

    Time frame: Baseline and Week 24

  17. Change From Baseline in Right Ventricular (RV) Mass Index at Week 24

    Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

    Time frame: Baseline and Week 24

  18. Change From Baseline in Right Ventricular (RV) Stroke Volume Index at Week 24

    Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

    Time frame: Baseline and Week 24

  19. Maximum Observed Drug Concentration in Plasma (Cmax)

    Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able. For the purposes of PK analysis, data for Cohorts 1, 2, and 3 following oral treprostinil administration were combined and compared to parenteral infusion (Cohort 1 Baseline data; Remodulin IV/SC).

    Time frame: Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)

  20. Last Observed Drug Concentration in Plasma (Clast)

    Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able.

    Time frame: Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)

  21. Average Drug Concentration in Plasma (Cavg)

    Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able.

    Time frame: Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)

  22. Observed Minimum Drug Concentration in Plasma (Cmin)

    Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able.

    Time frame: Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)

  23. Area Under the Concentration-Time Curve From Zero to Tau Hours Post-dose (AUCtau)

    Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able.

    Time frame: Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)

  24. Area Under the Concentration-Time Curve From Zero to 8 Hours Post-dose (AUC0-8)

    Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able.

    Time frame: Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)

07

Results

Posted Jan 4, 2019

Participant flow

Participant flow — Overall Study
MilestoneCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Started101012
Completed91012
Not completed100
Withdrew: Adverse event100

Outcome measures

PrimaryNumber 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.

Time frame:
Up to 24 weeks
Reported as:
Number · participants
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).
participantsCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Successfully transitioned/initiated within 4 weeks101012
Successfully maintained through 24 weeks91012
SecondaryCardiopulmonary Exercise Testing - Change From Baseline in Peak Oxygen Uptake (VO2) at Week 24

Cardiopulmonary Exercise Testing (CPET) was performed with progressive cycle ergometry and ventilatory expired gas analysis obtained using a metabolic cart at Baseline and Week 24/Premature Termination. CPET consisted of measuring oxygen uptake (VO2), carbon dioxide output (VCO2), minute ventilation (VE), and other variables in addition to a 12-lead ECG, blood pressure (BP) monitoring, and pulse oximetry.

Time frame:
Baseline and Week 24
Reported as:
Mean · mL/kg/min
Cardiopulmonary Exercise Testing - Change From Baseline in Peak Oxygen Uptake (VO2) at Week 24
mL/kg/minCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Cardiopulmonary Exercise Testing - Change From Baseline in Peak Oxygen Uptake (VO2) at Week 24-3.26 ± 7.342.18 ± 8.012.00 ± 3.47
SecondaryCardiopulmonary Exercise Testing - Change From Baseline in Minute Ventilation (VE)/Carbon Dioxide Output (VCO2) Slope at Week 24

Cardiopulmonary Exercise Testing (CPET) was performed with progressive cycle ergometry and ventilatory expired gas analysis obtained using a metabolic cart at Baseline and Week 24/Premature Termination. CPET consisted of measuring oxygen uptake (VO2), carbon dioxide output (VCO2), minute ventilation (VE), and other variables in addition to a 12-lead ECG, blood pressure (BP) monitoring, and pulse oximetry.

Time frame:
Baseline and Week 24
Reported as:
Mean · VE/VCO2 Slope
Cardiopulmonary Exercise Testing - Change From Baseline in Minute Ventilation (VE)/Carbon Dioxide Output (VCO2) Slope at Week 24
VE/VCO2 SlopeCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Cardiopulmonary Exercise Testing - Change From Baseline in Minute Ventilation (VE)/Carbon Dioxide Output (VCO2) Slope at Week 24-1.066 ± 3.1692.170 ± 5.1111.531 ± 3.821
SecondaryCardiopulmonary Exercise Testing - Change From Baseline in Peak Watts at Week 24

Cardiopulmonary Exercise Testing (CPET) was performed with progressive cycle ergometry and ventilatory expired gas analysis obtained using a metabolic cart at Baseline and Week 24/Premature Termination. CPET consisted of measuring oxygen uptake (VO2), carbon dioxide output (VCO2), minute ventilation (VE), and other variables in addition to a 12-lead ECG, blood pressure (BP) monitoring, and pulse oximetry.

Time frame:
Baseline and Week 24
Reported as:
Mean · Watts
Cardiopulmonary Exercise Testing - Change From Baseline in Peak Watts at Week 24
WattsCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Cardiopulmonary Exercise Testing - Change From Baseline in Peak Watts at Week 244.8 ± 10.3-2.8 ± 11.96.5 ± 12.9
SecondaryChange in Symptoms of PAH From Baseline to Week 24

PAH symptoms (fatigue, dyspnea, edema, dizziness, syncope, chest pain, orthopnea) were assessed at the Baseline Visit prior to the initiation of oral treprostinil dosing and at Week 24. Scores range from 0 (for the best condition) to 3 (for the worst condition).

Time frame:
Baseline and Week 24
Reported as:
Count of participants · Participants
Change in Symptoms of PAH From Baseline to Week 24
ParticipantsCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Chest Pain - Improved - Week 24002
Chest Pain - No Change - Week 24898
Chest Pain - Deteriorated - Week 24112
Dizziness - Improved - Week 24004
Dizziness - No Change - Week 24988
Dizziness - Deteriorated - Week 24020
Dyspnea - Improved - Week 24305
Dyspnea - No Change - Week 24486
Dyspnea - Deteriorated - Week 24221
Edema - Improved - Week 24001
Edema - No Change - Week 2481010
Edema - Deteriorated - Week 24101
Fatigue - Improved - Week 24032
Fatigue - No Change - Week 24569
Fatigue - Deteriorated - Week 24411
Orthopnea - Improved - Week 24003
Orthopnea - No Change - Week 249109
Orthopnea - Deteriorated - Week 24000
SecondaryChange in Panama Functional Class From Baseline to Week 24

Change from Baseline in subject clinical status was recorded according to the Panama Functional Class.

Time frame:
Baseline and Week 24
Reported as:
Count of participants · Participants
Change in Panama Functional Class From Baseline to Week 24
ParticipantsCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Improved - Week 24023
No Change - Week 24979
Deteriorated - Week 24010
SecondaryChange in WHO Functional Class From Baseline to Week 24

Change from Baseline in subject clinical status was recorded according to the WHO Functional Class.

Time frame:
Baseline and Week 24
Reported as:
Count of participants · Participants
Change in WHO Functional Class From Baseline to Week 24
ParticipantsCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Improved - Week 24013
No Change - Week 24989
Deteriorated - Week 24010
SecondaryChange in 6-Minute Walk Distance (6MWD) From Baseline to Week 24

The intent of the 6MWT was to evaluate exercise capacity associated with carrying out activities of daily living. Total distance covered in a total of 6 minutes was measured. Oxygen saturation and heart rate (HR) were measured at rest prior to the 6MWT and monitored continuously during the walk. Recovery monitoring (HR and oxygen saturation) was performed and documented at Minute 0 (immediately upon stopping the 6MWT), Minute 1, Minute 2, and Minute 3 post walk.

Time frame:
Baseline and Week 24
Reported as:
Mean · meters
Change in 6-Minute Walk Distance (6MWD) From Baseline to Week 24
metersCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change in 6-Minute Walk Distance (6MWD) From Baseline to Week 242.7 ± 94.222.1 ± 86.512.8 ± 49.6
SecondaryChange in Borg Dyspnea Score From Baseline to Week 24

The Borg dyspnea score was assessed prior to and following the completion of the 6MWT at Week 24. The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the 6MWT. Scores range from 0 (for the best condition) to 10 (for the worst condition).

Time frame:
Baseline and Week 24
Reported as:
Mean · score on a scale
Change in Borg Dyspnea Score From Baseline to Week 24
score on a scaleCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change in Borg Dyspnea Score From Baseline to Week 24-1.56 ± 3.510.05 ± 1.50-0.83 ± 1.59
SecondaryChange in Quality of Life Assessed Via the Pediatric Quality of Life Inventory (PedsQL) Questionnaire From Baseline to Week 24

Four subscales \[items\]: (Physical \[8\], Emotional \[5\], Social \[5\], School Functioning \[5\]). Subjects and subjects' parent(s) completed PedsQL at Week 24. Response to each item on the subscales were graded 0-4 (0=never a problem, 1=almost never a problem, 2=sometimes a problem, 3=often a problem, 4=almost always a problem). Response to each item was transformed from the 0-4 scale to a 0-100 scale as follows: 0=100, 1=75, 2=50, 3=25, 4=0. Using transformed values, mean was computed as sum of the items in each subscale over number of items answered in the same subscale. Two summary scores (Psychosocial Health Summary Score and Total Scale Score) were calculated with a range of 0-100 (higher values indicating better outcome). Psychosocial Health Summary Score was mean computed as sum of the items over the number of items answered in the Emotional, Social, and School Functioning Scales. Total Score was calculated as sum of all items over number of items answered on all the scales.

Time frame:
Baseline and Week 24
Reported as:
Mean · score on a scale
Change in Quality of Life Assessed Via the Pediatric Quality of Life Inventory (PedsQL) Questionnaire From Baseline to Week 24
score on a scaleCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Physical Functioning - Child - Week 245.57 ± 22.14-2.82 ± 11.095.48 ± 13.40
Emotional Functioning - Child - Week 248.33 ± 11.463.00 ± 13.982.92 ± 13.05
Social Functioning - Child - Week 249.44 ± 16.850.00 ± 15.091.25 ± 11.31
School Functioning - Child - Week 243.89 ± 23.29-6.50 ± 11.567.92 ± 21.37
Psychosocial Health - Child - Week 247.23 ± 13.52-1.17 ± 11.114.04 ± 11.85
Total Scale Score - Child - Week 246.64 ± 15.08-1.76 ± 8.544.53 ± 11.46
Physical Functioning - Parent - Week 241.72 ± 12.31-2.81 ± 14.981.29 ± 14.67
Emotional Functioning - Parent - Week 24-2.22 ± 15.632.50 ± 10.075.00 ± 18.95
Social Functioning - Parent - Week 24-1.11 ± 14.53-5.50 ± 18.9211.67 ± 16.28
School Functioning - Parent - Week 249.44 ± 16.85-5.50 ± 11.655.00 ± 13.14
Psychosocial Health - Parent - Week 242.04 ± 13.80-2.81 ± 11.487.22 ± 13.21
Total Scale Score - Parent - Week 241.93 ± 11.79-2.84 ± 12.295.17 ± 12.78
SecondaryChange in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-Pro BNP) From Baseline to Week 24

Plasma NT-proBNP concentration is a useful biomarker for PAH as it is associated with changes in right heart morphology and function.

Time frame:
Baseline and Week 24
Reported as:
Mean · pg/mL
Change in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-Pro BNP) From Baseline to Week 24
pg/mLCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change in Plasma N-terminal Pro-B-type Natriuretic Peptide (NT-Pro BNP) From Baseline to Week 2487.156 ± 281.66481.930 ± 245.534160.617 ± 549.953
SecondaryChange From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 24

Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

Time frame:
Baseline and Week 24
Reported as:
Mean · percentage of LVEF
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 24
percentage of LVEFCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 24-1.0 ± 1.42.4 ± 6.0-2.4 ± 3.1
SecondaryChange From Baseline in Left Ventricular (LV) Stroke Volume Index at Week 24

Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

Time frame:
Baseline and Week 24
Reported as:
Mean · mL/beat/m2
Change From Baseline in Left Ventricular (LV) Stroke Volume Index at Week 24
mL/beat/m2Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change From Baseline in Left Ventricular (LV) Stroke Volume Index at Week 24-4.003 ± 2.6886.336 ± 8.4481.113 ± 5.539
SecondaryChange From Baseline in Right Ventricular (RV) Cardiac Output Index at Week 24

Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

Time frame:
Baseline and Week 24
Reported as:
Mean · L/min/m2
Change From Baseline in Right Ventricular (RV) Cardiac Output Index at Week 24
L/min/m2Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change From Baseline in Right Ventricular (RV) Cardiac Output Index at Week 240.303 ± 0.2090.767 ± 1.0100.121 ± 1.047
SecondaryChange From Baseline in Right Ventricular End-diastolic Volume (RVEDV) Index at Week 24

Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

Time frame:
Baseline and Week 24
Reported as:
Mean · mL/m^2
Change From Baseline in Right Ventricular End-diastolic Volume (RVEDV) Index at Week 24
mL/m^2Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change From Baseline in Right Ventricular End-diastolic Volume (RVEDV) Index at Week 24-8.190 ± 12.88712.131 ± 14.38210.601 ± 26.115
SecondaryChange From Baseline in Right Ventricular Ejection Fraction (RVEF) at Week 24

Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

Time frame:
Baseline and Week 24
Reported as:
Mean · percentage of RVEF
Change From Baseline in Right Ventricular Ejection Fraction (RVEF) at Week 24
percentage of RVEFCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change From Baseline in Right Ventricular Ejection Fraction (RVEF) at Week 244.0 ± 7.60.4 ± 7.1-0.7 ± 2.7
SecondaryChange From Baseline in Right Ventricular End-systolic Volume (RVESV) Index at Week 24

Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

Time frame:
Baseline and Week 24
Reported as:
Mean · mL/m2
Change From Baseline in Right Ventricular End-systolic Volume (RVESV) Index at Week 24
mL/m2Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change From Baseline in Right Ventricular End-systolic Volume (RVESV) Index at Week 24-7.975 ± 12.6145.884 ± 12.9655.722 ± 13.807
SecondaryChange From Baseline in Right Ventricular (RV) Mass Index at Week 24

Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

Time frame:
Baseline and Week 24
Reported as:
Mean · g/m2
Change From Baseline in Right Ventricular (RV) Mass Index at Week 24
g/m2Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change From Baseline in Right Ventricular (RV) Mass Index at Week 242.375 ± 6.2263.041 ± 7.8900.614 ± 3.450
SecondaryChange From Baseline in Right Ventricular (RV) Stroke Volume Index at Week 24

Cardiac MRI imaging was performed in all subjects aged 10 years and older at Baseline and Week 24/Premature Termination; imaging was optionally performed in subjects under the age of 10 years. The subject's BP was taken immediately prior to the cMRI assessment in the supine position to measure vascular parameters.

Time frame:
Baseline and Week 24
Reported as:
Mean · mL/beat//m2
Change From Baseline in Right Ventricular (RV) Stroke Volume Index at Week 24
mL/beat//m2Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
Change From Baseline in Right Ventricular (RV) Stroke Volume Index at Week 24-0.215 ± 1.5576.193 ± 8.0151.458 ± 6.719
SecondaryMaximum Observed Drug Concentration in Plasma (Cmax)

Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able. For the purposes of PK analysis, data for Cohorts 1, 2, and 3 following oral treprostinil administration were combined and compared to parenteral infusion (Cohort 1 Baseline data; Remodulin IV/SC).

Time frame:
Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)
Reported as:
Geometric mean · ng/mL
Maximum Observed Drug Concentration in Plasma (Cmax)
ng/mLCohort 1 (Transitioning From Parenteral)Cohorts Combined After Oral Treprostinil Administration
Maximum Observed Drug Concentration in Plasma (Cmax)5.14 ± 39.44.91 ± 50.5
SecondaryLast Observed Drug Concentration in Plasma (Clast)

Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able.

Time frame:
Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)
Reported as:
Geometric mean · ng/mL
Last Observed Drug Concentration in Plasma (Clast)
ng/mLCohort 1 (Transitioning From Parenteral)Cohorts Combined After Oral Treprostinil Administration
Last Observed Drug Concentration in Plasma (Clast)4.66 ± 38.60.985 ± 104
SecondaryAverage Drug Concentration in Plasma (Cavg)

Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able.

Time frame:
Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)
Reported as:
Geometric mean · ng/mL
Average Drug Concentration in Plasma (Cavg)
ng/mLCohort 1 (Transitioning From Parenteral)Cohorts Combined After Oral Treprostinil Administration
Average Drug Concentration in Plasma (Cavg)4.28 ± 37.72.80 ± 54.5
SecondaryObserved Minimum Drug Concentration in Plasma (Cmin)

Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able.

Time frame:
Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)
Reported as:
Geometric mean · ng/mL
Observed Minimum Drug Concentration in Plasma (Cmin)
ng/mLCohort 1 (Transitioning From Parenteral)Cohorts Combined After Oral Treprostinil Administration
Observed Minimum Drug Concentration in Plasma (Cmin)3.45 ± 47.90.799 ± 88.5
SecondaryArea Under the Concentration-Time Curve From Zero to Tau Hours Post-dose (AUCtau)

Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able.

Time frame:
Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)
Reported as:
Geometric mean · h*ng/mL
Area Under the Concentration-Time Curve From Zero to Tau Hours Post-dose (AUCtau)
h*ng/mLCohort 1 (Transitioning From Parenteral)Cohorts Combined After Oral Treprostinil Administration
Area Under the Concentration-Time Curve From Zero to Tau Hours Post-dose (AUCtau)34.3 ± 37.722.2 ± 53.8
SecondaryArea Under the Concentration-Time Curve From Zero to 8 Hours Post-dose (AUC0-8)

Cohort 1 had three blood samples obtained at 'Time 0' and at 4 and 8 hours at the Baseline visit. All cohorts had five blood samples obtained from at 'Time 0' and at 2, 4, 6, and 8 hours at the Week 24 visit. Plasma samples were analyzed for treprostinil using a validated bioanalytical plasma assay. Individual and mean treprostinil plasma concentration data and treprostinil pharmacokinetic parameters, such as peak observed plasma concentration (Cmax), time to peak plasma concentration (Tmax), area under the plasma concentration-time curve (AUC0-inf), were determined as able.

Time frame:
Baseline (Cohort 1 only; 0, 4, 8 hours while receiving IV/SC Remodulin) and Week 24 (all cohorts; 0, 2, 4, 6, 8 hours post-dose oral treprostinil)
Reported as:
Geometric mean · h*ng/mL
Area Under the Concentration-Time Curve From Zero to 8 Hours Post-dose (AUC0-8)
h*ng/mLCohort 1 (Transitioning From Parenteral)Cohorts Combined After Oral Treprostinil Administration
Area Under the Concentration-Time Curve From Zero to 8 Hours Post-dose (AUC0-8)34.3 ± 37.722.4 ± 54.3

Adverse events

Collected over Adverse events were recorded from the time that each subject and/or caregiver signed the ICF until the time screen failure was documented, or until the subject was either discontinued from the study or all Week 24 study assessments were completed.. Non-serious events are listed at a 0% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Cohort 1 (Transitioning From Parental)0/10 (0%)5/10 (50%)10/10 (100%)
Cohort 2 (Transitioning From Inhaled)0/10 (0%)0/10 (0%)10/10 (100%)
Cohort 3 (Add-on to Current PAH Therapy)0/12 (0%)4/12 (33.3%)12/12 (100%)
Most frequent serious events
Most frequent serious events
EventCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
SeizureNervous system disorders2/100/100/12
Chest painGeneral disorders0/100/102/12
Device related infectionInfections and infestations1/100/100/12
Stoma site infectionInfections and infestations1/100/100/12
SyncopeNervous system disorders1/100/100/12
TachycardiaCardiac disorders0/100/101/12
PneumoniaInfections and infestations0/100/101/12
Bronchial hyperreactivityRespiratory, thoracic and mediastinal disorders0/100/101/12
DyspnoeaRespiratory, thoracic and mediastinal disorders0/100/101/12
Most frequent other events
Showing 10 of 104
Most frequent other events
EventCohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)
HeadacheNervous system disorders6/108/1012/12
VomitingGastrointestinal disorders9/105/107/12
DiarrhoeaGastrointestinal disorders6/107/109/12
NauseaGastrointestinal disorders7/105/109/12
FlushingVascular disorders6/104/108/12
Pain in jawMusculoskeletal and connective tissue disorders1/101/106/12
CoughRespiratory, thoracic and mediastinal disorders1/105/102/12
Abdominal pain upperGastrointestinal disorders4/104/105/12
Chest painGeneral disorders1/100/105/12
Pain in extremityMusculoskeletal and connective tissue disorders1/101/105/12

Baseline characteristics

Age, Categorical
Age, Categorical(Participants)Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)Total
<=18 years10101232
Between 18 and 65 years0000
>=65 years0000
Age, Continuous
Age, Continuous(years)Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)Total
Median10.0 (7 to 17)13.5 (8 to 17)13.5 (8 to 17)12 (7 to 17)
Sex: Female, Male
Sex: Female, Male(Participants)Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)Total
Female97723
Male1359
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)Total
Hispanic or Latino4217
Not Hispanic or Latino681125
Unknown or Not Reported0000
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)Total
American Indian or Alaska Native1001
Asian1124
Native Hawaiian or Other Pacific Islander0000
Black or African American0000
White791026
More than one race0000
Unknown or Not Reported1001
Region of Enrollment
Region of Enrollment(Participants)Cohort 1 (Transitioning From Parental)Cohort 2 (Transitioning From Inhaled)Cohort 3 (Add-on to Current PAH Therapy)Total
United States10101232
08

Study locations

9 sites
  • Lucile Packard Children's Hospital
    Palo Alto, California 94304, United States
  • University of California San Francisco
    San Francisco, California 94143, United States
  • Children's Hospital Colorado
    Aurora, Colorado 80045, United States
  • Boston Children's Hospital
    Boston, Massachusetts 02115, United States
  • Cincinnati Children's Hospital Medical Center
    Cincinnati, Ohio 45229, United States
  • The Children's Hospital of Philadelphia
    Philadelphia, Pennsylvania 19104, United States
  • Monroe Carell Jr Children's Hospital at Vanderbilt
    Nashville, Tennessee 37232, United States
  • Seattle Children's Hospital
    Seattle, Washington 98105, United States
  • Children's Hospital of Wisconsin
    Milwaukee, Wisconsin 53226, United States
09

References and documents

Publications

  • 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. PubMed 31215336 ↗
  • 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. PubMed 32398473 ↗

Study documents

  • Study protocol · Sep 1, 2016
  • Statistical analysis plan · Aug 15, 2017

Documents are hosted by the registry — open the source record to download them.

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Mar 30, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT02276872
Lead sponsor
United Therapeutics
Responsible party
Sponsor
First posted
Oct 28, 2014
Start date
Dec 18, 2014
Primary completion
Jul 20, 2017
Completion
Jul 20, 2017
Results posted
Jan 4, 2019
Last update
Mar 30, 2025

Study contacts

Dunbar Ivy, MD
principal investigator · Denver Children's Hospital

Oversight

Data monitoring committee
Yes
View the source record on ClinicalTrials.gov ↗

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