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

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.