Safety, Tolerability, and Pharmacokinetics of Oral Treprostinil in Pediatric PAH Patients Aged 7 to 17 Years
Condition: PAH
Intervention: oral treprostinil
Intervention MeSH terms: Treprostinil
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 7 Years
Maximum age: 17 Years
Healthy volunteers: No
Keywords: pediatric; treprostinil; transition; Remodulin

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.
    

Eligibility criteria:

        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:

          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.