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



Status:Completed
Healthy:No
Age Range:7 - 17
Updated:1/6/2019
Start Date:December 18, 2014
End Date:July 20, 2017

Use our guide to learn which trials are right for you!

A Multicenter, Open-Label, 24-Week, Uncontrolled Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of Oral Treprostinil Extended Release Tablets Following Transition From Remodulin or Inhaled Prostacyclin Therapy or as Add-on to Current PAH Therapy in De Novo Prostacyclin Pediatric Subjects Aged 7 to 17 Years With Pulmonary Arterial Hypertension

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.

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.

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.
We found this trial at
9
sites
13123 E 16th Ave
Aurora, Colorado 80045
(720) 777-1234
Principal Investigator: David Dunbar Ivy, MD
Children's Hospital Colorado At Children's Hospital Colorado, we see more, treat more and heal more...
?
mi
from
Aurora, CO
Click here to add this to my saved trials
3333 Burnet Avenue # Mlc3008
Cincinnati, Ohio 45229
 1-513-636-4200 
Principal Investigator: Russel Hirsch, MD
Phone: 513-803-1910
Cincinnati Children's Hospital Medical Center Patients and families from across the region and around the...
?
mi
from
Cincinnati, OH
Click here to add this to my saved trials
South 34th Street
Philadelphia, Pennsylvania 19104
 215-590-1000
Principal Investigator: Rachel Hopper, MD
Phone: 267-425-2094
Children's Hospital of Philadelphia Since its start in 1855 as the nation's first hospital devoted...
?
mi
from
Philadelphia, PA
Click here to add this to my saved trials
300 Longwood Ave
Boston, Massachusetts 02115
(617) 355-6000
Principal Investigator: Mary Mullen, MD, PhD
Phone: 617-355-5486
Boston Children's Hospital Boston Children's Hospital is a 395-bed comprehensive center for pediatric health care....
?
mi
from
Boston, MA
Click here to add this to my saved trials
9000 W Wisconsin Ave #270
Milwaukee, Wisconsin 53226
(414) 266-2000
Principal Investigator: Edward Kirkpatrick, DO
Phone: 414-266-4761
Children's Hospital of Wisconsin Nothing matters more than our children. At Children's Hospital of Wisconsin,...
?
mi
from
Milwaukee, WI
Click here to add this to my saved trials
Nashville, Tennessee 37232
Principal Investigator: Eric Austin, MD
Phone: 615-936-2233
?
mi
from
Nashville, TN
Click here to add this to my saved trials
Palo Alto, California 94304
Principal Investigator: Jeffrey Feinstein, MD, MPH
Phone: 650-723-8922
?
mi
from
Palo Alto, CA
Click here to add this to my saved trials
San Francisco, California 94143
?
mi
from
San Francisco, CA
Click here to add this to my saved trials
4800 Sand Point Way NE
Seattle, Washington 98105
(206) 987-2000
Principal Investigator: Delphine Yung, MD
Phone: 206-987-5708
Seattle Children's Hospital Seattle Children’s Hospital specializes in meeting the unique physical, emotional and developmental...
?
mi
from
Seattle, WA
Click here to add this to my saved trials