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

• Sponsor: United Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02276872
• Collaborator: (none)
• Enrollment: 32
• Locations: 9
• Arms: 3
• Actual Duration (Months): 31
• Patients Per Site: 3.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
PAH	Drug: oral treprostinil	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Dec 18, 2014
• Actual Primary Completion Date: Jul 20, 2017
• Actual Study Completion Date: Jul 20, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cohort 1 (Transitioning from Parental) Transitioned from IV or SC Remodulin to oral treprostinil	Drug: oral treprostinil; Other Names: Orenitram
Experimental: Cohort 2 (Transitioning from Inhaled) Transitioned from inhaled prostacyclin to oral treprostinil	Drug: oral treprostinil; Other Names: Orenitram
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; Other Names: Orenitram

Outcome Measures

Primary Outcome Measures

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). [Up to 24 weeks]

   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.

Secondary Outcome Measures

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

2. 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 (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.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

19. Maximum Observed Drug Concentration in Plasma (Cmax) [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)]

    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).

20. Last Observed Drug Concentration in Plasma (Clast) [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)]

    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.

21. Average Drug Concentration in Plasma (Cavg) [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)]

    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.

22. Observed Minimum Drug Concentration in Plasma (Cmin) [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)]

    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.

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

    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.

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

    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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 7 Years to 17 Years
• Sexes Eligible for Study: 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:

5. IPAH or HPAH

6. 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

7. 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%.

8. 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.

4. 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.

5. 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.

6. 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.

7. The subject was willing and able to swallow intact tablets whole without chewing, breaking, or splitting.

8. The subject was willing and able to comply with the dietary requirements associated with the oral treprostinil dosing regimen.

9. 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.

10. 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.

11. 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.

12. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Lucile Packard Children's Hospital	Palo Alto	California	United States	94304
2	University of California San Francisco	San Francisco	California	United States	94143
3	Children's Hospital Colorado	Aurora	Colorado	United States	80045
4	Boston Children's Hospital	Boston	Massachusetts	United States	02115
5	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
6	The Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
7	Monroe Carell Jr Children's Hospital at Vanderbilt	Nashville	Tennessee	United States	37232
8	Seattle Children's Hospital	Seattle	Washington	United States	98105
9	Children's Hospital of Wisconsin	Milwaukee	Wisconsin	United States	53226

Sponsors and Collaborators

• United Therapeutics

Investigators

• Principal Investigator: Dunbar Ivy, MD, Denver Children's Hospital

Study Documents (Full-Text)

• Statistical Analysis Plan - Aug 15, 2017
• Study Protocol - Sep 1, 2016

More Information

Publications

None provided.

• Responsible Party: United Therapeutics
• ClinicalTrials.gov Identifier: NCT02276872
• Other Study ID Numbers: TDE-PH-206
• First Posted: Oct 28, 2014
• Last Update Posted: Jan 4, 2019
• Last Verified: Dec 1, 2018

• Keywords provided by United Therapeutics: pediatric; treprostinil; transition; Remodulin
• Additional relevant MeSH terms: Treprostinil

Study Results

Participant Flow

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Period Title: Overall Study
STARTED	10	10	12
COMPLETED	9	10	12
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)	Total
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy	Total of all reporting groups
Overall Participants	10	10	12	32
Age (Count of Participants)
<=18 years	10 100%	10 100%	12 100%	32 100%
Between 18 and 65 years	0 0%	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	10.0	13.5	13.5	12
Sex: Female, Male (Count of Participants)
Female	9 90%	7 70%	7 58.3%	23 71.9%
Male	1 10%	3 30%	5 41.7%	9 28.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	4 40%	2 20%	1 8.3%	7 21.9%
Not Hispanic or Latino	6 60%	8 80%	11 91.7%	25 78.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 10%	0 0%	0 0%	1 3.1%
Asian	1 10%	1 10%	2 16.7%	4 12.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%	0 0%
White	7 70%	9 90%	10 83.3%	26 81.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 10%	0 0%	0 0%	1 3.1%
Region of Enrollment (Count of Participants)
United States	10 100%	10 100%	12 100%	32 100%

Outcome Measures

1. Primary Outcome

Title	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).
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	10	10	12
Successfully transitioned/initiated within 4 weeks	10 100%	10 100%	12 100%
Successfully maintained through 24 weeks	9 90%	10 100%	12 100%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects that Completed Testing at Week 24

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	5	9	12
Mean (Standard Deviation) [mL/kg/min]	-3.26 (7.34)	2.18 (8.01)	2.00 (3.47)

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects that Completed Testing at Week 24

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	5	9	12
Mean (Standard Deviation) [VE/VCO2 Slope]	-1.066 (3.169)	2.170 (5.111)	1.531 (3.821)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects that Completed Testing at Week 24

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	6	9	11
Mean (Standard Deviation) [Watts]	4.8 (10.3)	-2.8 (11.9)	6.5 (12.9)

5. Secondary Outcome

Title	Change in Symptoms of PAH From Baseline to Week 24
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects that Completed Study Week 24

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	9	10	12
Chest Pain - Improved - Week 24	0 0%	0 0%	2 16.7%
Chest Pain - No Change - Week 24	8 80%	9 90%	8 66.7%
Chest Pain - Deteriorated - Week 24	1 10%	1 10%	2 16.7%
Dizziness - Improved - Week 24	0 0%	0 0%	4 33.3%
Dizziness - No Change - Week 24	9 90%	8 80%	8 66.7%
Dizziness - Deteriorated - Week 24	0 0%	2 20%	0 0%
Dyspnea - Improved - Week 24	3 30%	0 0%	5 41.7%
Dyspnea - No Change - Week 24	4 40%	8 80%	6 50%
Dyspnea - Deteriorated - Week 24	2 20%	2 20%	1 8.3%
Edema - Improved - Week 24	0 0%	0 0%	1 8.3%
Edema - No Change - Week 24	8 80%	10 100%	10 83.3%
Edema - Deteriorated - Week 24	1 10%	0 0%	1 8.3%
Fatigue - Improved - Week 24	0 0%	3 30%	2 16.7%
Fatigue - No Change - Week 24	5 50%	6 60%	9 75%
Fatigue - Deteriorated - Week 24	4 40%	1 10%	1 8.3%
Orthopnea - Improved - Week 24	0 0%	0 0%	3 25%
Orthopnea - No Change - Week 24	9 90%	10 100%	9 75%
Orthopnea - Deteriorated - Week 24	0 0%	0 0%	0 0%

6. Secondary Outcome

Title	Change in Panama Functional Class From Baseline to Week 24
Description	Change from Baseline in subject clinical status was recorded according to the Panama Functional Class.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects that Completed Study Week 24

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	9	10	12
Improved - Week 24	0 0%	2 20%	3 25%
No Change - Week 24	9 90%	7 70%	9 75%
Deteriorated - Week 24	0 0%	1 10%	0 0%

7. Secondary Outcome

Title	Change in WHO Functional Class From Baseline to Week 24
Description	Change from Baseline in subject clinical status was recorded according to the WHO Functional Class.
Time Frame	Baseline and Week 24

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects that Completed Study Week 24

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	9	10	12
Improved - Week 24	0 0%	1 10%	3 25%
No Change - Week 24	9 90%	8 80%	9 75%
Deteriorated - Week 24	0 0%	1 10%	0 0%

8. Secondary Outcome

Title	Change in 6-Minute Walk Distance (6MWD) From Baseline to Week 24
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects that Completed Study Week 24

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	9	10	12
Mean (Standard Deviation) [meters]	2.7 (94.2)	22.1 (86.5)	12.8 (49.6)

9. Secondary Outcome

Title	Change in Borg Dyspnea Score From Baseline to Week 24
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects that Completed Study Week 24

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy oral treprostinil
Measure Participants	9	10	12
Mean (Standard Deviation) [score on a scale]	-1.56 (3.51)	0.05 (1.50)	-0.83 (1.59)

10. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects that Completed Study Week 24

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	9	10	12
Physical Functioning - Child - Week 24	5.57 (22.14)	-2.82 (11.09)	5.48 (13.40)
Emotional Functioning - Child - Week 24	8.33 (11.46)	3.00 (13.98)	2.92 (13.05)
Social Functioning - Child - Week 24	9.44 (16.85)	0.00 (15.09)	1.25 (11.31)
School Functioning - Child - Week 24	3.89 (23.29)	-6.50 (11.56)	7.92 (21.37)
Psychosocial Health - Child - Week 24	7.23 (13.52)	-1.17 (11.11)	4.04 (11.85)
Total Scale Score - Child - Week 24	6.64 (15.08)	-1.76 (8.54)	4.53 (11.46)
Physical Functioning - Parent - Week 24	1.72 (12.31)	-2.81 (14.98)	1.29 (14.67)
Emotional Functioning - Parent - Week 24	-2.22 (15.63)	2.50 (10.07)	5.00 (18.95)
Social Functioning - Parent - Week 24	-1.11 (14.53)	-5.50 (18.92)	11.67 (16.28)
School Functioning - Parent - Week 24	9.44 (16.85)	-5.50 (11.65)	5.00 (13.14)
Psychosocial Health - Parent - Week 24	2.04 (13.80)	-2.81 (11.48)	7.22 (13.21)
Total Scale Score - Parent - Week 24	1.93 (11.79)	-2.84 (12.29)	5.17 (12.78)

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects that Completed Study Week 24

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	9	10	12
Mean (Standard Deviation) [pg/mL]	87.156 (281.664)	81.930 (245.534)	160.617 (549.953)

12. Secondary Outcome

Title	Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 24
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects with both Baseline and Week 24 Measurements

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	4	9	9
Mean (Standard Deviation) [percentage of LVEF]	-1.0 (1.4)	2.4 (6.0)	-2.4 (3.1)

13. Secondary Outcome

Title	Change From Baseline in Left Ventricular (LV) Stroke Volume Index at Week 24
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects with both Baseline and Week 24 Measurements

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	4	9	9
Mean (Standard Error) [mL/beat/m2]	-4.003 (2.688)	6.336 (8.448)	1.113 (5.539)

14. Secondary Outcome

Title	Change From Baseline in Right Ventricular (RV) Cardiac Output Index at Week 24
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects with both Baseline and Week 24 Measurements

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	4	9	9
Mean (Standard Error) [L/min/m2]	0.303 (0.209)	0.767 (1.010)	0.121 (1.047)

15. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects with both Baseline and Week 24 Measurements

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	4	9	9
Mean (Standard Error) [mL/m^2]	-8.190 (12.887)	12.131 (14.382)	10.601 (26.115)

16. Secondary Outcome

Title	Change From Baseline in Right Ventricular Ejection Fraction (RVEF) at Week 24
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects with both Baseline and Week 24 Measurements

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	4	9	9
Mean (Standard Error) [percentage of RVEF]	4.0 (7.6)	0.4 (7.1)	-0.7 (2.7)

17. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects with both Baseline and Week 24 Measurements

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	4	9	9
Mean (Standard Error) [mL/m2]	-7.975 (12.614)	5.884 (12.965)	5.722 (13.807)

18. Secondary Outcome

Title	Change From Baseline in Right Ventricular (RV) Mass Index at Week 24
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects with both Baseline and Week 24 Measurements

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	4	9	9
Mean (Standard Error) [g/m2]	2.375 (6.226)	3.041 (7.890)	0.614 (3.450)

19. Secondary Outcome

Title	Change From Baseline in Right Ventricular (RV) Stroke Volume Index at Week 24
Description	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

Outcome Measure Data

Analysis Population Description

Safety Population - Number of Subjects with both Baseline and Week 24 Measurements

Arm/Group Title	Cohort 1 (Transitioning From Parental)	Cohort 2 (Transitioning From Inhaled)	Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Transitioned from inhaled prostacyclin to oral treprostinil	Treated with oral treprostinil as a de novo add-on to current PAH therapy
Measure Participants	4	9	9
Mean (Standard Error) [mL/beat//m2]	-0.215 (1.557)	6.193 (8.015)	1.458 (6.719)

20. Secondary Outcome

Title	Maximum Observed Drug Concentration in Plasma (Cmax)
Description	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)

Outcome Measure Data

Analysis Population Description

PK Population. To provide a larger sample size for 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).

Arm/Group Title	Cohort 1 (Transitioning From Parenteral)	Cohorts Combined After Oral Treprostinil Administration
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Combined PK data for Cohorts 1, 2, and 3 combined after oral treprostinil administration
Measure Participants	10	32
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	5.14 (39.4)	4.91 (50.5)

21. Secondary Outcome

Title	Last Observed Drug Concentration in Plasma (Clast)
Description	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)

Outcome Measure Data

Analysis Population Description

PK Population. To provide a larger sample size for 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).

Arm/Group Title	Cohort 1 (Transitioning From Parenteral)	Cohorts Combined After Oral Treprostinil Administration
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Combined PK data for Cohorts 1, 2, and 3 combined after oral treprostinil administration
Measure Participants	10	32
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	4.66 (38.6)	0.985 (104)

22. Secondary Outcome

Title	Average Drug Concentration in Plasma (Cavg)
Description	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)

Outcome Measure Data

Analysis Population Description

PK Population. To provide a larger sample size for 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).

Arm/Group Title	Cohort 1 (Transitioning From Parenteral)	Cohorts Combined After Oral Treprostinil Administration
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Combined PK data for Cohorts 1, 2, and 3 combined after oral treprostinil administration
Measure Participants	10	32
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	4.28 (37.7)	2.80 (54.5)

23. Secondary Outcome

Title	Observed Minimum Drug Concentration in Plasma (Cmin)
Description	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)

Outcome Measure Data

Analysis Population Description

PK Population. To provide a larger sample size for 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).

Arm/Group Title	Cohort 1 (Transitioning From Parenteral)	Cohorts Combined After Oral Treprostinil Administration
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Combined PK data for Cohorts 1, 2, and 3 combined after oral treprostinil administration
Measure Participants	10	32
Geometric Mean (Geometric Coefficient of Variation) [ng/mL]	3.45 (47.9)	0.799 (88.5)

24. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

PK Population. To provide a larger sample size for 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).

Arm/Group Title	Cohort 1 (Transitioning From Parenteral)	Cohorts Combined After Oral Treprostinil Administration
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Combined PK data for Cohorts 1, 2, and 3 combined after oral treprostinil administration
Measure Participants	10	32
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	34.3 (37.7)	22.2 (53.8)

25. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

PK Population. To provide a larger sample size for 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).

Arm/Group Title	Cohort 1 (Transitioning From Parenteral)	Cohorts Combined After Oral Treprostinil Administration
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil	Combined PK data for Cohorts 1, 2, and 3 combined after oral treprostinil administration
Measure Participants	10	32
Geometric Mean (Geometric Coefficient of Variation) [h*ng/mL]	34.3 (37.7)	22.4 (54.3)

Adverse Events

Time Frame	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.
Arm/Group Title	Cohort 1 (Transitioning From Parental)		Cohort 2 (Transitioning From Inhaled)		Cohort 3 (Add-on to Current PAH Therapy)
Arm/Group Description	Transitioned from IV or SC Remodulin to oral treprostinil		Transitioned from inhaled prostacyclin to oral treprostinil		Treated with oral treprostinil as a de novo add-on to current PAH therapy
All Cause Mortality
	Cohort 1 (Transitioning From Parental)		Cohort 2 (Transitioning From Inhaled)		Cohort 3 (Add-on to Current PAH Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)		0/12 (0%)
Serious Adverse Events
	Cohort 1 (Transitioning From Parental)		Cohort 2 (Transitioning From Inhaled)		Cohort 3 (Add-on to Current PAH Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	5/10 (50%)		0/10 (0%)		4/12 (33.3%)
Cardiac disorders
Tachycardia	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
General disorders
Chest pain	0/10 (0%)	0	0/10 (0%)	0	2/12 (16.7%)	2
Infections and infestations
Device related infection	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Pneumonia	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Stoma site infection	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Nervous system disorders
Seizure	2/10 (20%)	2	0/10 (0%)	0	0/12 (0%)	0
Syncope	1/10 (10%)	2	0/10 (0%)	0	0/12 (0%)	0
Respiratory, thoracic and mediastinal disorders
Bronchial hyperreactivity	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Dyspnoea	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	Cohort 1 (Transitioning From Parental)		Cohort 2 (Transitioning From Inhaled)		Cohort 3 (Add-on to Current PAH Therapy)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/10 (100%)		10/10 (100%)		12/12 (100%)
Cardiac disorders
Arrhythmia	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Cyanosis	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Palpitations	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Pericardial effusion	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Right atrial enlargement	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Right ventricular hypertrophy	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Tachycardia	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Eye disorders
Excessive eye blinking	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Eye pain	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Perioribital oedema	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Gastrointestinal disorders
Diarrhoea	6/10 (60%)	6	7/10 (70%)	7	9/12 (75%)	10
Nausea	7/10 (70%)	7	5/10 (50%)	6	9/12 (75%)	9
Vomiting	9/10 (90%)	9	5/10 (50%)	6	7/12 (58.3%)	7
Abdominal pain upper	4/10 (40%)	4	4/10 (40%)	4	5/12 (41.7%)	6
Abdominal pain	0/10 (0%)	0	2/10 (20%)	2	2/12 (16.7%)	2
Gastrooesophageal reflux disease	1/10 (10%)	2	1/10 (10%)	1	1/12 (8.3%)	1
Dyspepsia	1/10 (10%)	1	1/10 (10%)	1	0/12 (0%)	0
Anorectal discomfort	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Dyschezia	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Faeces soft	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Flatulence	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Gingival bleeding	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Haematochezia	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
General disorders
Chest pain	1/10 (10%)	1	0/10 (0%)	0	5/12 (41.7%)	6
Fatigue	2/10 (20%)	2	1/10 (10%)	1	3/12 (25%)	3
Pyrexia	1/10 (10%)	1	1/10 (10%)	1	2/12 (16.7%)	2
Pain	0/10 (0%)	0	0/10 (0%)	0	2/12 (16.7%)	2
Facial pain	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Feeling hot	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Influenza like illness	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Malaise	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Oedema	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Immune system disorders
Hypersensitivity	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Infections and infestations
Viral upper respiratory tract infection	2/10 (20%)	2	4/10 (40%)	5	2/12 (16.7%)	2
Ear infection	2/10 (20%)	2	0/10 (0%)	0	0/12 (0%)	0
Gastroenteritis	1/10 (10%)	1	1/10 (10%)	1	0/12 (0%)	0
Gastroenteritis viral	2/10 (20%)	2	0/10 (0%)	0	0/12 (0%)	0
Pharyngitis streptococcal	1/10 (10%)	1	1/10 (10%)	1	0/12 (0%)	0
Sinusitis	0/10 (0%)	0	0/10 (0%)	0	2/12 (16.7%)	2
Upper respiratory tract infection	1/10 (10%)	1	0/10 (0%)	0	1/12 (8.3%)	1
Device related infection	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Hand-foot-and-mouth disease	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Impetigo	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Kidney infection	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Nasopharyngitis	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Pneumonia	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Stoma site infection	1/10 (10%)	2	0/10 (0%)	0	0/12 (0%)	0
Injury, poisoning and procedural complications
Heat exhaustion	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Investigations
N-terminal prohormone brain natriuretic peptide increased	2/10 (20%)	2	1/10 (10%)	2	1/12 (8.3%)	1
Weight decreased	0/10 (0%)	0	1/10 (10%)	1	1/12 (8.3%)	1
Aspartate aminotransferase increased	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Blood creatinine increased	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Blood iron decreased	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Platelet count decreased	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	1/10 (10%)	1	1/10 (10%)	1	2/12 (16.7%)	2
Dehydration	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Hyperkalaemia	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Musculoskeletal and connective tissue disorders
Pain in jaw	1/10 (10%)	1	1/10 (10%)	1	6/12 (50%)	6
Pain in extremity	1/10 (10%)	1	1/10 (10%)	1	5/12 (41.7%)	7
Arthralgia	1/10 (10%)	1	0/10 (0%)	0	1/12 (8.3%)	1
Back pain	1/10 (10%)	1	1/10 (10%)	1	0/12 (0%)	0
Muscle spasms	0/10 (0%)	0	0/10 (0%)	0	2/12 (16.7%)	2
Musculoskeletal pain	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Musculoskeletal stiffness	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Nervous system disorders
Headache	6/10 (60%)	6	8/10 (80%)	9	12/12 (100%)	12
Dizziness	3/10 (30%)	3	1/10 (10%)	1	4/12 (33.3%)	4
Syncope	2/10 (20%)	3	1/10 (10%)	1	0/12 (0%)	0
Presyncope	0/10 (0%)	0	1/10 (10%)	1	1/12 (8.3%)	1
Seizure	2/10 (20%)	2	0/10 (0%)	0	0/12 (0%)	0
Disturbance in attention	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Migraine	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Paraesthesia	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Periodic limb movement disorder	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Psychiatric disorders
Depression	0/10 (0%)	0	1/10 (10%)	1	1/12 (8.3%)	1
Anxiety	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Enuresis	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Intentional self injury	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Stress	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Renal and urinary disorders
Dysuria	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Reproductive system and breast disorders
Erection increased	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Menorrhagia	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Metrorrhagia	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Pelvic pain	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Vaginal haemorrhage	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Respiratory, thoracic and mediastinal disorders
Cough	1/10 (10%)	1	5/10 (50%)	5	2/12 (16.7%)	2
Dyspnoea	0/10 (0%)	0	1/10 (10%)	1	4/12 (33.3%)	5
Oropharyngeal pain	1/10 (10%)	1	2/10 (20%)	2	2/12 (16.7%)	2
Epistaxis	1/10 (10%)	1	1/10 (10%)	1	1/12 (8.3%)	1
Nasal congestion	0/10 (0%)	0	1/10 (10%)	1	1/12 (8.3%)	1
Asthma	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Bronchial hyperreactivity	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Dysphonia	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Pulmonary congestion	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Pulmonary hypertension	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Rhinorrhoea	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Snoring	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1
Skin and subcutaneous tissue disorders
Rash	2/10 (20%)	2	0/10 (0%)	0	0/12 (0%)	0
Eczema	0/10 (0%)	0	1/10 (10%)	1	0/12 (0%)	0
Night sweats	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Swelling face	1/10 (10%)	1	0/10 (0%)	0	0/12 (0%)	0
Vascular disorders
Flushing	6/10 (60%)	6	4/10 (40%)	4	8/12 (66.7%)	8
Hypotension	0/10 (0%)	0	1/10 (10%)	1	2/12 (16.7%)	2
Pallor	1/10 (10%)	1	0/10 (0%)	0	1/12 (8.3%)	1
Hypertension	0/10 (0%)	0	0/10 (0%)	0	1/12 (8.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Institution and/or Principal Investigator agree not to publish or publicly present any interim results of the Study without the prior written consent of Sponsor, not to be unreasonably withheld or delayed. Institution and/or Principal Investigator further agree to provide Sponsor with drafts of any such publication or presentation for review and approval no less than 30 days prior to submission for publication or the date of public presentation.