Trial Outcomes & Findings for FREEDOM-C: Oral Treprostinil in Combination With an Endothelin Receptor Antagonist (ERA) and/or a Phosphodiesterase-5 (PDE-5) Inhibitor for the Treatment of Pulmonary Arterial Hypertension (PAH) (NCT NCT00325442)

NCT ID: NCT00325442

Last Updated: 2017-08-02

Results Overview

Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 16, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS). The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 354 participants
• Primary outcome timeframe: Baseline and 16 Weeks
• Results posted on: 2017-08-02

Participant Flow

354 subjects were randomized with 350 subjects receiving a dose of study drug and subsequently analyzed from 20 October 2006 to 17 September 2008 at 70 sites across the United States, Canada, Europe, Israel, and Australia.

Participant milestones

Measure	Placebo Arm Subjects were randomly allocated to receive oral placebo twice daily.	Active Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Study STARTED	176	174
Overall Study COMPLETED	167	153
Overall Study NOT COMPLETED	9	21

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

FREEDOM-C: Oral Treprostinil in Combination With an Endothelin Receptor Antagonist (ERA) and/or a Phosphodiesterase-5 (PDE-5) Inhibitor for the Treatment of Pulmonary Arterial Hypertension (PAH)

Baseline characteristics by cohort

Measure	Placebo Arm n=176 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	Total n=350 Participants Total of all reporting groups
Age, Categorical <=18 years	5 Participants n=5 Participants	3 Participants n=7 Participants	8 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	149 Participants n=5 Participants	151 Participants n=7 Participants	300 Participants n=5 Participants
Age, Categorical >=65 years	22 Participants n=5 Participants	20 Participants n=7 Participants	42 Participants n=5 Participants
Age, Continuous	49.5 years STANDARD_DEVIATION 13.3 • n=5 Participants	51.1 years STANDARD_DEVIATION 12.3 • n=7 Participants	50.3 years STANDARD_DEVIATION 12.8 • n=5 Participants
Sex: Female, Male Female	140 Participants n=5 Participants	148 Participants n=7 Participants	288 Participants n=5 Participants
Sex: Female, Male Male	36 Participants n=5 Participants	26 Participants n=7 Participants	62 Participants n=5 Participants
Distance Traversed (meters) During Six Minute Walk Test at Baseline	345.4 meters STANDARD_DEVIATION 75.5 • n=5 Participants	346.1 meters STANDARD_DEVIATION 71.4 • n=7 Participants	345.7 meters STANDARD_DEVIATION 73.4 • n=5 Participants
Baseline WHO Functional Classification WHO Functional Class I	1 participants n=5 Participants	2 participants n=7 Participants	3 participants n=5 Participants
Baseline WHO Functional Classification WHO Functional Class II	31 participants n=5 Participants	41 participants n=7 Participants	72 participants n=5 Participants
Baseline WHO Functional Classification WHO Functional Class III	139 participants n=5 Participants	127 participants n=7 Participants	266 participants n=5 Participants
Baseline WHO Functional Classification WHO Functional Class IV	5 participants n=5 Participants	4 participants n=7 Participants	9 participants n=5 Participants
PAH Etiology Idiopathic / familial PAH	119 participants n=5 Participants	113 participants n=7 Participants	232 participants n=5 Participants
PAH Etiology PAH associated with collagen vasular disease	43 participants n=5 Participants	49 participants n=7 Participants	92 participants n=5 Participants
PAH Etiology PAH associated wtih congenital heart defect	11 participants n=5 Participants	11 participants n=7 Participants	22 participants n=5 Participants
PAH Etiology PAH associated with HIV infection	3 participants n=5 Participants	1 participants n=7 Participants	4 participants n=5 Participants
Background PAH Therapy ERA	51 participants n=5 Participants	55 participants n=7 Participants	106 participants n=5 Participants
Background PAH Therapy PDE5-I	43 participants n=5 Participants	45 participants n=7 Participants	88 participants n=5 Participants
Background PAH Therapy ERA and PDE5-I	82 participants n=5 Participants	74 participants n=7 Participants	156 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline and 16 Weeks

Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 16, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS).

The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.

Outcome measures

Measure	Placebo Arm n=176 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) 6MWD at Baseline	362.5 meters Interval 302.0 to 400.0	362.5 meters Interval 304.0 to 397.0	—
Six Minute Walk Distance (6MWD) 6MWD at Week 16	367.0 meters Interval 283.0 to 420.5	381.0 meters Interval 323.0 to 420.0	—
Six Minute Walk Distance (6MWD) Change in 6MWD from Baseline to Week 16	4.8 meters Interval -22.0 to 35.5	14.5 meters Interval -10.0 to 47.0	—

SECONDARY outcome

Timeframe: Baseline and 16 Weeks

Population: One subject in the placebo arm did not have a Baseline Borg score value.

The Borg dyspnea score is a 10-point scale rating the maximum level of dyspnea experienced during the 6-minute walk test. The Borg dyspnea score was assessed immediately following the 6-minute walk test. Scores ranged from 0 (for no shortness of breath) to 10 (for greatest shortness of breath ever experienced).

Outcome measures

Measure	Placebo Arm n=175 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Borg Dyspnea Score Borg dyspnea score at Baseline	4.26 units on a scale Standard Deviation 2.25	4.22 units on a scale Standard Deviation 2.24	—
Borg Dyspnea Score Borg dyspnea score at Week 16	4.64 units on a scale Standard Deviation 2.62	4.18 units on a scale Standard Deviation 2.59	—
Borg Dyspnea Score Change in Borg dyspnea score from BL to Wk 16	0.38 units on a scale Standard Deviation 2.06	-0.03 units on a scale Standard Deviation 2.13	—

SECONDARY outcome

Timeframe: Baseline and 16 Weeks

Definition of clinical worsening required one of the following:

1. Death (all causes excluding accident)

2. Transplantation or atrial septostomy

3. Clinical deterioration as defined by:

1. Hospitalization as a result of PAH, or

2. ≥ 20% decrease in 6-minute walk distance from Baseline (or too ill to walk) and a decrease in WHO functional class And

3. Initiation of new PAH specific therapy (i.e., ERA, PDE5I, prostacyclin).

Outcome measures

Measure	Placebo Arm n=176 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Clinical Worsening Assessment	12 participants	8 participants	—

SECONDARY outcome

Timeframe: Baseline and 16 Weeks

Population: Five subjects in the placebo arm and three subjects in the active arm did not have a Baseline dypsnea-fatigue index score.

The dyspnea-fatigue index has three components, each rated on a scale of 0 to 4, for the magnitude of the task that evokes dyspnea or fatigue, the magnitude of the pace (or effort) with which the task is performed and the associated functional impairment in general activities. The ratings for each component were added to form an aggregate score, which could range from 0, for the worst condition, to 12, for the best.

Outcome measures

Measure	Placebo Arm n=171 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=171 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Dyspnea-Fatigue Index Dyspnea-fatigue index at Baseline	5.5 units on a scale Standard Deviation 2.2	5.7 units on a scale Standard Deviation 2.1	—
Dyspnea-Fatigue Index Dyspnea-fatigue index at Week 16	5.1 units on a scale Standard Deviation 2.5	5.7 units on a scale Standard Deviation 2.5	—
Dyspnea-Fatigue Index Change in dyspnea-fatigue index from BL to Wk 16	-0.4 units on a scale Standard Deviation 1.9	0.0 units on a scale Standard Deviation 1.9	—

SECONDARY outcome

Timeframe: Week 16

Class I: Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope.

Class II: Patients with pulmonary hypertension resulting in slight limitation of physical activity. These patients are comfortable at rest, but ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope.

Class III: Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope.

Class IV: Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity.

Outcome measures

Measure	Placebo Arm n=176 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
World Health Organization Functional Classification for PAH WHO Class I	1 participants	2 participants	—
World Health Organization Functional Classification for PAH WHO Class II	48 participants	58 participants	—
World Health Organization Functional Classification for PAH WHO Class III	114 participants	103 participants	—
World Health Organization Functional Classification for PAH WHO Class IV	13 participants	11 participants	—

SECONDARY outcome

Timeframe: Baseline and 12 weeks

Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 12, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS).

The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.

Outcome measures

Measure	Placebo Arm n=176 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) 6MWD at Week 12	366.4 meters Interval 280.5 to 424.0	378.0 meters Interval 320.0 to 425.0	—
Six Minute Walk Distance (6MWD) Change in 6MWD from Baseline to Week 12	5.8 meters Interval -23.5 to 29.5	16.5 meters Interval -15.0 to 51.0	—
Six Minute Walk Distance (6MWD) 6MWD at Baseline	362.5 meters Interval 302.0 to 400.0	362.5 meters Interval 304.0 to 397.0	—

SECONDARY outcome

Timeframe: Baseline and 8 weeks

Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 8, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS).

The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.

Outcome measures

Measure	Placebo Arm n=176 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) 6MWD at Baseline	362.5 meters Interval 302.0 to 400.0	362.5 meters Interval 304.0 to 397.0	—
Six Minute Walk Distance (6MWD) 6MWD at Week 8	368.5 meters Interval 294.5 to 416.0	379.0 meters Interval 310.0 to 415.0	—
Six Minute Walk Distance (6MWD) Change in 6MWD from Baseline to Week 8	7.0 meters Interval -22.0 to 30.5	15.0 meters Interval -9.0 to 42.0	—

SECONDARY outcome

Timeframe: Baseline and 4 weeks

Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 4, correlates with the historical clinical standard for assessing patient functional status in the treatment of PAH and is considered an objective measure of patient functional status by the American Thoracic Society (ATS).

The six minute walk test was to be conducted 3 to 6 hours after the previous dose of study drug.

Outcome measures

Measure	Placebo Arm n=176 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) 6MWD at Baseline	362.5 meters Interval 302.0 to 400.0	362.5 meters Interval 304.0 to 397.0	—
Six Minute Walk Distance (6MWD) 6MWD at Week 4	363.0 meters Interval 299.0 to 410.5	370.5 meters Interval 312.0 to 410.0	—
Six Minute Walk Distance (6MWD) Change in 6MWD from Baseline to Week 4	2.1 meters Interval -17.5 to 24.5	5.5 meters Interval -8.0 to 31.0	—

SECONDARY outcome

Timeframe: Baseline and 16 weeks

Defined symptoms of PAH including fatigue, dyspnea, edema, dizziness, syncope, chest pain, and orthopnea were assessed at Baseline prior to starting study drug and during the Treatment Phase at Week 16. Severity grade values (i.e., 0, 1, 2, or 3 in increasing severity) were assigned for each symptom. The outcome data describes the change in severity values from Baseline to Week 16 for each defined symptom of PAH.

Outcome measures

Measure	Placebo Arm n=176 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Change in Symptoms of PAH From Baseline to Week 16 Change in fatigue symptoms	0.0 units on a scale Standard Error 0.0	0.01 units on a scale Standard Error 0.10	—
Change in Symptoms of PAH From Baseline to Week 16 Change in dypsnea symptoms	0.00 units on a scale Standard Error 0.00	-0.01 units on a scale Standard Error 0.09	—
Change in Symptoms of PAH From Baseline to Week 16 Change in edema symptoms	0.00 units on a scale Standard Error 0.00	-0.06 units on a scale Standard Error 0.10	—
Change in Symptoms of PAH From Baseline to Week 16 Change in dizziness symptoms	0.00 units on a scale Standard Error 0.00	-0.16 units on a scale Standard Error 0.11	—
Change in Symptoms of PAH From Baseline to Week 16 Change in syncope symptoms	0.00 units on a scale Standard Error 0.00	-0.10 units on a scale Standard Error 0.09	—
Change in Symptoms of PAH From Baseline to Week 16 Change in chest pain symptoms	0.00 units on a scale Standard Error 0.00	-0.09 units on a scale Standard Error 0.11	—
Change in Symptoms of PAH From Baseline to Week 16 Change in orthopnea symptoms	0.00 units on a scale Standard Error 0.00	-0.20 units on a scale Standard Error 0.10	—

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 1 (126 - 302 meters).

Outcome measures

Measure	Placebo Arm n=45 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=43 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters) 6MWD at Baseline	247.0 meters Interval 191.0 to 288.0	255.0 meters Interval 204.0 to 289.0	—
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters) 6MWD at Week 16	241.0 meters Interval 141.0 to 286.0	265.0 meters Interval 189.0 to 325.0	—
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters) Change in 6MWD from Baseline to Week 16	-5.6 meters Interval -39.0 to 16.0	17.0 meters Interval -13.0 to 43.0	—

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 2 (303 - 362 meters).

Outcome measures

Measure	Placebo Arm n=43 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=44 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters) 6MWD at Baseline	332.0 meters Interval 323.0 to 354.0	339.0 meters Interval 323.5 to 350.5	—
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters) 6MWD at Week 16	348.0 meters Interval 300.0 to 376.0	359.0 meters Interval 329.5 to 400.5	—
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters) Change in 6MWD from Baseline to Week 16	12.0 meters Interval -22.0 to 37.0	17.0 meters Interval -0.4 to 53.0	—

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 3 (363 - 397 meters).

Outcome measures

Measure	Placebo Arm n=42 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=45 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters) 6MWD at Baseline	385.0 meters Interval 378.0 to 390.0	383.0 meters Interval 376.0 to 390.0	—
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters) 6MWD at Week 16	388.0 meters Interval 358.0 to 429.0	396.0 meters Interval 370.0 to 417.0	—
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters) Change in 6MWD from Baseline to Week 16	6.5 meters Interval -22.0 to 43.0	13.0 meters Interval -8.0 to 44.0	—

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 4 (398 - 450 meters).

Outcome measures

Measure	Placebo Arm n=46 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=42 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters) 6MWD at Baseline	425.5 meters Interval 410.0 to 440.0	425.0 meters Interval 412.0 to 430.0	—
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters) 6MWD at Week 16	442.0 meters Interval 411.0 to 468.0	438.5 meters Interval 395.0 to 483.0	—
Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters) Change in 6MWD from Baseline to Week 16	15.0 meters Interval -6.0 to 49.0	15.0 meters Interval -20.0 to 59.0	—

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: Of 174 subjects randomized to receive oral treprostinil, 153 subjects who completed the study and 6 additional subjects who did not complete the study but discontinued the study due to adverse events were included in this analysis.

In general, the dose of study drug was increased in 0.5 mg increments every 3 days, in the absence of dose-limiting drug-related AEs, to ensure the subject received the optimal clinical dose throughout the study.

Outcome measures

Measure	Placebo Arm n=58 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=49 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg n=52 Participants Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Change in Six Minute Walk Distance (6MWD) From Baseline in Subjects Who Received Oral Treprostinil by Last Study Drug Dose and Reason for Discontinuation	3.8 meters Interval -8.0 to 26.0	18.0 meters Interval -3.0 to 56.0	34.0 meters Interval 3.0 to 52.0

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: The subjects in this subgroup had a minimum tablet strength of 1 mg for initiation of study drug dosing and dose titration.

Outcome measures

Measure	Placebo Arm n=51 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=51 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg 6MWD at Baseline	348.0 meters Interval 282.0 to 385.0	349.0 meters Interval 311.0 to 380.0	—
Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg 6MWD at Week 16	350.0 meters Interval 243.0 to 431.0	379.0 meters Interval 324.7 to 405.0	—
Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg Change in 6MWD from Baseline to Week 16	15.0 meters Interval -26.0 to 55.0	22.0 meters Interval 5.0 to 45.0	—

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: The subjects in this subgroup had a minimum tablet strength of 0.5 mg for initiation of study drug dosing and dose titration.

Outcome measures

Measure	Placebo Arm n=99 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=100 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg 6MWD at Baseline	366.0 meters Interval 302.0 to 410.0	370.0 meters Interval 297.0 to 411.0	—
Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg 6MWD at Week 16	370.0 meters Interval 283.0 to 430.0	375.5 meters Interval 301.0 to 439.5	—
Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg Change in 6MWD from Baseline to Week 16	7.0 meters Interval -19.0 to 30.0	7.0 meters Interval -19.0 to 46.5	—

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: The subjects in this subgroup had a minimum tablet strength of 0.25 mg for initiation of study drug dosing and dose titration.

Outcome measures

Measure	Placebo Arm n=26 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=23 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg 6MWD at Baseline	374.0 meters Interval 319.0 to 408.0	384.0 meters Interval 306.0 to 405.0	—
Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg 6MWD at Week 16	374.0 meters Interval 320.0 to 399.0	398.0 meters Interval 340.0 to 438.0	—
Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg Change in 6MWD from Baseline to Week 16	-1.0 meters Interval -30.0 to 12.0	21.0 meters Interval -7.0 to 78.0	—

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: The subjects in this subgroup were receiving treatment with an ERA for 90 days or greater at the time of randomization.

Outcome measures

Measure	Placebo Arm n=51 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=55 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA 6MWD at Baseline	382.0 meters Interval 325.0 to 403.0	372.0 meters Interval 325.0 to 398.0	—
Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA 6MWD at Week 16	377.0 meters Interval 303.0 to 423.0	385.0 meters Interval 306.4 to 422.0	—
Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA Change in 6MWD from Baseline to Week 16	-3.0 meters Interval -22.0 to 30.0	4.0 meters Interval -16.0 to 40.0	—

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: The subjects in this subgroup were receiving treatment with a PDE5-I for 90 days or greater at the time of randomization.

Outcome measures

Measure	Placebo Arm n=43 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=45 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I 6MWD at Baseline	360.0 meters Interval 302.0 to 397.0	348.0 meters Interval 296.0 to 390.0	—
Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I 6MWD at Week 16	357.0 meters Interval 318.0 to 424.0	373.0 meters Interval 307.0 to 411.0	—
Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I Change in 6MWD from Baseline to Week 16	8.0 meters Interval -31.0 to 47.0	23.0 meters Interval -3.0 to 47.0	—

POST_HOC outcome

Timeframe: Baseline and 16 weeks

Population: The subjects in this subgroup were receiving treatment with an ERA and PDE5-I for 90 days or greater at the time of randomization.

Outcome measures

Measure	Placebo Arm n=82 Participants Subjects were randomly allocated to receive oral placebo twice daily.	Active n=74 Participants Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.	3.5 - 16 mg Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I 6MWD at Baseline	351.5 meters Interval 290.0 to 400.0	358.5 meters Interval 300.0 to 412.0	—
Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I 6MWD at Week 16	359.2 meters Interval 243.0 to 418.0	381.0 meters Interval 325.0 to 425.0	—
Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I Change in 6MWD from Baseline to Week 16	8.0 meters Interval -20.0 to 35.0	14.5 meters Interval -13.0 to 47.0	—

Adverse Events

Placebo Arm

Serious events: 33 serious events

Other events: 157 other events

Deaths: 0 deaths

Active

Serious events: 32 serious events

Other events: 173 other events

Deaths: 0 deaths

Serious adverse events

Measure	Placebo Arm n=176 participants at risk Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 participants at risk Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Respiratory, thoracic and mediastinal disorders Pulmonary arterial hypertension	4.5% 8/176 • Number of events 8 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	5.2% 9/174 • Number of events 9 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders right ventricular failure	1.1% 2/176 • Number of events 2 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	3.4% 6/174 • Number of events 7 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
General disorders syncope	1.7% 3/176 • Number of events 3 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	1.1% 2/174 • Number of events 4 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Respiratory, thoracic and mediastinal disorders dyspnea	1.7% 3/176 • Number of events 3 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders atrial flutter	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	1.1% 2/174 • Number of events 2 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Renal and urinary disorders renal failure acute	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	1.7% 3/174 • Number of events 4 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders chest pain	1.1% 2/176 • Number of events 2 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Vascular disorders hypotension	1.1% 2/176 • Number of events 2 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Infections and infestations lower respiratory tract infection	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders nausea	1.1% 2/176 • Number of events 2 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Respiratory, thoracic and mediastinal disorders pneumonia	1.1% 2/176 • Number of events 2 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders vomiting	1.1% 2/176 • Number of events 2 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Blood and lymphatic system disorders anemia	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders aortic stenosis	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders bradycardia	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) breast cancer	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders cardiac arrest	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders cardiac failure	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders cardiac failure congestive	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Respiratory, thoracic and mediastinal disorders cough	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders diarrhea hemorrhagic	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Vascular disorders epistaxis	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Vascular disorders fluid overload	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Vascular disorders fluid retention	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders gastroenteritis viral	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Hepatobiliary disorders hepatitis	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Hepatobiliary disorders hepatitis toxic	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Metabolism and nutrition disorders hyperparathyroidism secondary	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
General disorders hypersensitivity	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Respiratory, thoracic and mediastinal disorders hypoxia	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Infections and infestations infection	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Blood and lymphatic system disorders international normalized ratio increased	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders intestinal obstruction	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Metabolism and nutrition disorders iron deficiency anemia	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Hepatobiliary disorders liver function test abnormal	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders low cardiac output syndrome	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders Mallory-Weiss syndrome	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Nervous system disorders multiple sclerosis	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders myalgia	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) ovarian cyst	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders pain in extremity	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders pericarditis constrictive	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Vascular disorders pulmonary hemorrhage	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Infections and infestations pyrexia	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders spinal osteoarthritis	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Nervous system disorders subarachnoid hemorrhage	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Nervous system disorders subdural hematoma	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Psychiatric disorders suicide attempt	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders tibia fracture	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders bradyarrhythmia	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders large intestinal hemorrhage	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Infections and infestations central line infection	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Hepatobiliary disorders hepatic enzyme increased	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Infections and infestations streptococcal infection	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.57% 1/174 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Infections and infestations respiratory tract infection	0.57% 1/176 • Number of events 1 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	0.00% 0/174 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.

Other adverse events

Measure	Placebo Arm n=176 participants at risk Subjects were randomly allocated to receive oral placebo twice daily.	Active n=174 participants at risk Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Nervous system disorders headache	36.9% 65/176 • Number of events 69 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	86.2% 150/174 • Number of events 164 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders nausea	34.1% 60/176 • Number of events 65 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	64.4% 112/174 • Number of events 126 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders diarrhea	27.3% 48/176 • Number of events 49 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	60.9% 106/174 • Number of events 115 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Vascular disorders flushing	15.3% 27/176 • Number of events 28 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	48.9% 85/174 • Number of events 87 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders pain in jaw	11.9% 21/176 • Number of events 22 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	43.1% 75/174 • Number of events 77 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders vomiting	8.0% 14/176 • Number of events 18 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	43.7% 76/174 • Number of events 82 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders pain in extremity	9.7% 17/176 • Number of events 17 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	31.0% 54/174 • Number of events 62 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Ear and labyrinth disorders dizziness	15.9% 28/176 • Number of events 33 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	17.2% 30/174 • Number of events 33 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
General disorders fatigue	9.7% 17/176 • Number of events 18 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	14.4% 25/174 • Number of events 25 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Vascular disorders edema peripheral	9.7% 17/176 • Number of events 19 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	8.6% 15/174 • Number of events 15 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders myalgia	3.4% 6/176 • Number of events 6 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	13.8% 24/174 • Number of events 26 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Respiratory, thoracic and mediastinal disorders nasopharyngitis	9.1% 16/176 • Number of events 16 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	7.5% 13/174 • Number of events 14 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Respiratory, thoracic and mediastinal disorders upper respiratory tract infection	9.7% 17/176 • Number of events 21 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	6.3% 11/174 • Number of events 11 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders chest pain	8.0% 14/176 • Number of events 15 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	6.9% 12/174 • Number of events 12 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Cardiac disorders palpitations	5.1% 9/176 • Number of events 9 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	9.8% 17/174 • Number of events 18 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Respiratory, thoracic and mediastinal disorders dyspnea	6.8% 12/176 • Number of events 12 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	7.5% 13/174 • Number of events 14 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders back pain	5.7% 10/176 • Number of events 10 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	7.5% 13/174 • Number of events 13 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
General disorders pain	3.4% 6/176 • Number of events 7 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	9.8% 17/174 • Number of events 17 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders arthralgia	2.3% 4/176 • Number of events 4 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	10.3% 18/174 • Number of events 19 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Respiratory, thoracic and mediastinal disorders cough	6.2% 11/176 • Number of events 11 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	6.3% 11/174 • Number of events 11 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Nervous system disorders insomnia	4.0% 7/176 • Number of events 7 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	8.6% 15/174 • Number of events 15 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Vascular disorders abdominal distention	5.7% 10/176 • Number of events 10 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	6.3% 11/174 • Number of events 11 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Respiratory, thoracic and mediastinal disorders nasal congestion	5.7% 10/176 • Number of events 10 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	6.3% 11/174 • Number of events 11 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Vascular disorders pulmonary arterial hypertension	6.2% 11/176 • Number of events 12 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	5.7% 10/174 • Number of events 10 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Skin and subcutaneous tissue disorders rash	4.5% 8/176 • Number of events 8 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	5.7% 10/174 • Number of events 11 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
General disorders syncope	6.2% 11/176 • Number of events 14 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	4.0% 7/174 • Number of events 9 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders constipation	4.5% 8/176 • Number of events 8 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	5.2% 9/174 • Number of events 9 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Gastrointestinal disorders dyspepsia	4.5% 8/176 • Number of events 10 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	5.2% 9/174 • Number of events 9 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders abdominal pain upper	4.5% 8/176 • Number of events 8 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	4.6% 8/174 • Number of events 8 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Vascular disorders epistaxis	5.1% 9/176 • Number of events 10 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	4.0% 7/174 • Number of events 7 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Metabolism and nutrition disorders decreased appetite	1.1% 2/176 • Number of events 2 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	7.5% 13/174 • Number of events 13 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
General disorders abdominal pain	2.8% 5/176 • Number of events 5 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	4.6% 8/174 • Number of events 8 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Psychiatric disorders anxiety	2.3% 4/176 • Number of events 4 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	4.6% 8/174 • Number of events 10 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Musculoskeletal and connective tissue disorders musculoskeletal pain	1.7% 3/176 • Number of events 4 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	5.2% 9/174 • Number of events 9 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
General disorders oropharyngeal pain	4.5% 8/176 • Number of events 8 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	1.7% 3/174 • Number of events 3 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Nervous system disorders migraine	0.00% 0/176 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.	4.6% 8/174 • Number of events 8 • Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.

Additional Information

Kevin Laliberte, PharmD; Senior Director, Product Development

United Therapeutics Corporation

Phone: 919-425-8176

Email: klaliberte@unither.com

Results disclosure agreements

• Principal investigator is a sponsor employee Any publication of the results of this trial must be consistent with the United Therapeutics publication policy. The rights of the investigator and of the sponsor with regard to publication of the results of this trial are described in the investigator contract.
• Publication restrictions are in place

Restriction type: OTHER