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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)

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ClinicalTrials.gov Identifier: NCT00325442
Recruitment Status : Completed
First Posted : May 12, 2006
Results First Posted : June 10, 2013
Last Update Posted : August 2, 2017
Sponsor:
Information provided by (Responsible Party):
United Therapeutics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Pulmonary Hypertension
Interventions Drug: Oral treprostinil (UT-15C) sustained release tablets
Drug: Placebo
Enrollment 354
Recruitment Details 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.
Pre-assignment Details  
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description Subjects were randomly allocated to receive oral placebo twice daily. Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Period Title: Overall Study
Started 176 174
Completed 167 153
Not Completed 9 21
Arm/Group Title Placebo Arm Active Total
Hide Arm/Group Description Subjects were randomly allocated to receive oral placebo twice daily. Subjects in this arm were randomly allocated to receive oral treprostinil twice daily. Total of all reporting groups
Overall Number of Baseline Participants 176 174 350
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 176 participants 174 participants 350 participants
<=18 years
5
   2.8%
3
   1.7%
8
   2.3%
Between 18 and 65 years
149
  84.7%
151
  86.8%
300
  85.7%
>=65 years
22
  12.5%
20
  11.5%
42
  12.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 176 participants 174 participants 350 participants
49.5  (13.3) 51.1  (12.3) 50.3  (12.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 176 participants 174 participants 350 participants
Female
140
  79.5%
148
  85.1%
288
  82.3%
Male
36
  20.5%
26
  14.9%
62
  17.7%
Distance Traversed (meters) During Six Minute Walk Test at Baseline  
Mean (Standard Deviation)
Unit of measure:  Meters
Number Analyzed 176 participants 174 participants 350 participants
345.4  (75.5) 346.1  (71.4) 345.7  (73.4)
Baseline WHO Functional Classification   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 176 participants 174 participants 350 participants
WHO Functional Class I 1 2 3
WHO Functional Class II 31 41 72
WHO Functional Class III 139 127 266
WHO Functional Class IV 5 4 9
[1]
Measure Description:

Class I: PH without limitation of physical activity (PA); no undue dyspnea or fatigue, chest pain, or near syncope.

Class II: PH resulting in slight limitation of PA; comfortable at rest; ordinary PA causes undue dyspnea or fatigue, chest pain or near syncope.

Class III: PH resulting in marked limitation of PA; comfortable at rest; ordinary PA causes undue dyspnea or fatigue, chest pain, or near syncope.

Class IV: PH with inability to carry out any PA without symptoms and signs of right heart failure. Dyspnea and/or fatigue may be present at rest. Discomfort is increased by any PA.

PAH Etiology  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 176 participants 174 participants 350 participants
Idiopathic / familial PAH 119 113 232
PAH associated with collagen vasular disease 43 49 92
PAH associated wtih congenital heart defect 11 11 22
PAH associated with HIV infection 3 1 4
Background PAH Therapy  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 176 participants 174 participants 350 participants
ERA 51 55 106
PDE5-I 43 45 88
ERA and PDE5-I 82 74 156
1.Primary Outcome
Title Six Minute Walk Distance (6MWD)
Hide Description

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.

Time Frame Baseline and 16 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 176 174
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
362.5
(302.0 to 400.0)
362.5
(304.0 to 397.0)
6MWD at Week 16
367.0
(283.0 to 420.5)
381.0
(323.0 to 420.0)
Change in 6MWD from Baseline to Week 16
4.8
(-22.0 to 35.5)
14.5
(-10.0 to 47.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.072
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 11.0
Confidence Interval (2-Sided) 95%
0 to 22
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Borg Dyspnea Score
Hide Description 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).
Time Frame Baseline and 16 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
One subject in the placebo arm did not have a Baseline Borg score value.
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 175 174
Mean (Standard Deviation)
Unit of Measure: units on a scale
Borg dyspnea score at Baseline 4.26  (2.25) 4.22  (2.24)
Borg dyspnea score at Week 16 4.64  (2.62) 4.18  (2.59)
Change in Borg dyspnea score from BL to Wk 16 0.38  (2.06) -0.03  (2.13)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in Borg dyspnea score from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.062
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
-1.0 to 0.0
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Clinical Worsening Assessment
Hide Description

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).
Time Frame Baseline and 16 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 176 174
Measure Type: Number
Unit of Measure: participants
12 8
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.491
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
4.Secondary Outcome
Title Dyspnea-Fatigue Index
Hide Description 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.
Time Frame Baseline and 16 Weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Five subjects in the placebo arm and three subjects in the active arm did not have a Baseline dypsnea-fatigue index score.
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 171 171
Mean (Standard Deviation)
Unit of Measure: units on a scale
Dyspnea-fatigue index at Baseline 5.5  (2.2) 5.7  (2.1)
Dyspnea-fatigue index at Week 16 5.1  (2.5) 5.7  (2.5)
Change in dyspnea-fatigue index from BL to Wk 16 -0.4  (1.9) 0.0  (1.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in dyspnea-fatigue index from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.011
Comments [Not Specified]
Method Wilcoxon sum-rank test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 0.0
Confidence Interval (2-Sided) 95%
0.0 to 1.0
Estimation Comments [Not Specified]
5.Secondary Outcome
Title World Health Organization Functional Classification for PAH
Hide Description

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.

Time Frame Week 16
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 176 174
Measure Type: Number
Unit of Measure: participants
WHO Class I 1 2
WHO Class II 48 58
WHO Class III 114 103
WHO Class IV 13 11
6.Secondary Outcome
Title Six Minute Walk Distance (6MWD)
Hide Description

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.

Time Frame Baseline and 12 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 176 174
Median (Full Range)
Unit of Measure: meters
6MWD at Baseline
362.5
(302.0 to 400.0)
362.5
(304.0 to 397.0)
6MWD at Week 12
366.4
(280.5 to 424.0)
378.0
(320.0 to 425.0)
Change in 6MWD from Baseline to Week 12
5.8
(-23.5 to 29.5)
16.5
(-15.0 to 51.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 12
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.015
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 13.0
Confidence Interval (2-Sided) 95%
3.0 to 23.0
Estimation Comments [Not Specified]
7.Secondary Outcome
Title Six Minute Walk Distance (6MWD)
Hide Description

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.

Time Frame Baseline and 8 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 176 174
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
362.5
(302.0 to 400.0)
362.5
(304.0 to 397.0)
6MWD at Week 8
368.5
(294.5 to 416.0)
379.0
(310.0 to 415.0)
Change in 6MWD from Baseline to Week 8
7.0
(-22.0 to 30.5)
15.0
(-9.0 to 42.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 8
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.051
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann
Estimated Value 9.0
Confidence Interval (2-Sided) 95%
0.0 to 18.0
Estimation Comments [Not Specified]
8.Secondary Outcome
Title Six Minute Walk Distance (6MWD)
Hide Description

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.

Time Frame Baseline and 4 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 176 174
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
362.5
(302.0 to 400.0)
362.5
(304.0 to 397.0)
6MWD at Week 4
363.0
(299.0 to 410.5)
370.5
(312.0 to 410)
Change in 6MWD from Baseline to Week 4
2.1
(-17.5 to 24.5)
5.5
(-8.0 to 31.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 4
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.238
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann ( H-L)
Estimated Value 4
Confidence Interval (2-Sided) 95%
-2.4 to 12.0
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Change in Symptoms of PAH From Baseline to Week 16
Hide Description 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.
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 176 174
Mean (Standard Error)
Unit of Measure: units on a scale
Change in fatigue symptoms 0.0  (0.0) 0.01  (0.10)
Change in dypsnea symptoms 0.00  (0.00) -0.01  (0.09)
Change in edema symptoms 0.00  (0.00) -0.06  (0.10)
Change in dizziness symptoms 0.00  (0.00) -0.16  (0.11)
Change in syncope symptoms 0.00  (0.00) -0.10  (0.09)
Change in chest pain symptoms 0.00  (0.00) -0.09  (0.11)
Change in orthopnea symptoms 0.00  (0.00) -0.20  (0.10)
10.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartiles: Quartile 1 (126-302 Meters)
Hide Description [Not Specified]
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 1 (126 - 302 meters).
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 45 43
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
247.0
(191.0 to 288.0)
255.0
(204.0 to 289.0)
6MWD at Week 16
241.0
(141.0 to 286.0)
265.0
(189.0 to 325.0)
Change in 6MWD from Baseline to Week 16
-5.6
(-39.0 to 16.0)
17.0
(-13.0 to 43.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.121
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 24
Confidence Interval (2-Sided) 95%
0 to 45
Estimation Comments [Not Specified]
11.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 2 (303 - 362 Meters)
Hide Description [Not Specified]
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 2 (303 - 362 meters).
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 43 44
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
332.0
(323.0 to 354.0)
339.0
(323.5 to 350.5)
6MWD at Week 16
348.0
(300.0 to 376.0)
359.0
(329.5 to 400.5)
Change in 6MWD from Baseline to Week 16
12.0
(-22.0 to 37.0)
17.0
(-0.4 to 53.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.069
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 15
Confidence Interval (2-Sided) 95%
-7 to 41
Estimation Comments [Not Specified]
12.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 3 (363 - 397 Meters)
Hide Description [Not Specified]
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 3 (363 - 397 meters).
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 42 45
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
385.0
(378.0 to 390.0)
383.0
(376.0 to 390.0)
6MWD at Week 16
388.0
(358.0 to 429.0)
396.0
(370.0 to 417.0)
Change in 6MWD from Baseline to Week 16
6.5
(-22.0 to 43.0)
13.0
(-8.0 to 44.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.889
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 4
Confidence Interval (2-Sided) 95%
-15 to 24
Estimation Comments [Not Specified]
13.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by Baseline 6MWD Quartile: Quartile 4 (398 - 450 Meters)
Hide Description [Not Specified]
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The study population was divided into quartiles by Baseline 6MWD. The subjects in this subgroup were in quartile 4 (398 - 450 meters).
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 46 42
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
425.5
(410.0 to 440.0)
425.0
(412.0 to 430.0)
6MWD at Week 16
442.0
(411.0 to 468.0)
438.5
(395.0 to 483.0)
Change in 6MWD from Baseline to Week 16
15.0
(-6.0 to 49.0)
15.0
(-20.0 to 59.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.966
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 0
Confidence Interval (2-Sided) 95%
-23 to 24
Estimation Comments [Not Specified]
14.Post-Hoc Outcome
Title Change in Six Minute Walk Distance (6MWD) From Baseline in Subjects Who Received Oral Treprostinil by Last Study Drug Dose and Reason for Discontinuation
Hide Description 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.
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Less Than 1 mg or Discontinuation Due to Adverse Events 1.25 - 3.25 mg 3.5 - 16 mg
Hide Arm/Group Description:
Subjects in this group received less than or equal to 1 mg oral treprostinil twice daily or discontinued treatment due to adverse events.
Subjects in this group recieved 1.25 to 3.25 mg oral treprostinil twice daily.
Subjects in this group received 3.5 to 16 mg oral treprostinil twice daily.
Overall Number of Participants Analyzed 58 49 52
Median (Inter-Quartile Range)
Unit of Measure: meters
3.8
(-8.0 to 26.0)
18.0
(-3.0 to 56.0)
34.0
(3.0 to 52.0)
15.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by Lowest Dose Strength Available at Randomization: Smallest Dose Available 1 mg
Hide Description [Not Specified]
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The subjects in this subgroup had a minimum tablet strength of 1 mg for initiation of study drug dosing and dose titration.
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 51 51
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
348.0
(282.0 to 385.0)
349.0
(311.0 to 380.0)
6MWD at Week 16
350.0
(243.0 to 431.0)
379.0
(324.7 to 405.0)
Change in 6MWD from Baseline to Week 16
15.0
(-26.0 to 55.0)
22.0
(5.0 to 45.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.853
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 5
Confidence Interval (2-Sided) 95%
-16 to 28
Estimation Comments [Not Specified]
16.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomizaiton: Dose Strength 0.5 mg
Hide Description [Not Specified]
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The subjects in this subgroup had a minimum tablet strength of 0.5 mg for initiation of study drug dosing and dose titration.
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 99 100
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
366.0
(302.0 to 410.0)
370.0
(297.0 to 411.0)
6MWD at Week 16
370.0
(283.0 to 430.0)
375.5
(301.0 to 439.5)
Change in 6MWD from Baseline to Week 16
7.0
(-19.0 to 30.0)
7.0
(-19.0 to 46.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.327
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 7
Confidence Interval (2-Sided) 95%
-7 to 21
Estimation Comments [Not Specified]
17.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by Lowest Study Drug Dose Strength Available at Randomization: Study Drug Dose 0.25 mg
Hide Description [Not Specified]
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The subjects in this subgroup had a minimum tablet strength of 0.25 mg for initiation of study drug dosing and dose titration.
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 26 23
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
374.0
(319.0 to 408.0)
384.0
(306.0 to 405.0)
6MWD at Week 16
374.0
(320.0 to 399.0)
398.0
(340.0 to 438.0)
Change in 6MWD from Baseline to Week 16
-1.0
(-30.0 to 12.0)
21.0
(-7.0 to 78.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.085
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 29.5
Confidence Interval (2-Sided) 95%
1 to 73
Estimation Comments [Not Specified]
18.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA
Hide Description [Not Specified]
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The subjects in this subgroup were receiving treatment with an ERA for 90 days or greater at the time of randomization.
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 51 55
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
382.0
(325.0 to 403.0)
372.0
(325.0 to 398.0)
6MWD at Week 16
377.0
(303.0 to 423.0)
385.0
(306.4 to 422.0)
Change in 6MWD from Baseline to Week 16
-3.0
(-22.0 to 30.0)
4.0
(-16.0 to 40.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.615
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 5
Confidence Interval (2-Sided) 95%
-12 to 24
Estimation Comments [Not Specified]
19.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by Background PAH Therapy: PDE5-I
Hide Description [Not Specified]
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The subjects in this subgroup were receiving treatment with a PDE5-I for 90 days or greater at the time of randomization.
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 43 45
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
360.0
(302.0 to 397.0)
348.0
(296.0 to 390.0)
6MWD at Week 16
357.0
(318.0 to 424.0)
373.0
(307.0 to 411.0)
Change in 6MWD from Baseline to Week 16
8.0
(-31.0 to 47.0)
23.0
(-3.0 to 47.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.230
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 17
Confidence Interval (2-Sided) 95%
-6 to 40
Estimation Comments [Not Specified]
20.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by Background PAH Therapy: ERA and PDE5-I
Hide Description [Not Specified]
Time Frame Baseline and 16 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
The subjects in this subgroup were receiving treatment with an ERA and PDE5-I for 90 days or greater at the time of randomization.
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description:
Subjects were randomly allocated to receive oral placebo twice daily.
Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 82 74
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
351.5
(290.0 to 400.0)
358.5
(300.0 to 412.0)
6MWD at Week 16
359.2
(243.0 to 418.0)
381.0
(325.0 to 425.0)
Change in 6MWD from Baseline to Week 16
8.0
(-20.0 to 35.0)
14.5
(-13.0 to 47.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo Arm, Active
Comments Change in 6MWD from Baseline to Week 16
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.209
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 10
Confidence Interval (2-Sided) 95%
-6 to 28
Estimation Comments [Not Specified]
Time Frame Adverse events were recorded throughout the 16 week study which was conducted between October 2006 and September 2008.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Arm Active
Hide Arm/Group Description Subjects were randomly allocated to receive oral placebo twice daily. Subjects in this arm were randomly allocated to receive oral treprostinil twice daily.
All-Cause Mortality
Placebo Arm Active
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo Arm Active
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   33/176 (18.75%)      32/174 (18.39%)    
Blood and lymphatic system disorders     
anemia * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
international normalized ratio increased * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
Cardiac disorders     
right ventricular failure * 1  2/176 (1.14%)  2 6/174 (3.45%)  7
atrial flutter * 1  1/176 (0.57%)  1 2/174 (1.15%)  2
chest pain * 1  2/176 (1.14%)  2 0/174 (0.00%)  0
aortic stenosis * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
bradycardia * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
cardiac arrest * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
cardiac failure * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
cardiac failure congestive * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
low cardiac output syndrome * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
pericarditis constrictive * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
bradyarrhythmia * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
Gastrointestinal disorders     
nausea * 1  2/176 (1.14%)  2 0/174 (0.00%)  0
vomiting * 1  2/176 (1.14%)  2 0/174 (0.00%)  0
diarrhea hemorrhagic * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
gastroenteritis viral * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
intestinal obstruction * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
Mallory-Weiss syndrome * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
large intestinal hemorrhage * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
General disorders     
syncope * 1  3/176 (1.70%)  3 2/174 (1.15%)  4
hypersensitivity * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
Hepatobiliary disorders     
hepatitis * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
hepatitis toxic * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
liver function test abnormal * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
hepatic enzyme increased * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
Infections and infestations     
lower respiratory tract infection * 1  1/176 (0.57%)  1 1/174 (0.57%)  1
infection * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
pyrexia * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
central line infection * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
streptococcal infection * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
respiratory tract infection * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
Metabolism and nutrition disorders     
hyperparathyroidism secondary * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
iron deficiency anemia * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
Musculoskeletal and connective tissue disorders     
myalgia * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
pain in extremity * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
spinal osteoarthritis * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
tibia fracture * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
breast cancer * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
ovarian cyst * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
Nervous system disorders     
multiple sclerosis * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
subarachnoid hemorrhage * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
subdural hematoma * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
Psychiatric disorders     
suicide attempt * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
Renal and urinary disorders     
renal failure acute * 1  0/176 (0.00%)  0 3/174 (1.72%)  4
Respiratory, thoracic and mediastinal disorders     
Pulmonary arterial hypertension * 1  8/176 (4.55%)  8 9/174 (5.17%)  9
dyspnea * 1  3/176 (1.70%)  3 1/174 (0.57%)  1
pneumonia * 1  2/176 (1.14%)  2 0/174 (0.00%)  0
cough * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
hypoxia * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
Vascular disorders     
hypotension * 1  2/176 (1.14%)  2 0/174 (0.00%)  0
epistaxis * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
fluid overload * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
fluid retention * 1  1/176 (0.57%)  1 0/174 (0.00%)  0
pulmonary hemorrhage * 1  0/176 (0.00%)  0 1/174 (0.57%)  1
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (12.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Arm Active
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   157/176 (89.20%)      173/174 (99.43%)    
Cardiac disorders     
chest pain * 1  14/176 (7.95%)  15 12/174 (6.90%)  12
palpitations * 1  9/176 (5.11%)  9 17/174 (9.77%)  18
Ear and labyrinth disorders     
dizziness * 1  28/176 (15.91%)  33 30/174 (17.24%)  33
Gastrointestinal disorders     
nausea * 1  60/176 (34.09%)  65 112/174 (64.37%)  126
diarrhea * 1  48/176 (27.27%)  49 106/174 (60.92%)  115
vomiting * 1  14/176 (7.95%)  18 76/174 (43.68%)  82
constipation * 1  8/176 (4.55%)  8 9/174 (5.17%)  9
dyspepsia * 1  8/176 (4.55%)  10 9/174 (5.17%)  9
General disorders     
fatigue * 1  17/176 (9.66%)  18 25/174 (14.37%)  25
pain * 1  6/176 (3.41%)  7 17/174 (9.77%)  17
syncope * 1  11/176 (6.25%)  14 7/174 (4.02%)  9
abdominal pain * 1  5/176 (2.84%)  5 8/174 (4.60%)  8
oropharyngeal pain * 1  8/176 (4.55%)  8 3/174 (1.72%)  3
Metabolism and nutrition disorders     
decreased appetite * 1  2/176 (1.14%)  2 13/174 (7.47%)  13
Musculoskeletal and connective tissue disorders     
pain in jaw * 1  21/176 (11.93%)  22 75/174 (43.10%)  77
pain in extremity * 1  17/176 (9.66%)  17 54/174 (31.03%)  62
myalgia * 1  6/176 (3.41%)  6 24/174 (13.79%)  26
back pain * 1  10/176 (5.68%)  10 13/174 (7.47%)  13
arthralgia * 1  4/176 (2.27%)  4 18/174 (10.34%)  19
abdominal pain upper * 1  8/176 (4.55%)  8 8/174 (4.60%)  8
musculoskeletal pain * 1  3/176 (1.70%)  4 9/174 (5.17%)  9
Nervous system disorders     
headache * 1  65/176 (36.93%)  69 150/174 (86.21%)  164
insomnia * 1  7/176 (3.98%)  7 15/174 (8.62%)  15
migraine * 1  0/176 (0.00%)  0 8/174 (4.60%)  8
Psychiatric disorders     
anxiety * 1  4/176 (2.27%)  4 8/174 (4.60%)  10
Respiratory, thoracic and mediastinal disorders     
nasopharyngitis * 1  16/176 (9.09%)  16 13/174 (7.47%)  14
upper respiratory tract infection * 1  17/176 (9.66%)  21 11/174 (6.32%)  11
dyspnea * 1  12/176 (6.82%)  12 13/174 (7.47%)  14
cough * 1  11/176 (6.25%)  11 11/174 (6.32%)  11
nasal congestion * 1  10/176 (5.68%)  10 11/174 (6.32%)  11
Skin and subcutaneous tissue disorders     
rash * 1  8/176 (4.55%)  8 10/174 (5.75%)  11
Vascular disorders     
flushing * 1  27/176 (15.34%)  28 85/174 (48.85%)  87
edema peripheral * 1  17/176 (9.66%)  19 15/174 (8.62%)  15
abdominal distention * 1  10/176 (5.68%)  10 11/174 (6.32%)  11
pulmonary arterial hypertension * 1  11/176 (6.25%)  12 10/174 (5.75%)  10
epistaxis * 1  9/176 (5.11%)  10 7/174 (4.02%)  7
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (12.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
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.
Results Point of Contact
Name/Title: Kevin Laliberte, PharmD; Senior Director, Product Development
Organization: United Therapeutics Corporation
Phone: 919-425-8176
Responsible Party: United Therapeutics
ClinicalTrials.gov Identifier: NCT00325442     History of Changes
Other Study ID Numbers: TDE-PH-301
First Submitted: May 11, 2006
First Posted: May 12, 2006
Results First Submitted: January 18, 2013
Results First Posted: June 10, 2013
Last Update Posted: August 2, 2017