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FREEDOM - M: Oral Treprostinil as Monotherapy for the Treatment of Pulmonary Arterial Hypertension (PAH)

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ClinicalTrials.gov Identifier: NCT00325403
Recruitment Status : Completed
First Posted : May 12, 2006
Results First Posted : March 18, 2013
Last Update Posted : March 18, 2013
Sponsor:
Information provided by (Responsible Party):
United Therapeutics

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Treatment
Condition Pulmonary Hypertension
Interventions Drug: Oral treprostinil (UT-15C) Sustained Release Tablets
Other: Placebo
Enrollment 349
Recruitment Details 349 subjects participated in the study from 24 October 2006 to 29 April 2011 at 52 of 77 sites across the United States, Puerto Rico, Canada, Europe, Israel, India, Mexico, and China. The primary endpoint was analyzed using the primary analysis population which included 228 subjects who had access to 0.25 mg tablets at the time of randomization.
Pre-assignment Details  
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description These subjects were randomly allocated to receive matching oral placebo twice daily (every 12 hours +/- 1 hour) and were included in the primary analysis population. Dose increases were made in the absence of dose-limiting drug-related AEs, to ensure the subject received the optimal clinical dose throughout the study. These subjects were randomly allocated to receive oral treprostinil twice daily (every 12 hours +/- 1 hour) and were included in the primary analysis population. Dose increases were made in the absence of dose-limiting drug-related AEs, to ensure the subject received the optimal clinical dose throughout the study.
Period Title: Overall Study
Started 116 233
Completed 98 [1] 182 [2]
Not Completed 18 51
[1]
98 subjects receiving placebo completed the study on study drug
[2]
182 subjects receiving oral treprostinil completed the study on study drug
Arm/Group Title Placebo UT-15C (Oral Treprostinil) Total
Hide Arm/Group Description These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population. These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population Total of all reporting groups
Overall Number of Baseline Participants 77 151 228
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 77 participants 151 participants 228 participants
<=18 years
1
   1.3%
9
   6.0%
10
   4.4%
Between 18 and 65 years
69
  89.6%
141
  93.4%
210
  92.1%
>=65 years
7
   9.1%
1
   0.7%
8
   3.5%
Age Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 77 participants 151 participants 228 participants
42.5  (13.5) 37.8  (13.5) 39.4  (13.7)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 77 participants 151 participants 228 participants
Female
58
  75.3%
108
  71.5%
166
  72.8%
Male
19
  24.7%
43
  28.5%
62
  27.2%
PAH Etiology  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 77 participants 151 participants 228 participants
Idiopathic or heritable PAH 56 114 170
PAH associated w collagen vascular disease 17 26 43
PAH associated w repaired congenital heart defect 3 10 13
PAH associated w HIV infection 1 1 2
Baseline Six Minute Walk Distance  
Mean (Standard Deviation)
Unit of measure:  Meters
Number Analyzed 77 participants 151 participants 228 participants
327.6  (70.7) 331.3  (64.9) 330.0  (66.8)
WHO Functional Classification   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 77 participants 151 participants 228 participants
WHO Class I 1 1 2
WHO Class II 24 52 76
WHO Class III 52 98 150
[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.

1.Primary 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.

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 12. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.

Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Analyses were conducted using the modified intention to treat (mITT) group, which includes subjects with access to 0.25 mg tablets at randomization (n=228). All alpha was spent on this subgroup, thereby maintaining an overall type I error rate of 0.05. For sensitivity purposes, efficacy analyses were also performed on all enrolled subjects (n=349).
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 77 151
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
339
(282 to 381)
350
(283 to 386)
6MWD at Week 12
343
(246 to 403)
370
(300 to 418)
Change in 6MWD from Baseline to Week 12
-5
(-41 to 49)
25
(-16 to 63)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments Using an allocation ratio of 2:1 between oral treprostinil and placebo, a fixed sample size of approximately 195 subjects with access to 0.25 mg tablets at randomization would provide at least 90% power at a significance level of 0.01 (two-sided hypothesis) to detect a between-treatment difference in the change from Baseline to Week 12 in distance traversed during the 6-minute walk, assuming a true underlying treatment difference of 45 meters with a SD of 75 meters in both treatment groups.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0125
Comments P-Value
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 23
Confidence Interval (2-Sided) 95%
4 to 41
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Six Minute Walk Distance (6MWD)
Hide Description

Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 11, a time expected to correlate with trough treprostinil concentration.

The six minute walk test was to be conducted 8 to 13 hours after the previous dose of study drug.

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 11. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.

Time Frame Baseline and Week 11
Hide Outcome Measure Data
Hide Analysis Population Description
Analyses were conducted using the modified intention to treat (mITT) group, which includes subjects with access to 0.25 mg tablets at randomization (n=228). All alpha was spent on this subgroup, thereby maintaining an overall type I error rate of 0.05. For sensitivity purposes, efficacy analyses were also performed on all enrolled subjects (n=349).
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 77 151
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
339
(282 to 381)
350
(283 to 386)
6MWD at Week 11
335
(254 to 400)
350
(290 to 400)
Change in 6MWD from Baseline to Week 11
0
(-54 to 36)
8
(-25 to 50)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0653
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 13
Confidence Interval (2-Sided) 95%
-2 to 33
Estimation Comments [Not Specified]
3.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.

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 8. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.

Time Frame Baseline and Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
Analyses were conducted using the modified intention to treat (mITT) group, which includes subjects with access to 0.25 mg tablets at randomization (n=228). All alpha was spent on this subgroup, thereby maintaining an overall type I error rate of 0.05. For sensitivity purposes, efficacy analyses were also performed on all enrolled subjects (n=349).
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 77 151
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
339
(282 to 381)
350
(283 to 386)
6MWD at Week 8
347
(240 to 398)
355
(300 to 408)
Change in 6MWD from Baseline to Week 8
0
(-36 to 35)
17
(-15 to 54)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0307
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%
1 to 33
Estimation Comments [Not Specified]
4.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.

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 4. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.

Time Frame Baseline and Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
Analyses were conducted using the modified intention to treat (mITT), which includes subjects who had access to 0.25 mg tablets at randomization (n=228). All alpha was spent on this subgroup, thereby maintaining an overall type I error rate of 0.05. For sensitivity purposes, efficacy analyses were also performed on all enrolled subjects (n=349).
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 77 151
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
339
(282 to 381)
350
(283 to 386)
6MWD at Week 4
350
(254 to 387)
360
(285 to 400)
Change in 6MWD from Baseline to Week 4
0
(-28 to 17)
7
(-15 to 42)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0518
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 12
Confidence Interval (2-Sided) 95%
0 to 24
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Clinical Worsening Assessment
Hide Description

Definition of clinical worsening included patients who met at least one of the following criteria during the 12 weeks of the study:

  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. greater than or equal to 20% decrease in 6MWD 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, PDE5-I, prostacyclin)
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 77 151
Measure Type: Number
Unit of Measure: participants
8 15
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 1.000
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
6.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 Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Subjects with a WHO functional classification assessment at Week 12.
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 77 151
Measure Type: Number
Unit of Measure: participants
WHO Class I 1 2
WHO Class II 29 59
WHO Class III 38 75
WHO Class IV 9 15
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.7380
Comments In cases where the “value corresponding to overall poorest relative change” was imputed for walk distance, a value of “IV” was used for the WHO functional classification for PAH.
Method Wilcoxon rank sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 0
Estimation Comments The values for the estimated parameter and 95% confidence interval were calculated.
7.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 Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 77 151
Median (Inter-Quartile Range)
Unit of Measure: units on a scale
Borg dyspnea score at Baseline
3
(2 to 6)
3
(2 to 4)
Borg dyspnea score at Week 12
3
(2 to 5)
3
(1 to 5)
Change in Borg dyspnea score from Baseline to Wk12
0
(-1 to 1)
0
(-1 to 1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4887
Comments [Not Specified]
Method Wilcoxon rank-sum test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 0
Confidence Interval (2-Sided) 95%
-1 to 0
Estimation Comments [Not Specified]
8.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 Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
Two subjects (one in the placebo arm and one in the oral treprostinil arm) from the primary analysis population (n=228) did not have a Baseline dyspnea-fatigue index score and were not included in this analysis.
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 76 150
Mean (Standard Deviation)
Unit of Measure: units on a scale
Dyspnea-fatigue index at Baseline 5.8  (2.4) 6.2  (2.1)
Dyspnea-fatigue index at Week 12 5.5  (2.9) 5.9  (2.8)
Change in dyspnea-fatigue index from BL to Wk 12 -0.3  (2.5) -0.3  (2.4)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6116
Comments [Not Specified]
Method Wilcoxon sum-rank test
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 0
Confidence Interval (2-Sided) 95%
0 to 1
Estimation Comments [Not Specified]
9.Secondary Outcome
Title Symptoms of PAH
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 12. Severity grade values (i.e., 0, 1, 2, or 3 in increasing severity) were assigned for each symptom.
Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 77 151
Mean (Standard Deviation)
Unit of Measure: units on a scale
Change in fatigue symptoms 0.1  (1.0) 0.0  (1.0)
Change in dyspnea symptoms -0.1  (0.9) -0.2  (0.9)
Change in edema symptoms 0.3  (1.0) 0.2  (1.1)
Change in dizziness symptoms 0.0  (1.0) 0.3  (1.0)
Change in syncope symptoms 0.3  (1.0) 0.3  (0.9)
Change in chest pain symptoms 0.1  (0.9) 0.2  (1.0)
Change in orthopnea symptoms 0.2  (0.9) 0.2  (1.0)
10.Post-Hoc Outcome
Title Six Minute Walk Distance by Baseline WHO Functional Classification III or IV
Hide Description

Exploratory efficacy analyses were to determine the effect of Baseline WHO functional class on treatment effect for change in 6MWD.

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 12. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.

Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 52 98
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
333.5
(269 to 382.5)
330
(265 to 378)
6MWD at Week 12
316.5
(231.5 to 385)
354
(265 to 400)
Change in 6MWD from Baseline to Week 12
-8.5
(-50.5 to 40)
20.5
(-20 to 63)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0326
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 26
Confidence Interval (2-Sided) 95%
1 to 49
Estimation Comments [Not Specified]
11.Post-Hoc Outcome
Title Six Minute Walk Distance by Baseline WHO Functional Classification: I or II
Hide Description

Exploratory efficacy analyses were to determine the effect of Baseline WHO functional class on treatment effect for change in 6MWD.

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 12. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.

Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 25 53
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
370
(297 to 378)
366
(315 to 390)
6MWD at Week 12
379
(274 to 429)
391
(348 to 431)
Change in 6MWD from Baseline to Week 12
18
(-30 to 55)
27
(-5 to 67)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2275
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 16.0
Confidence Interval (2-Sided) 95%
-15 to 47
Estimation Comments [Not Specified]
12.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) by PAH Etiology: Idiopathic or Heritable PAH
Hide Description

Exploratory efficacy analyses were to determine the effect of PAH etiology (idiopathic/heritable, associated with collagen vascular disease, and other etiologies) on treatment effect for change in 6MWD.

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 12. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.

Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population.
These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
Overall Number of Participants Analyzed 56 114
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
332.5
(260 to 379)
346
(281 to 390)
6MWD at Week 12
310.5
(242.5 to 380)
380
(304 to 420)
Change in 6MWD from BL to Wk 12
-7.5
(-50.5 to 42)
25
(-13 to 67)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0024
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 32
Confidence Interval (2-Sided) 95%
10 to 55
Estimation Comments [Not Specified]
13.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) for the Entire Study Population
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). This outcome measure was assessed using data collected from all subjects enrolled in the study, regardless of tablet strength availability at randomization.

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

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Wk 12. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference i

Time Frame Baseline and Week 12
Hide Outcome Measure Data
Hide Analysis Population Description
This analysis was performed using data from all subjects enrolled in the study, regardless of tablet strength availability at randomization.
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily.
These subjects were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 116 233
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
338.5
(265.5 to 383.5)
347
(288 to 387)
6MWD at Week 12
329.5
(231.5 to 397.5)
370
(304 to 420)
Change in 6MWD from Baseline to Week 12
0
(-46 to 40)
25
(-12 to 63)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 25.5
Confidence Interval (2-Sided) 95%
10 to 41
Estimation Comments [Not Specified]
14.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) for the Entire Study Population
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Placebo corrected change in six minute walk distance (6MWD) from Baseline to Week 11, a time expected to correlate with trough treprostinil concentration. This outcome measure was assessed using data from all subjects enrolled in the study, regardless of tablet strength availability at the time of randomization.

The six minute walk test was to be conducted 8 to 13 hours after the previous dose of study drug.

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 11. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.

Time Frame Baseline and Week 11
Hide Outcome Measure Data
Hide Analysis Population Description
This analysis was performed using data from all subjects enrolled in the study, regardless of tablet strength availability at randomization.
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily.
These subjects were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 116 233
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
338.5
(265.5 to 383.5)
347
(288 to 387)
6MWD at Week 11
326.5
(206 to 398)
351
(303 to 403)
Change in 6MWD from Baseline to Week 11
-2
(-58.5 to 36)
6
(-18 to 48)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0025
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%
3 to 33
Estimation Comments [Not Specified]
15.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) for the Entire Study Population
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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). This outcome measure was assessed using data from all subjects enrolled in the study, regardless of tablet strength availability at randomization.

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

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 8. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.

Time Frame Baseline and Week 8
Hide Outcome Measure Data
Hide Analysis Population Description
This analysis was performed using data from all subjects enrolled in the study, regardless of tablet strength availability at randomization.
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily.
These subjects were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 116 233
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
338.5
(265.5 to 383.5)
347
(288 to 387)
6MWD at Week 8
339.5
(227 to 392)
360
(300 to 411)
Change in 6MWD from Baseline to Week 8
1.0
(-38.5 to 34.5)
17.0
(-13 to 54)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0008
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 20
Confidence Interval (2-Sided) 95%
7 to 34
Estimation Comments [Not Specified]
16.Post-Hoc Outcome
Title Six Minute Walk Distance (6MWD) for the Entire Study Population
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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). This outcome measure was assessed using data from all subjects enrolled in the study, regardless of tablet strength availability at randomization.

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

The Hodges-Lehmann median difference between treatment groups was used to estimate the treatment effect on 6MWD from Baseline to Week 4. A rank-based methodology was used instead of parametric-based methodology to avoid statistical bias caused by extreme outliers resulting from the handling of data that are missing due to death or clinical worsening of PAH. It is a more robust estimator than the between-treatment difference in medians.

Time Frame Baseline and Week 4
Hide Outcome Measure Data
Hide Analysis Population Description
This analysis was performed using data from all subjects enrolled in the study, regardless of tablet strength availability at randomization.
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description:
These subjects were randomly allocated to receive placebo twice daily.
These subjects were randomly allocated to receive oral treprostinil twice daily.
Overall Number of Participants Analyzed 116 233
Median (Inter-Quartile Range)
Unit of Measure: meters
6MWD at Baseline
338.5
(265.5 to 383.5)
347
(288 to 387)
6MWD at Week 4
339.5
(251 to 387)
358
(288 to 403.2)
Change in 6MWD from Baseline to Week 4
-4
(-31.5 to 20)
7
(-13 to 42)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, UT-15C (Oral Treprostinil)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0025
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Hodges-Lehmann (H-L)
Estimated Value 14
Confidence Interval (2-Sided) 95%
3.9 to 25
Estimation Comments [Not Specified]
Time Frame Adverse events were recorded throughout the 12 week study which was conducted between October 2006 and April 2011.
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo UT-15C (Oral Treprostinil)
Hide Arm/Group Description These subjects were randomly allocated to receive placebo twice daily and were included in the primary analysis population. These subjects were randomly allocated to receive oral treprostinil twice daily and were included in the primary analysis population.
All-Cause Mortality
Placebo UT-15C (Oral Treprostinil)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Placebo UT-15C (Oral Treprostinil)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   15/77 (19.48%)      27/151 (17.88%)    
Cardiac disorders     
right ventricular failure * 1  3/77 (3.90%)  3 10/151 (6.62%)  12
pulmonary hypertension * 1  4/77 (5.19%)  4 3/151 (1.99%)  3
cardiac failure * 1  0/77 (0.00%)  0 1/151 (0.66%)  2
cardiac failure congestive * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
cardio-respiratory arrest * 1  1/77 (1.30%)  1 0/151 (0.00%)  0
circulatory collapse * 1  1/77 (1.30%)  1 0/151 (0.00%)  0
cor pulmonale acute * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
palpitations * 1  1/77 (1.30%)  1 0/151 (0.00%)  0
pulmonary edema * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
sudden cardiac death * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
Gastrointestinal disorders     
diarrhea * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
diarrhea infectious * 1  1/77 (1.30%)  1 0/151 (0.00%)  0
gastritis * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
gastroenteritis * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
nausea * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
vomiting * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
General disorders     
death * 1  2/77 (2.60%)  2 2/151 (1.32%)  2
presyncope * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
sudden death * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
syncope * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
Immune system disorders     
systemic lupus erythematosus * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
Infections and infestations     
septic shock * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
Musculoskeletal and connective tissue disorders     
chest pain * 1  1/77 (1.30%)  1 2/151 (1.32%)  2
Nervous system disorders     
anterograde amnesia * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
headache * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
Renal and urinary disorders     
acute renal failure * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
urinary tract infection * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
renal impairment * 1  0/77 (0.00%)  0 1/151 (0.66%)  2
Respiratory, thoracic and mediastinal disorders     
pneumonia * 1  3/77 (3.90%)  4 1/151 (0.66%)  1
pulmonary embolism * 1  0/77 (0.00%)  0 2/151 (1.32%)  2
hemoptysis * 1  1/77 (1.30%)  1 1/151 (0.66%)  1
paroxysmal noturnal dypsnea * 1  1/77 (1.30%)  1 0/151 (0.00%)  0
lower respiratory tract infection * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
respiratory tract infection * 1  1/77 (1.30%)  1 0/151 (0.00%)  0
Skin and subcutaneous tissue disorders     
skin ulcer * 1  0/77 (0.00%)  0 1/151 (0.66%)  1
Vascular disorders     
collagen-vascular disease * 1  1/77 (1.30%)  1 0/151 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (14.0)
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo UT-15C (Oral Treprostinil)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   68/77 (88.31%)      138/151 (91.39%)    
Cardiac disorders     
right ventricular failure * 1  3/77 (3.90%)  3 10/151 (6.62%)  12
Endocrine disorders     
hypokalemia * 1  2/77 (2.60%)  3 13/151 (8.61%)  16
Gastrointestinal disorders     
diarrhea * 1  12/77 (15.58%)  12 46/151 (30.46%)  54
nausea * 1  14/77 (18.18%)  14 45/151 (29.80%)  50
vomiting * 1  12/77 (15.58%)  12 26/151 (17.22%)  31
gastritis * 1  1/77 (1.30%)  1 7/151 (4.64%)  7
General disorders     
fatigue * 1  6/77 (7.79%)  6 14/151 (9.27%)  15
decreased appetite * 1  4/77 (5.19%)  4 12/151 (7.95%)  12
pain * 1  0/77 (0.00%)  0 7/151 (4.64%)  7
asthenia * 1  4/77 (5.19%)  4 6/151 (3.97%)  9
oropharyngeal pain * 1  4/77 (5.19%)  4 1/151 (0.66%)  1
dizziness * 1  11/77 (14.29%)  11 17/151 (11.26%)  19
Infections and infestations     
pyrexia * 1  8/77 (10.39%)  8 7/151 (4.64%)  7
upper respiratory tract infection * 1  5/77 (6.49%)  5 8/151 (5.30%)  8
Musculoskeletal and connective tissue disorders     
Pain in extremity * 1  6/77 (7.79%)  6 21/151 (13.91%)  25
pain in jaw * 1  3/77 (3.90%)  3 17/151 (11.26%)  18
abdominal pain * 1  4/77 (5.19%)  4 13/151 (8.61%)  13
abdominal discomfort * 1  0/77 (0.00%)  0 9/151 (5.96%)  9
upper abdominal pain * 1  2/77 (2.60%)  2 8/151 (5.30%)  12
back pain * 1  2/77 (2.60%)  2 7/151 (4.64%)  8
arthralgia * 1  1/77 (1.30%)  1 7/151 (4.64%)  7
muscle spasms * 1  4/77 (5.19%)  4 5/151 (3.31%)  8
Nervous system disorders     
headache * 1  15/77 (19.48%)  17 95/151 (62.91%)  131
insomnia * 1  2/77 (2.60%)  2 11/151 (7.28%)  12
Respiratory, thoracic and mediastinal disorders     
nasopharyngitis * 1  4/77 (5.19%)  4 9/151 (5.96%)  12
pulmonary hypertension * 1  5/77 (6.49%)  5 3/151 (1.99%)  3
cough * 1  9/77 (11.69%)  9 14/151 (9.27%)  15
dyspnea * 1  8/77 (10.39%)  8 7/151 (4.64%)  8
Skin and subcutaneous tissue disorders     
rash * 1  0/77 (0.00%)  0 7/151 (4.64%)  7
Vascular disorders     
flushing * 1  5/77 (6.49%)  5 23/151 (15.23%)  25
peripheral edema * 1  5/77 (6.49%)  5 13/151 (8.61%)  15
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (14.0)
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
Layout table for Results Point of Contact information
Name/Title: Kevin Laliberte; Senior Director, Product Development
Organization: United Therapeutics Corporation
Phone: 919-425-8176
EMail: klaliberte@unither.com
Layout table for additonal information
Responsible Party: United Therapeutics
ClinicalTrials.gov Identifier: NCT00325403     History of Changes
Other Study ID Numbers: TDE-PH-302
First Submitted: May 11, 2006
First Posted: May 12, 2006
Results First Submitted: January 3, 2013
Results First Posted: March 18, 2013
Last Update Posted: March 18, 2013