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

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

Population: 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).

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

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

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

Population: 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.

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

Population: 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).

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

Population: 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).

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

Population: 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).

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

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

Population: Subjects with a WHO functional classification assessment at Week 12.

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

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

Population: This analysis was performed using data from all subjects enrolled in the study, regardless of tablet strength availability at randomization.

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

Population: This analysis was performed using data from all subjects enrolled in the study, regardless of tablet strength availability at randomization.

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

Population: This analysis was performed using data from all subjects enrolled in the study, regardless of tablet strength availability at randomization.

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

Population: This analysis was performed using data from all subjects enrolled in the study, regardless of tablet strength availability at randomization.

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

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