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)

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).

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:
4. Hospitalization as a result of PAH, or
5. ≥ 20% decrease in 6-minute walk distance from Baseline (or too ill to walk) and a decrease in WHO functional class And
6. Initiation of new PAH specific therapy (i.e., ERA, PDE5I, prostacyclin).

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.

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.

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.

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.

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.

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.