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

Study Overview
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Brief Summary
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This study was an international, multicenter, randomized (2:1 active:placebo), double-blind, placebo-controlled study in subjects with PAH who were NOT currently receiving approved therapy for their PAH. Study visits occurred at 4 week intervals for 12 weeks (with an additional visit at Week 11) with the key measure of efficacy being the 6-minute walk test. Study procedures included routine blood tests, medical history, physical exams, disease evaluation, and exercise tests. Two optional substudies were also a part of FREEDOM-M at select centers - a hemodynamic substudy with a right heart catheterization at Baseline and Week 12 and a genetics and biomarkers substudy with blood samples collected at Baseline and Week 12. Patients who completed all assessments for 12 weeks were also eligible to enter an open-label, extension phase study (FREEDOM - EXT).

Official Title
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A 12-Week, International, Multicenter, Double-Blind, Randomized, Placebo-Controlled Comparison of the Efficacy and Safety of Oral UT-15C Sustained Release Tablets in Subjects With Pulmonary Arterial Hypertension

Conditions
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Pulmonary Hypertension

Intervention / Treatment
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* Drug: Oral treprostinil (UT-15C) Sustained Release Tablets
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 12 and 75 years of age, inclusive. Body weight at least 40 kg with a Body Mass Index < 45 PAH that is either idiopathic/heritable; associated with repaired congenital systemic-to-pulmonary shunts (repaired ≥ 5 years); associated with collagen vascular disease; associated with HIV. Previous testing (e.g., right heart catheterization, echocardiography) consistent with the diagnosis of PAH. Baseline 6-minute walk distance between 200 and 425 meters, inclusive. Reliable and cooperative with protocol requirements. Exclusion Criteria: Nursing or pregnant. Currently receiving an endothelin receptor antagonist, a phosphodiesterase-5 inhibitor, or prostacyclin within 30 days of Baseline. PAH due to conditions other than noted in the above inclusion criteria. History of uncontrolled sleep apnea, renal insufficiency, anemia, left sided heart disease, uncontrolled systemic hypertension, or parenchymal lung disease. Use of an investigational drug within 30 days of Baseline.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: UT-15C (oral treprositnil)<br>Subjects receive UT-15C (oral treprostinil) twice daily. | Drug: Oral treprostinil (UT-15C) Sustained Release Tablets<br>* Sustained release oral tablet, twice daily<br>* Other names: treprostinil diethanolamine;|
| Placebo Comparator: Placebo<br>Subjects receive placebo (sugar pill) twice daily. | Other: Placebo<br>* Placebo oral tablet twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six Minute Walk Distance (6MWD) | 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. | Baseline and Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Six Minute Walk Distance (6MWD) | 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. | Baseline and Week 11 | 
| Six Minute Walk Distance (6MWD) | 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. | Baseline and Week 8 | 
| Six Minute Walk Distance (6MWD) | 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. | Baseline and Week 4 | 
| Clinical Worsening Assessment | Definition of clinical worsening included patients who met at least one of the following criteria during the 12 weeks of the study: Death (all causes excluding accident) Transplantation or atrial septostomy Clinical deterioration as defined by: Hospitalization as a result of PAH, or greater than or equal to 20% decrease in 6MWD from Baseline (or too ill to walk) and a decrease in WHO functional class And Initiation of new PAH specific therapy (i.e., ERA, PDE5-I, prostacyclin) | Baseline and Week 12 | 
| World Health Organization Functional Classification for PAH | 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. | Baseline and Week 12 | 
| Borg Dyspnea Score | 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). | Baseline and Week 12 | 
| Dyspnea-Fatigue Index | 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. | Baseline and Week 12 | 
| Symptoms of PAH | 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. | Baseline and Week 12 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary Arterial Hypertension