Pulmonary Arterial Hypertension
Conditions
Keywords
PAH, PH, FREEDOM, 6 minute walk test, treprostinil, open label
Brief summary
This study is an international, multi-center, open-label study designed to provide oral treprostinil (UT-15C) to eligible subjects with pulmonary arterial hypertension who have completed the TDE-PH-310 study. The purpose of this study is to assess the long-term safety of UT-15C and to assess the effects of long-term treatment with UT-15C on exercise capacity.
Interventions
DRUGUT-15C (treprostinil diolamine)
UT-15C extended release oral tablet three times daily
Sponsors
United Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Participated in United Therapeutics Study TDE-PH-310 * All women of childbearing potential (WOCBP) must have practiced true abstinence from intercourse when it was in line with their preferred and usual lifestyle or used 2 different forms of highly effective contraception for the duration of the study and for at least 30 days after discontinuing study medication. * Males who participated in the study must have used a condom during the length of the study and for at least 48 hours after their last dose of study medication.
Exclusion criteria
* The subject was pregnant or lactating. * The subject had received infused or inhaled prostacyclin therapy for 29 days or more. * The subject was prematurely discontinued from TDE-PH-310 for reasons other than a clinical worsening event. * The subject developed a concurrent illness or condition during the conduct of TDE-PH-310 which, in the opinion of the Investigator, would represent a risk to their overall health if they enrolled in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Adverse Events | Participants will be followed every 12 weeks, at minimum, until they discontinue the study or the study is discontinued by the sponsor or for a period up to 2.5 years | All subjects who received oral treprostinil in TDE-PH-311 were included in the Safety population. All AEs were captured from the time the ICF was signed. All AEs were followed until resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for up to 30 days if the AE extended beyond the final visit. All SAEs were followed until resolution, death, or the subject was lost to follow-up, even if they were ongoing more than 30 days after completion of the final visit. The overall summary of AEs includes the number of subjects with any AE, the number of subjects with any study drug-related AEs, the number of subjects with AEs leading to study drug withdrawal, the number of subjects with any serious AEs, the number of subjects with any severe AEs, and the number of subjects with any study drug-related severe/serious AEs. AEs were coded using the Medical Dictionary for Regulatory Activities. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in 6-Minute Walk Distance From Baseline | Baseline to Week 48 | A summary of change from Baseline in 6MWD at Week 48 for the Safety Population is provided. The Safety Population is all subjects who received oral treprostinil in TDE-PH-311. |
| Change in Borg Dyspnea Score From Baseline to Week 48 | Baseline to Week 48 | Change in Borg Dyspnea Score from at Week 48 is provided for the Safety Population (all subjects who received oral treprostinil in TDE-PH-311). The Borg Dyspnea Scale is a 0 to 10 rated numerical score used to measure dyspnea as reported by the patient during submaximal exercise and was administered during six-minute walk testing (6MWT), one of the most common and frequently used measures to assess disease severity in PAH. The numbers on the scale are as follows: 0 (no shortness of breath \[SOB\]), 0.5 (very very slight SOB), 1 (very slight SOB), 3 (moderate SOB), 4 (somewhat severe SOB), 5 (severe SOB), 7 (very severe SOB), 9 (very very severe SOB), 10 (maximal SOB). |
| Change From Baseline to Week 48 in WHO Functional Class | Baseline to Week 48 | Change from Baseline at Week 48 in WHO FC in the Safety Population (all subjects who received oral treprostinil in TDE-PH-311). The World Health Organization functional classification (WHO-FC) is a clinician-rated assessment used widely to assess PAH severity and functioning. Class I (least severe): Patients are without limitation of physical activity. Class II: Patients are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III: Marked limitation of physical activity. They are comfortable at rest. Class IV (most severe): Inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. |
| Change in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 48 | Baseline to Week 48 | Change in N-terminal pro-brain natriuretic peptide from Baseline at Week 48 for the Safety Population (any subject who received oral treprostinil in TDE-PH-311) |
Countries
Argentina, Australia, Austria, Brazil, Canada, Chile, China, Denmark, France, Germany, Greece, India, Israel, Italy, Mexico, Netherlands, Poland, Singapore, South Korea, Sweden, Taiwan, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| UT-15C Open label access
UT-15C (treprostinil diethanolamine): UT-15C sustained release oral tablet for three times daily administration | 470 |
| Total | 470 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 63 |
| Overall Study | Death | 69 |
| Overall Study | Lost to Follow-up | 8 |
| Overall Study | Other Reason Not Specified | 6 |
| Overall Study | Progressive Disease | 20 |
| Overall Study | Protocol Violation | 8 |
| Overall Study | Withdrawal by Subject | 24 |
Baseline characteristics
| Characteristic | UT-15C |
|---|---|
| 6-Minute Walk Distance (6MWD) at Baseline | 392.0 meters STANDARD_DEVIATION 128.1 |
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 72 Participants |
| Age, Categorical Between 18 and 65 years | 398 Participants |
| Age, Continuous | 47.2 years STANDARD_DEVIATION 15.1 |
| Background PAH Therapy at Randomization in Parent Study Endothelin Receptor Antagonist (ERA) alone | 122 Participants |
| Background PAH Therapy at Randomization in Parent Study Phosphodiesterase Type 5 Inhibitor (PDE5-I) Alone/Soluble Guanylate Cyclase (sGC) Stimulator Alone | 348 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 135 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 334 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Etiology of Pulmonary Arterial Hypertension (PAH) Collagen Vascular Disease | 114 Participants |
| Etiology of Pulmonary Arterial Hypertension (PAH) Congenital Heart Defect | 38 Participants |
| Etiology of Pulmonary Arterial Hypertension (PAH) HIV Infection | 8 Participants |
| Etiology of Pulmonary Arterial Hypertension (PAH) Idiopathic of Heritable PAH | 299 Participants |
| Etiology of Pulmonary Arterial Hypertension (PAH) Other | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 213 Participants |
| Race (NIH/OMB) Black or African American | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants |
| Race (NIH/OMB) White | 245 Participants |
| Sex: Female, Male Female | 374 Participants |
| Sex: Female, Male Male | 96 Participants |
| Time since Diagnosis | 3.16 years STANDARD_DEVIATION 2.69 |
| WHO Functional Class at Baseline I | 41 Participants |
| WHO Functional Class at Baseline II | 226 Participants |
| WHO Functional Class at Baseline III | 182 Participants |
| WHO Functional Class at Baseline IV | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 74 / 470 |
| other Total, other adverse events | 467 / 470 |
| serious Total, serious adverse events | 206 / 470 |
Outcome results
Primary
Number of Adverse Events
All subjects who received oral treprostinil in TDE-PH-311 were included in the Safety population. All AEs were captured from the time the ICF was signed. All AEs were followed until resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for up to 30 days if the AE extended beyond the final visit. All SAEs were followed until resolution, death, or the subject was lost to follow-up, even if they were ongoing more than 30 days after completion of the final visit. The overall summary of AEs includes the number of subjects with any AE, the number of subjects with any study drug-related AEs, the number of subjects with AEs leading to study drug withdrawal, the number of subjects with any serious AEs, the number of subjects with any severe AEs, and the number of subjects with any study drug-related severe/serious AEs. AEs were coded using the Medical Dictionary for Regulatory Activities.
Time frame: Participants will be followed every 12 weeks, at minimum, until they discontinue the study or the study is discontinued by the sponsor or for a period up to 2.5 years
Population: All subjects who received oral treprostinil in TDE-PH-311 were included in the Safety population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| UT-15C | Number of Adverse Events | Serious AE | 206 events |
| UT-15C | Number of Adverse Events | Adverse Event | 450 events |
| UT-15C | Number of Adverse Events | Study Drug Related AE | 362 events |
| UT-15C | Number of Adverse Events | AE Leading to Study Drug Withdrawal | 126 events |
| UT-15C | Number of Adverse Events | Severe AE | 182 events |
| UT-15C | Number of Adverse Events | Study Drug Related Severe AE | 67 events |
| UT-15C | Number of Adverse Events | Study Drug Related Serious AE | 37 events |
Secondary
Change From Baseline to Week 48 in WHO Functional Class
Change from Baseline at Week 48 in WHO FC in the Safety Population (all subjects who received oral treprostinil in TDE-PH-311). The World Health Organization functional classification (WHO-FC) is a clinician-rated assessment used widely to assess PAH severity and functioning. Class I (least severe): Patients are without limitation of physical activity. Class II: Patients are comfortable at rest. Ordinary physical activity causes undue dyspnea or fatigue, chest pain or near syncope. Class III: Marked limitation of physical activity. They are comfortable at rest. Class IV (most severe): Inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure.
Time frame: Baseline to Week 48
Population: Safety Population was analyzed. Baseline is defined as the last measurement prior to the first dose of oral treprostinil in TDE PH 311.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| UT-15C | Change From Baseline to Week 48 in WHO Functional Class | -0.2 score on a scale | Standard Deviation 0.6 |
Secondary
Change in 6-Minute Walk Distance From Baseline
A summary of change from Baseline in 6MWD at Week 48 for the Safety Population is provided. The Safety Population is all subjects who received oral treprostinil in TDE-PH-311.
Time frame: Baseline to Week 48
Population: All participants are subjects who received oral treprostinil in TDE-PH-311. For post-Baseline visits, only subjects with measurements at Baseline and the corresponding visit are included. Baseline is defined as the last measurement prior to the first dose of oral treprostinil in TDE-PH-311.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| UT-15C | Change in 6-Minute Walk Distance From Baseline | 20.1 meters | Standard Deviation 79.6 |
Secondary
Change in Borg Dyspnea Score From Baseline to Week 48
Change in Borg Dyspnea Score from at Week 48 is provided for the Safety Population (all subjects who received oral treprostinil in TDE-PH-311). The Borg Dyspnea Scale is a 0 to 10 rated numerical score used to measure dyspnea as reported by the patient during submaximal exercise and was administered during six-minute walk testing (6MWT), one of the most common and frequently used measures to assess disease severity in PAH. The numbers on the scale are as follows: 0 (no shortness of breath \[SOB\]), 0.5 (very very slight SOB), 1 (very slight SOB), 3 (moderate SOB), 4 (somewhat severe SOB), 5 (severe SOB), 7 (very severe SOB), 9 (very very severe SOB), 10 (maximal SOB).
Time frame: Baseline to Week 48
Population: Safety Population (all subjects who received oral treprostinil in TDE-PH-311). For post-Baseline visits, only subjects with measurements at Baseline and the corresponding visit are included. Baseline is defined as the last measurement prior to the first dose of oral treprostinil in TDE-PH-311.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| UT-15C | Change in Borg Dyspnea Score From Baseline to Week 48 | -0.49 score on a scale | Standard Deviation 1.92 |
Secondary
Change in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 48
Change in N-terminal pro-brain natriuretic peptide from Baseline at Week 48 for the Safety Population (any subject who received oral treprostinil in TDE-PH-311)
Time frame: Baseline to Week 48
Population: Subjects in the Safety Population were analyzed. For post-Baseline visits, only subjects with measurements at Baseline and the corresponding visit are included. Baseline is defined as the last measurement prior to the first dose of oral treprostinil in TDE-PH-311.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| UT-15C | Change in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 48 | -179.23 pg/mL | Standard Deviation 1968.99 |