Pulmonary Arterial Hypertension
Conditions
Brief summary
This study provided/continued to provide oral treprostinil (UT-15C SR; treprostinil diethanolamine) to eligible subjects who participated in Studies TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, and TDE-PH-308. The study assessed the long term safety of oral treprostinil and the effect of continued treatment with oral treprostinil on exercise capacity after 1 year of treatment.
Detailed description
This was an international, multicenter, open-label study designed to provide oral treprostinil for eligible subjects who participated in Studies TDE-PH-301, TDE-PH-302, TDE-PH-308, TDE-PH-202, TDE PH 203, and TDE-PH-205. Subjects randomly allocated to receive oral treprostinil in Studies TDE-PH-301, TDE-PH-302, or TDE-PH-308 and enrolled in this open-label study completed visits at Months 6, 12, 24, 36, and yearly visits thereafter. Subjects randomly allocated to receive placebo in Studies TDE-PH-301, TDE-PH-302, or TDE-PH-308 completed visits at Months 3, 6, 12, 24, 36, and yearly visits thereafter. Subjects that transitioned from Studies TDE-PH-202, TDE-PH-203, and TDE-PH-205 (that had an open-label study design) followed the regimen for subjects receiving oral treprostinil. A 6-Minute Walk Test (6MWT) and Borg dyspnea score were conducted at the visit which occurred 12 months after the subject's first exposure to oral treprostinil. Adverse events (AEs) were reported continuously throughout the study; any AEs ongoing at the time of discharge from Studies TDE PH-301, TDE PH-302, TDE-PH-308, TDE-PH-202, TDE-PH-203, and TDE-PH-205 were recorded as AEs and marked as ongoing from previous study in the subject's electronic Case Report Form (eCRF). Study drug dosing and pulmonary arterial hypertension (PAH) concomitant medication usage were assessed at each scheduled study visit and recorded in the subject's eCRF.
Interventions
Oral sustained release tablet, twice or thrice daily. Open label study with active drug, no other intervention arms.
Sponsors
United Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. The subject remained on study drug and completed all assessments during the Treatment Phase of the previous study (TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE PH-302, or TDE-PH-308) OR the subject permanently discontinued study drug during the Treatment Phase of the previous study due to clinical worsening (as defined in the protocol of the previous study), completed premature termination assessments prior to discontinuing study drug, completed all remaining scheduled study visits, AND received placebo during the Treatment Phase of the previous studies OR the subject was randomized into Group 1 or Group 2 in Study TDE PH 202, permanently discontinued study drug during the 12-week Treatment Phase due to clinical worsening, completed all premature termination assessments prior to discontinuing study drug, and completed all remaining scheduled study visits and assessments (with the exception of the hemodynamic measurements) through Week 12. Such subjects should have started treatment with oral treprostinil in the open-label study at 0.25 mg twice daily (BID). 2. The subject voluntarily gave informed consent to participate in the study. 3. Women of childbearing potential includes any female who had experienced menarche and who had not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or was not postmenopausal (defined as amenorrhea for at least 12 consecutive months). Sexually active women of childbearing potential must have used 2 effective forms of contraception during the length of the study. Medically acceptable forms of effective contraception included: (1) approved hormonal contraceptives (such as birth control pills), (2) barrier methods (such as a condom or diaphragm) used with a spermicide, (3) an intrauterine device, (4) partner vasectomy, or (5) abstinence. Males participating in the study must have used a condom during the length of the study, and for at least 48 hours after discontinuing study medication. Protocol Amendment A.1AU included the required assessment for Austrian subjects to perform urine pregnancy tests every 4 weeks during the study.
Exclusion criteria
1. The subject permanently discontinued study drug during the previous study (TDE PH 202, TDE-PH-203, TDE PH 205, TDE-PH-301, TDE-PH-302, or TDE PH 308) due to treatment-related adverse events (AEs). 2. The subject permanently discontinued study drug during the Treatment Phase of the previous study (TDE-PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE-PH-308) due to clinical worsening (as defined in those study protocols) and did not undergo premature termination assessments prior to discontinuing study drug, and/or did not complete all remaining study visits through the final scheduled visit. 3. The subject prematurely discontinued study drug during the Treatment Phase of the previous study due to clinical worsening (as defined in those study protocols), completed premature termination assessments prior to discontinuing study drug, completed all remaining scheduled study visits AND received oral treprostinil during the Treatment Phase of the previous study (TDE PH-202, TDE-PH-203, TDE-PH-301, TDE-PH-302, or TDE PH-308). Subjects enrolled in Study TDE-PH-202 who were randomized into the individual maximum tolerated dose (iMTD) group who clinically worsened could not participate. Subjects who permanently discontinued study drug during the 12-week Treatment Phase due to treatment-related AEs were not eligible even if they completed all remaining scheduled study visits. Subjects who permanently discontinued study drug during the 12 week Treatment Phase and did not undergo premature termination assessments prior to discontinuing study drug and/or who did not complete all remaining study visits through the Week 12 visit were also not eligible. 4. The subject developed any concurrent illness or condition during the conduct of the previous study, including but not restricted to: sleep apnea, chronic renal insufficiency, anemia, uncontrolled systemic hypertension, or left sided heart disease, unless their physician felt that entry into this study would not be detrimental to their overall health.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Exercise Capacity at Month 12 | From First Visit (Visit 1) to Month 12 | Assess the effect of continued therapy with oral treprostinil on exercise capacity as assessed by the change from Baseline in 6-Minute Walk Test (6MWT) after 1 year of treatment. The 6MWT is the clinical standard for assessing subject functional status in the treatment of PAH and has been considered an objective measure of subject functional status by the American Thoracic Society. The distance a subject can walk in 6 minutes is recorded in meters. |
Countries
Australia, Austria, Belgium, Canada, China, France, Germany, India, Ireland, Israel, Italy, Mexico, Netherlands, Poland, Portugal, Puerto Rico, Spain, Sweden, United Kingdom, United States
Participant flow
Recruitment details
Baseline values for demographic parameters were defined and collected in the same manner for subjects who received either placebo or oral treprostinil in the preceding studies. Note that Studies TDE-PH-202 (NCT01104870), TDE-PH-203 (NCT01477333), and TDE-PH-205 (NCT01588405) had an open-label design; therefore, all Baseline demographic parameters were based on values collected at the time of enrollment in the previous study.
Pre-assignment details
Subjects eligible for TDE-PH-304 previously participated in Studies TDE-PH-202 (NCT01104870), TDE-PH-203 (NCT01477333), and TDE-PH-205 (NCT01588405), TDE-PH-301 (NCT00325442), TDE-PH-302 (NCT00325403), or TDE PH-308 (NCT00887978).
Participants by arm
| Arm | Count |
|---|---|
| Oral Treprostinil Subjects eligible for TDE-PH-304 previously participated in Studies TDE PH-202, TDE-PH-203, TDE-PH-205, TDE-PH-301, TDE-PH-302, or TDE PH-308. | 894 |
| Total | 894 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 172 |
| Overall Study | Death | 174 |
| Overall Study | Limited Study Drug Effectiveness | 7 |
| Overall Study | Lost to Follow-up | 17 |
| Overall Study | Lung Transplant | 5 |
| Overall Study | Non-compliance with Study Procedures | 7 |
| Overall Study | Patient Self-discontinuation | 1 |
| Overall Study | PI Decision | 8 |
| Overall Study | Pregnancy | 1 |
| Overall Study | Progressive Disease | 163 |
| Overall Study | Protocol Violation | 13 |
| Overall Study | Surgery | 1 |
| Overall Study | Unable to Tolerate Study Drug | 2 |
| Overall Study | Use of Excluded Medication | 2 |
| Overall Study | Withdrawal by Subject | 113 |
Baseline characteristics
| Characteristic | Oral Treprostinil |
|---|---|
| Age, Continuous | 47.7 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 83 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 809 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants |
| PAH Etiology Collagen Vascular Disease | 224 Participants |
| PAH Etiology Idiopathic Pulmonary Arterial Hypertension/ Heritable Pulmonary Arterial Hypertension | 608 Participants |
| PAH Etiology Missing | 2 Participants |
| PAH Etiology Other | 60 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 34 Participants |
| Race (NIH/OMB) Asian | 219 Participants |
| Race (NIH/OMB) Black or African American | 46 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 2 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 4 Participants |
| Race (NIH/OMB) White | 589 Participants |
| Region of Enrollment Australia | 44 participants |
| Region of Enrollment Austria | 7 participants |
| Region of Enrollment Belgium | 6 participants |
| Region of Enrollment Canada | 19 participants |
| Region of Enrollment China | 124 participants |
| Region of Enrollment France | 22 participants |
| Region of Enrollment Germany | 14 participants |
| Region of Enrollment India | 79 participants |
| Region of Enrollment Ireland | 2 participants |
| Region of Enrollment Israel | 22 participants |
| Region of Enrollment Italy | 13 participants |
| Region of Enrollment Mexico | 38 participants |
| Region of Enrollment Netherlands | 15 participants |
| Region of Enrollment Poland | 16 participants |
| Region of Enrollment Portugal | 1 participants |
| Region of Enrollment Puerto Rico | 1 participants |
| Region of Enrollment Spain | 6 participants |
| Region of Enrollment Sweden | 2 participants |
| Region of Enrollment United Kingdom | 27 participants |
| Region of Enrollment United States | 436 participants |
| Sex: Female, Male Female | 696 Participants |
| Sex: Female, Male Male | 198 Participants |
| World Health Organization (WHO) Functional Class I | 18 Participants |
| World Health Organization (WHO) Functional Class II | 298 Participants |
| World Health Organization (WHO) Functional Class III | 527 Participants |
| World Health Organization (WHO) Functional Class IV | 11 Participants |
| World Health Organization (WHO) Functional Class Missing | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 174 / 894 |
| other Total, other adverse events | 890 / 894 |
| serious Total, serious adverse events | 547 / 894 |
Outcome results
Primary
Change in Exercise Capacity at Month 12
Assess the effect of continued therapy with oral treprostinil on exercise capacity as assessed by the change from Baseline in 6-Minute Walk Test (6MWT) after 1 year of treatment. The 6MWT is the clinical standard for assessing subject functional status in the treatment of PAH and has been considered an objective measure of subject functional status by the American Thoracic Society. The distance a subject can walk in 6 minutes is recorded in meters.
Time frame: From First Visit (Visit 1) to Month 12
Population: All subjects enrolled in the study with Baseline and matched follow-up 6MWTs.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Oral Treprostinil | Change in Exercise Capacity at Month 12 | 22.0 meters |