Back to resultsStudy to Assess the Tolerability and the Safety of the Transition From Inhaled Treprostinil to Oral Selexipag in Patients With Pulmonary Arterial Hypertension (TRANSIT-1)
Primary Purpose
Pulmonary Arterial Hypertension
Status
Completed
Phase
Phase 3
Locations
United States
Study Type
Interventional
Intervention
Selexipag
Sponsored by
About this trial
This is an interventional treatment trial for Pulmonary Arterial Hypertension
Eligibility Criteria
Inclusion Criteria:
- Male and female patients aged from 18 to 75 years (inclusive) with pulmonary arterial hypertension (PAH).
- Etiology of PAH belonging to one of the following subgroups: idiopathic PAH, Heritable PAH, drug or toxin induced, associated with connective tissue disease, associated with HIV infection, associated with congenital heart disease with simple systemic-to-pulmonary shunt at least 1 year after surgical repair.
- Women of childbearing potential are eligible only if the following apply: Negative serum pregnancy test at Visit 1 and a negative urine pregnancy test at Visit on Day 1, agreement to undertake monthly urine pregnancy tests during the study and up to 30 days after study drug discontinuation, agreement to use efficient methods of birth control from Visit 1 up to at least 30 days after study treatment discontinuation.
- Documented hemodynamic diagnosis of PAH by right heart catheterization (RHC).
- Inhaled treprostinil treatment ongoing for at least 90 days and at stable dose for at least 30 days prior to Day 1.
- WHO functional class (FC) II or III at Visit 1 and Visit 2.
- 6-minute walk distance (6MWD) ≥ 300 m at Visit 1.
- On background oral PAH therapy for at least 90 days and on a stable dose for 30 days prior to Visit 2. Acceptable concomitant PAH therapies are one or two of the following: a) Endothelin receptor antagonist (ERA), b) Phosphodiesterase type 5 (PDE-5) inhibitor or soluble guanylate cyclase (sGC) stimulator.
Exclusion Criteria:
- Treatment with any prostacyclin or prostacyclin analogs other than inhaled treprostinil within 90 days before Day 1, or patients scheduled to receive any of these treatments within the duration of the study.
- Any hospitalization within 90 days before Day 1.
- Worsening in WHO FC within 30 days prior to Day 1.
- At any time prior to Day 1, documented moderate or severe obstructive or restrictive lung disease.
- Known or suspicion of pulmonary veno-occlusive disease (PVOD).
- Anemia: < 80 g/L (5.0 mmol/L) hemoglobin.
- Clinically relevant thyroid disease (hypo- or hyperthyroidism).
- Known and documented severe hepatic impairment.
- Uncontrolled hypertension.
- Sitting systolic blood pressure < 85 mmHg.
- Acute myocardial infarction within the last 90 days prior to Visit 1.
- History of left-sided heart disease.
- Left ventricular disease/dysfunction risk factors.
- Documented pericardial effusion within 90 days prior to Visit 1.
- Documented severe renal insufficiency.
- Receiving or having received any investigational drugs within 90 days before Day 1.
- Having received selexipag at any time before Day 1.
- Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements.
- Recently conducted or planned cardio-pulmonary rehabilitation program based on exercise training during the study.
- Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.
- Known concomitant life-threatening disease with a life expectancy < 12 months.
- Females who are lactating or pregnant or plan to become pregnant during the study.
- Known hypersensitivity to any of the excipients of the drug formulation.
Sites / Locations
- UCSD Medical Center -La Jolla
- UCSF Medical Center
- Harbor UCLA Medical Center
- Emory University
- Piedmont Healthcare Research Institute
- Kentuckiana Pulmonary Associates
- University of Michigan Health System
- Washington University School of Medicine
- Duke Unversity
- University of Pennsylvania
- Allegheny General Hospital
- University of Pittsburgh Medical Center Health System
- UT Southwestern
- Houston Methodist Hospital
- Sentara Cardiovascular Research Instistute
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Selexipag, Open Label
Arm Description
Subjects on inhaled treprostinil treatment participate in a 16-week main treatment period including down-titration of treprostinil to end of Week 8 and parallel up-titration of selexipag to the maximum tolerated dose (MTD) up to Week 12, for each individual patient but not above 1600 mcg twice daily. From Week 12 up to Week 16, patients continue selexipag at their individual MTD. Patients could continue the study drug selexipag during the extended treatment period from Week 16 until commercial availability of selexipag.
Outcomes
Primary Outcome Measures
Percentage of Subjects With Sustained Treatment Transition
A sustained treatment transition is considered if the 3 following criteria are met a) being on study treatment (selexipag) at Week 16, and b) not having a study treatment interruption(s) of a total of 8 days or more prior to Week 16, and c) absence of inhaled treprostinil or any prostanoid treatment after Week 8 up to Week 16.
The percentage of subjects with a sustained treatment transition is calculated with 95% confidence interval (CI) using the Clopper-Pearson method.
Percentage of Subjects With Treatment-emergent Adverse Events (AEs),
Percentage of subjects with treatment-emergent AEs (serious and non serious), regardless of relationship to selexipag
Number of Subjects With Adverse Events Leading to Premature Discontinuation of Selexipag
Number of subjects with adverse events leading to premature discontinuation of selexipag is determined from the first dose of selexipag up to the last dose of selexipag
Absolute Change From Baseline Over Time in Blood Pressure
Both systolic(SBP) and diastolic (DBP) arterial blood pressure were measured in a sitting position after at least 5 minutes of rest at scheduled time points. Median change from baseline to pre-specified post-baseline visits are calculated
Absolute Change From Baseline Over Time in Heart Rate (HR)
Pulse rate is measured after at least 5 minutes of rest in a sitting position. Median change from baseline to pre-specified post-baseline visits are calculated.
Maximal Tolerated Dose
This is the individual maximal tolerated dose (MTD) observed at Week 12 in the subjects still on selexipag at Week 16.
MTD is defined as the dose of selexipag reached with the last dose change up to Week 12
Time to Discontinuation of Inhaled Treprostinil.
Median time from baseline (Day1) to the end of down-titration of inhaled treprostinil is calculated
Secondary Outcome Measures
Percentage of Subjects With WHO Functional Class (FC) Change From Baseline
The World Health Organization (WHO) defines 4 classes to classify the functional status of patients with pulmonary hypertension:
Class I (FC I): No limitation of physical activity. Class II (FC II): Slight limitation of physical activity. Class III (FC III): Marked limitation of physical activity. Class IV (FC IV): Inability to carry out any physical activity without symptoms.
Number of patients with improvement (shift from a higher to a lower class), worsening (shift from a lower to a higher class) or no change in WHO functional class at end of study compared to baseline are determined.
Absolute Change in 6-minute Walk Distance (6MWD) at Trough
The 6MWT is a non-encouraged test, which measures the distance (in meters) covered by the subject during a 6-minute walk. It is performed in a 30-meters long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed.
Absolute change from baseline to Week 16 in 6MWD is measured at trough levels of inhaled treprostinil and/or selexipag. The trough level of inhaled treprostinil is defined as the last dose having been taken not less than 4 hours and not more than 48 hours prior to the 6MWT at Visit 1 (screening). The trough level of selexipag was defined as the last dose having been taken not less than 8 hours and not more than 7 days prior to the 6MWT at Visit 5 (Week 16).
Percentage of Patients With Change in 6-minute Walk Distance (6MWD)
Percentage of patients with an increase (> 8% of baseline), maintenance (+/- 8% of baseline), or decrease (< -8% of baseline) in their 6MWD (at trough) from baseline to Week 16. The ± 8% boundaries for change in 6MWD reflect the approximately 8% coefficient of variation in the reproducibility of the 6MWD.
The trough level of inhaled treprostinil is defined as the last dose having been taken not less than 4 hours and not more than 48 hours prior to the 6MWD test at Visit 1 (screening). The trough level of selexipag was defined as the last dose having been taken not less than 8 hours and not more than 7 days prior to the 6MWD test at Visit 5 (Week 16).
Geometric Mean of the Ratio in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) of Week 16 to Baseline
Changes in NT-proBNP levels in plasma are expressed by the geometric mean of the ratio of Week 16 to baseline
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT02471183
Brief Title
Study to Assess the Tolerability and the Safety of the Transition From Inhaled Treprostinil to Oral Selexipag in Patients With Pulmonary Arterial Hypertension
Acronym
TRANSIT-1
Official Title
Multicenter, Open-label, Single-group Study to Assess the Tolerability and the Safety of the Transition From Inhaled Treprostinil to Oral Selexipag in Adult Patients With Pulmonary Arterial Hypertension
Study Type
Interventional
2. Study Status
Record Verification Date
December 2017
Overall Recruitment Status
Completed
Study Start Date
October 12, 2015 (Actual)
Primary Completion Date
December 5, 2016 (Actual)
Study Completion Date
December 5, 2016 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Actelion
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
This study enrolls patients with pulmonary arterial hypertension (PAH) treated with inhaled treprostinil. During the study, the treatment with inhaled treprostinil will be tapered off and simultaneously replaced with an oral treatment (selexipag) targeting the disease in a similar way. The purpose of the study is i) to investigate the safety and tolerability of oral selexipag in patients who transition from inhaled treprostinil, ii) to investigate the effects of oral selexipag on PAH severity and exercise ability before and after transition, and iii) to gain new information about the patients experience taking oral selexipag compared to inhaled treprostinil. Study participants may stay in the study until the FDA has granted marketing authorization.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pulmonary Arterial Hypertension
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
34 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Selexipag, Open Label
Arm Type
Experimental
Arm Description
Subjects on inhaled treprostinil treatment participate in a 16-week main treatment period including down-titration of treprostinil to end of Week 8 and parallel up-titration of selexipag to the maximum tolerated dose (MTD) up to Week 12, for each individual patient but not above 1600 mcg twice daily.
From Week 12 up to Week 16, patients continue selexipag at their individual MTD. Patients could continue the study drug selexipag during the extended treatment period from Week 16 until commercial availability of selexipag.
Intervention Type
Drug
Intervention Name(s)
Selexipag
Other Intervention Name(s)
Uptravi, ACT-293987
Intervention Description
Tablets for oral administration containing 200 micrograms (mcg) of selexipag to be administered twice a day. The individual dose is to be established during the first 12 weeks of the study. Doses are in the range from 200 micrograms (1 tablet) to 1,600 micrograms (8 tablets).
Primary Outcome Measure Information:
Title
Percentage of Subjects With Sustained Treatment Transition
Description
A sustained treatment transition is considered if the 3 following criteria are met a) being on study treatment (selexipag) at Week 16, and b) not having a study treatment interruption(s) of a total of 8 days or more prior to Week 16, and c) absence of inhaled treprostinil or any prostanoid treatment after Week 8 up to Week 16.
The percentage of subjects with a sustained treatment transition is calculated with 95% confidence interval (CI) using the Clopper-Pearson method.
Time Frame
At Week 16
Title
Percentage of Subjects With Treatment-emergent Adverse Events (AEs),
Description
Percentage of subjects with treatment-emergent AEs (serious and non serious), regardless of relationship to selexipag
Time Frame
26 weeks on average (from the first dose of selexipag up to 30 days after the last dose of selexipag)
Title
Number of Subjects With Adverse Events Leading to Premature Discontinuation of Selexipag
Description
Number of subjects with adverse events leading to premature discontinuation of selexipag is determined from the first dose of selexipag up to the last dose of selexipag
Time Frame
Up to 22 weeks on average
Title
Absolute Change From Baseline Over Time in Blood Pressure
Description
Both systolic(SBP) and diastolic (DBP) arterial blood pressure were measured in a sitting position after at least 5 minutes of rest at scheduled time points. Median change from baseline to pre-specified post-baseline visits are calculated
Time Frame
Baseline, Week 4, Week 12, Week 16
Title
Absolute Change From Baseline Over Time in Heart Rate (HR)
Description
Pulse rate is measured after at least 5 minutes of rest in a sitting position. Median change from baseline to pre-specified post-baseline visits are calculated.
Time Frame
Baseline, Week 4, Week 12, Week 16
Title
Maximal Tolerated Dose
Description
This is the individual maximal tolerated dose (MTD) observed at Week 12 in the subjects still on selexipag at Week 16.
MTD is defined as the dose of selexipag reached with the last dose change up to Week 12
Time Frame
At Week 12, in subjects still on selexipag at Week 16
Title
Time to Discontinuation of Inhaled Treprostinil.
Description
Median time from baseline (Day1) to the end of down-titration of inhaled treprostinil is calculated
Time Frame
Baseline to Week 16
Secondary Outcome Measure Information:
Title
Percentage of Subjects With WHO Functional Class (FC) Change From Baseline
Description
The World Health Organization (WHO) defines 4 classes to classify the functional status of patients with pulmonary hypertension:
Class I (FC I): No limitation of physical activity. Class II (FC II): Slight limitation of physical activity. Class III (FC III): Marked limitation of physical activity. Class IV (FC IV): Inability to carry out any physical activity without symptoms.
Number of patients with improvement (shift from a higher to a lower class), worsening (shift from a lower to a higher class) or no change in WHO functional class at end of study compared to baseline are determined.
Time Frame
Baseline and Week 16
Title
Absolute Change in 6-minute Walk Distance (6MWD) at Trough
Description
The 6MWT is a non-encouraged test, which measures the distance (in meters) covered by the subject during a 6-minute walk. It is performed in a 30-meters long flat corridor, where the patient is instructed to walk as far as possible, back and forth around two cones, with the permission to slow down, rest, or stop if needed.
Absolute change from baseline to Week 16 in 6MWD is measured at trough levels of inhaled treprostinil and/or selexipag. The trough level of inhaled treprostinil is defined as the last dose having been taken not less than 4 hours and not more than 48 hours prior to the 6MWT at Visit 1 (screening). The trough level of selexipag was defined as the last dose having been taken not less than 8 hours and not more than 7 days prior to the 6MWT at Visit 5 (Week 16).
Time Frame
Baseline and Week 16
Title
Percentage of Patients With Change in 6-minute Walk Distance (6MWD)
Description
Percentage of patients with an increase (> 8% of baseline), maintenance (+/- 8% of baseline), or decrease (< -8% of baseline) in their 6MWD (at trough) from baseline to Week 16. The ± 8% boundaries for change in 6MWD reflect the approximately 8% coefficient of variation in the reproducibility of the 6MWD.
The trough level of inhaled treprostinil is defined as the last dose having been taken not less than 4 hours and not more than 48 hours prior to the 6MWD test at Visit 1 (screening). The trough level of selexipag was defined as the last dose having been taken not less than 8 hours and not more than 7 days prior to the 6MWD test at Visit 5 (Week 16).
Time Frame
Baseline and Week 16
Title
Geometric Mean of the Ratio in N-terminal Pro B-type Natriuretic Peptide (NT-proBNP) of Week 16 to Baseline
Description
Changes in NT-proBNP levels in plasma are expressed by the geometric mean of the ratio of Week 16 to baseline
Time Frame
Baseline and Week 16
Other Pre-specified Outcome Measures:
Title
Change From Baseline to Week 16 in the Treatment Satisfaction Questionnaire for Medication Questionnaire (TSQM II)
Description
The Treatment Satisfaction Questionnaire for Medication, Version II (TSQM II) is a validated tool that evaluate the subject's satisfaction with the study treatment. It includes a total of 11 questions related to satisfaction with treatment effectiveness, side effects,convenience, and global satisfaction.
TSQM scores range from 0 to 100 for each domain; a higher score indicates higher satisfaction with treatment.
Time Frame
Baseline and Week 16
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Male and female patients aged from 18 to 75 years (inclusive) with pulmonary arterial hypertension (PAH).
Etiology of PAH belonging to one of the following subgroups: idiopathic PAH, Heritable PAH, drug or toxin induced, associated with connective tissue disease, associated with HIV infection, associated with congenital heart disease with simple systemic-to-pulmonary shunt at least 1 year after surgical repair.
Women of childbearing potential are eligible only if the following apply: Negative serum pregnancy test at Visit 1 and a negative urine pregnancy test at Visit on Day 1, agreement to undertake monthly urine pregnancy tests during the study and up to 30 days after study drug discontinuation, agreement to use efficient methods of birth control from Visit 1 up to at least 30 days after study treatment discontinuation.
Documented hemodynamic diagnosis of PAH by right heart catheterization (RHC).
Inhaled treprostinil treatment ongoing for at least 90 days and at stable dose for at least 30 days prior to Day 1.
WHO functional class (FC) II or III at Visit 1 and Visit 2.
6-minute walk distance (6MWD) ≥ 300 m at Visit 1.
On background oral PAH therapy for at least 90 days and on a stable dose for 30 days prior to Visit 2. Acceptable concomitant PAH therapies are one or two of the following: a) Endothelin receptor antagonist (ERA), b) Phosphodiesterase type 5 (PDE-5) inhibitor or soluble guanylate cyclase (sGC) stimulator.
Exclusion Criteria:
Treatment with any prostacyclin or prostacyclin analogs other than inhaled treprostinil within 90 days before Day 1, or patients scheduled to receive any of these treatments within the duration of the study.
Any hospitalization within 90 days before Day 1.
Worsening in WHO FC within 30 days prior to Day 1.
At any time prior to Day 1, documented moderate or severe obstructive or restrictive lung disease.
Known or suspicion of pulmonary veno-occlusive disease (PVOD).
Anemia: < 80 g/L (5.0 mmol/L) hemoglobin.
Clinically relevant thyroid disease (hypo- or hyperthyroidism).
Known and documented severe hepatic impairment.
Uncontrolled hypertension.
Sitting systolic blood pressure < 85 mmHg.
Acute myocardial infarction within the last 90 days prior to Visit 1.
History of left-sided heart disease.
Left ventricular disease/dysfunction risk factors.
Documented pericardial effusion within 90 days prior to Visit 1.
Documented severe renal insufficiency.
Receiving or having received any investigational drugs within 90 days before Day 1.
Having received selexipag at any time before Day 1.
Acute or chronic impairment (other than dyspnea), limiting the ability to comply with study requirements.
Recently conducted or planned cardio-pulmonary rehabilitation program based on exercise training during the study.
Psychotic, addictive or other disorder limiting the ability to provide informed consent or to comply with study requirements.
Known concomitant life-threatening disease with a life expectancy < 12 months.
Females who are lactating or pregnant or plan to become pregnant during the study.
Known hypersensitivity to any of the excipients of the drug formulation.
Facility Information:
Facility Name
UCSD Medical Center -La Jolla
City
La Jolla
State/Province
California
Country
United States
Facility Name
UCSF Medical Center
City
San Francisco
State/Province
California
Country
United States
Facility Name
Harbor UCLA Medical Center
City
Torrance
State/Province
California
Country
United States
Facility Name
Emory University
City
Atlanta
State/Province
Georgia
Country
United States
Facility Name
Piedmont Healthcare Research Institute
City
Austell
State/Province
Georgia
Country
United States
Facility Name
Kentuckiana Pulmonary Associates
City
Louisville
State/Province
Kentucky
Country
United States
Facility Name
University of Michigan Health System
City
Ann Arbor
State/Province
Michigan
Country
United States
Facility Name
Washington University School of Medicine
City
Saint Louis
State/Province
Missouri
Country
United States
Facility Name
Duke Unversity
City
Durham
State/Province
North Carolina
Country
United States
Facility Name
University of Pennsylvania
City
Philadelphia
State/Province
Pennsylvania
Country
United States
Facility Name
Allegheny General Hospital
City
Pittsburgh
State/Province
Pennsylvania
Country
United States
Facility Name
University of Pittsburgh Medical Center Health System
City
Pittsburgh
State/Province
Pennsylvania
Country
United States
Facility Name
UT Southwestern
City
Dallas
State/Province
Texas
Country
United States
Facility Name
Houston Methodist Hospital
City
Houston
State/Province
Texas
Country
United States
Facility Name
Sentara Cardiovascular Research Instistute
City
Norfolk
State/Province
Virginia
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
30391194
Citation
Frost A, Janmohamed M, Fritz JS, McConnell JW, Poch D, Fortin TA, Miller CE, Chin KM, Fisher M, Eggert M, McEvoy C, Benza RL, Farber HW, Kim NH, Pfister T, Shiraga Y, McLaughlin V. Safety and tolerability of transition from inhaled treprostinil to oral selexipag in pulmonary arterial hypertension: Results from the TRANSIT-1 study. J Heart Lung Transplant. 2019 Jan;38(1):43-50. doi: 10.1016/j.healun.2018.09.003. Epub 2018 Sep 12.
Results Reference
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Study to Assess the Tolerability and the Safety of the Transition From Inhaled Treprostinil to Oral Selexipag in Patients With Pulmonary Arterial Hypertension
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