Pulmonary Hypertension, Interstitial Lung Disease, Combined Pulmonary Fibrosis and Emphysema
Conditions
Keywords
Treprostinil, PH, ILD, CPFE, 6 Minute Walk Test
Brief summary
This is a multicenter, open-label trial to evaluate the safety and efficacy of inhaled treprostinil in subjects with pre-capillary pulmonary hypertension (PH) associated with interstitial lung disease (ILD) including combined pulmonary fibrosis and emphysema (CPFE). The study will include about 266 patients who completed all required assessments in the RIN-PH-201 study at approximately 100 clinical trial centers. The study will continue Your participation in this study is voluntary and will last until you discontinue from the study or the study ends. The study will continue until each subject reaches the Week 108 visit or until inhaled treprostinil become commercially available for patients with PH associated with ILD including CPFE (whichever is sooner).
Interventions
Inhaled treprostinil up to 15 breaths (90 mcg) four 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 No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject voluntarily gives informed consent to participate in the study. 2. The subject participated in study RIN-PH-201, remained on study drug, was compliant with RIN-PH-201 study procedures or was enrolled in study RIN-PH-201 at the time that the study was discontinued by the sponsor. 3. Females of reproductive potential must be non-pregnant (as confirmed by a urine pregnancy test at Baseline) and non-lactating, and will: * Either abstain from intercourse (when it is in line with their preferred and usual lifestyle), or * Use two medically acceptable, highly-effective forms of contraception for the duration of study, and at least 30 days after discontinuing study drug. 4. Males must use a condom for the duration of treatment and for at least 48 hours after discontinuing study drug.
Exclusion criteria
1. The subject is pregnant or lactating. 2. The subject was prematurely discontinued from study RIN-PH-201. 3. The subject developed a concurrent illness or condition during the conduct of RIN-PH-201 which, in the opinion of the Investigator, would represent a risk to overall health if they enrolled in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Baseline through Week 124 in RIN-PH-202 (Combined data from parent study RIN-PH-201 [NCT02630316] and this open-label extension study RIN-PH-202) | The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline correlates with the current clinical standard for assessing patient functional status in the treatment of PH and is considered an objective measure of patient functional status. Subjects will be instructed to walk down a corridor at a comfortable speed as far as they can manage for 6 minutes. Distance \<500 meters suggests considerable exercise limitation; Distance 500-800 meters suggests moderate limitation; Distance \>800 meters (with no rests) suggests mild or no limitation. Peak exposure 6MWD will occur by conducting 6MWT within 10 to 60 minutes after the most recent dose of study drug dose. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline | Baseline through Week 124 in RIN-PH-202 (Combined data from parent study RIN-PH-201 [NCT02630316] and this open-label extension study RIN-PH-202) | The N-terminal pro-BNP (NT-proBNP) serum concentration is a useful biomarker associated with changes in right heart morphology and function. NT-proBNP serum concentration will be assessed to compare the severity of heart failure at Baseline and each visit through Week 124. Blood for NT-proBNP assessment must be drawn prior to conducting the 6-minute walk test (6MWT). |
| Change in Percent Predicted Forced Vital Capacity (FVC) From Baseline | Baseline and Weeks 12, 48, and 108 | Change in pulmonary function following inhaled treprostinil therapy will be measured by Forced Vital Capacity (FVC), calculated from a Pulmonary Function Test (PFT) performed at Baseline and Weeks 12, 48, and 108. |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Inhaled Treprostinil Open-label access
Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily and titrated up to a maximum of 12 breaths four times daily | 242 |
| Total | 242 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 29 |
| Overall Study | Death | 56 |
| Overall Study | Lack of Efficacy | 2 |
| Overall Study | Lost to Follow-up | 1 |
| Overall Study | Lung Transplant | 5 |
| Overall Study | Principal Investigator Terminated Study Site | 1 |
| Overall Study | Progressive Disease | 12 |
| Overall Study | Protocol Violation | 1 |
| Overall Study | Study Terminated by Sponsor | 24 |
| Overall Study | Withdrawal by Sponsor Prior to Dose Administration | 1 |
| Overall Study | Withdrawal by Subject | 41 |
Baseline characteristics
| Characteristic | Inhaled Treprostinil |
|---|---|
| 6-Minute Walk Distance (6MWD) | 270.0 meters |
| Age, Continuous | 70.0 years |
| Current Diagnosis Chronic hypersensitivity pneumonitis | 13 Participants |
| Current Diagnosis Combined pulmonary fibrosis and emphysema | 59 Participants |
| Current Diagnosis Connective tissue disease | 57 Participants |
| Current Diagnosis Idiopathic interstitial pneumonia | 108 Participants |
| Current Diagnosis Occupational lung disease | 5 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 224 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Mean Pulmonary Artery Pressure | 34.5 mmHg |
| N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) | 465.70 pg/mL |
| Pulmonary Capillary Wedge Pressure | 10.0 mmHg |
| Pulmonary Vascular Resistance | 5.100 Wood units |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants |
| Race (NIH/OMB) Asian | 8 Participants |
| Race (NIH/OMB) Black or African American | 53 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 | 0 Participants |
| Race (NIH/OMB) White | 178 Participants |
| Sex: Female, Male Female | 116 Participants |
| Sex: Female, Male Male | 126 Participants |
| Time Since Diagnosis | 0.51 years |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 56 / 242 |
| other Total, other adverse events | 229 / 242 |
| serious Total, serious adverse events | 133 / 242 |
Outcome results
Primary
Change in Peak 6-Minute Walk Distance (6MWD) From Baseline
The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline correlates with the current clinical standard for assessing patient functional status in the treatment of PH and is considered an objective measure of patient functional status. Subjects will be instructed to walk down a corridor at a comfortable speed as far as they can manage for 6 minutes. Distance \<500 meters suggests considerable exercise limitation; Distance 500-800 meters suggests moderate limitation; Distance \>800 meters (with no rests) suggests mild or no limitation. Peak exposure 6MWD will occur by conducting 6MWT within 10 to 60 minutes after the most recent dose of study drug dose.
Time frame: Baseline through Week 124 in RIN-PH-202 (Combined data from parent study RIN-PH-201 [NCT02630316] and this open-label extension study RIN-PH-202)
Population: Values are combined data from the Safety Populations of parent study RIN-PH-201 (n=326; NCT02630316) and this open-label extension study RIN-PH-202 (n=243) as presented in the RIN-PH-202 CSR over the course of 124 weeks (16-week treatment in RIN-PH-201 and up to 108 weeks in RIN-PH-202). The number of subjects analyzed at each week decreased as only those remaining on RIN-PH-202 who had not discontinued early due to the reasons show in the Participant Flow section were evaluated.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 52 | 3.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 100 | -11.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 4 | 1.5 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 8 | 5.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 12 | 9.5 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 16 | 10.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 20 | 12.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 28 | 10.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 40 | 3.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 64 | -2.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 76 | -2.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 88 | -5.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 112 | -24.0 meters |
| Inhaled Treprostinil | Change in Peak 6-Minute Walk Distance (6MWD) From Baseline | Week 124 | -16.0 meters |
Secondary
Change in Percent Predicted Forced Vital Capacity (FVC) From Baseline
Change in pulmonary function following inhaled treprostinil therapy will be measured by Forced Vital Capacity (FVC), calculated from a Pulmonary Function Test (PFT) performed at Baseline and Weeks 12, 48, and 108.
Time frame: Baseline and Weeks 12, 48, and 108
Population: Subjects from the Placebo Group in parent study RIN-PH-201
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Inhaled Treprostinil | Change in Percent Predicted Forced Vital Capacity (FVC) From Baseline | Week 12 | 0.5 Percent Predicted FVC |
| Inhaled Treprostinil | Change in Percent Predicted Forced Vital Capacity (FVC) From Baseline | Week 48 | 2.0 Percent Predicted FVC |
| Inhaled Treprostinil | Change in Percent Predicted Forced Vital Capacity (FVC) From Baseline | Week 108 | 3.0 Percent Predicted FVC |
Secondary
Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline
The N-terminal pro-BNP (NT-proBNP) serum concentration is a useful biomarker associated with changes in right heart morphology and function. NT-proBNP serum concentration will be assessed to compare the severity of heart failure at Baseline and each visit through Week 124. Blood for NT-proBNP assessment must be drawn prior to conducting the 6-minute walk test (6MWT).
Time frame: Baseline through Week 124 in RIN-PH-202 (Combined data from parent study RIN-PH-201 [NCT02630316] and this open-label extension study RIN-PH-202)
Population: RIN-PH-202 CSR over the course of 124 weeks (16-week treatment in RIN-PH-201 and up to 108 weeks in RIN-PH-202). The number of subjects analyzed at each week decreased as only those remaining on RIN-PH-202 who had not discontinued early due to the reasons show in the Participant Flow section were evaluated.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Inhaled Treprostinil | Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline | Week 8 | -5.10 pg/mL |
| Inhaled Treprostinil | Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline | Week 16 | -1.30 pg/mL |
| Inhaled Treprostinil | Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline | Week 64 | 10.2 pg/mL |
| Inhaled Treprostinil | Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline | Week 124 | 31.90 pg/mL |