Pulmonary Hypertension, Interstitial Lung Disease, Combined Pulmonary Fibrosis and Emphysema
Conditions
Keywords
Treprostinil, PH, ILD, CPFE, 6 Minute Walk Test
Brief summary
This was a multicenter, randomized (1:1 inhaled treprostinil: placebo), double-blinded, placebo-controlled 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 included 326 patients at approximately 120 clinical trial centers. The treatment phase of the study lasted approximately 16 weeks. Patients who completed all required assessments were eligible to enter an open-label, extension study (RIN-PH-202).
Detailed description
Study RIN-PH-201 was a multicenter, randomized, double-blind, placebo controlled, 16 week, parallel group study designed to investigate the safety and efficacy of inhaled treprostinil in subjects with PH-ILD. Subjects initiated inhaled treprostinil or placebo at a dose of 3 breaths (18 mcg) 4 times daily (QID) (during waking hours). Study drug doses were maximized throughout the study. Dose escalations (additional 1 breath QID) could occur up to every 3 days with a target dosing regimen of 9 breaths (54 mcg) QID and a maximum dose of 12 breaths (72 mcg) QID, as clinically tolerated. Subjects were assessed during Screening and Baseline to determine eligibility for the study. Once eligible, 5 Treatment Phase visits to the clinic were required at Week 4, Week 8, Week 12, Week 15, and Week 16 (final study visit). An Early Termination (ET) Visit was conducted for subjects who discontinued prior to Week 16; all assessments planned for the final Week 16 Visit were conducted during the ET Visit, if applicable. Subjects were contacted at least weekly by telephone or email to assess tolerance to study drug, AEs, and changes to concomitant medications. Efficacy assessments consisted of 6-minute walk distance (6MWD), plasma N-terminal prohormone brain natriuretic peptide (NT-proBNP) concentration, and incidence of clinical worsening. Exploratory endpoints included change in St. George's Respiratory Questionnaire (SGRQ), change in distance saturation product (DSP), time to exacerbation of underlying lung disease, and pulmonary function tests (PFT). Safety assessments consisted of the development of AEs, vital signs, clinical laboratory parameters, ECG parameters, hospitalizations due to cardiopulmonary indications, exacerbations of underlying lung disease, and oxygenation. Subjects who remained on study drug, completed all assessments during the 16-week Treatment Phase, and met all eligibility criteria were eligible for the open-label extension study (RIN-PH-202). Additionally, subjects who withdrew from study drug prior to Week 16 due to clinical worsening and returned to the clinic for scheduled visits (excluding the Week 15 Visit) were eligible for RIN PH-202.
Interventions
Inhaled treprostinil (6 mcg/breath) administered four times daily
DRUGPlacebo
Placebo administered four times daily
Sponsors
United Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Subject voluntarily gave informed consent to participate in the study. 2. Males and females aged 18 years or older at the time of informed consent. a. Females of reproductive potential were non-pregnant (as confirmed by a urine pregnancy test at screening) and non-lactating, and: i. Abstained from intercourse (when in line with their preferred and usual lifestyle), or ii. Used 2 medically acceptable, highly effective forms of contraception for the duration of study, and at least 30 days after discontinuing study drug. b. Males with a partner of childbearing potential used condoms for the duration of treatment and for at least 48 hours after discontinuing study drug. 3. The subject had a confirmed diagnosis of WHO Group 3 PH based on computed tomography (CT) imaging which was performed within 6 months prior to randomization and demonstrated evidence of diffuse parenchymal lung disease. Subjects had any form of ILD or CPFE. 4. Subjects were required to have a right heart catheterization (RHC) within 1 year prior to randomization with the following documented parameters: 1. Pulmonary vascular resistance (PVR) \>3 Wood Units (WU) and 2. A pulmonary capillary wedge pressure (PCWP) of \<15 mmHg and 3. A mean pulmonary arterial pressure (mPAP) of \>25 mmHg 5. Baseline 6MWD ≥100 m. 6. Subjects on a chronic medication for underlying lung disease (ie, pirfenidone, nintedanib, etc) were on a stable and optimized dose for ≥30 days prior to randomization. 7. In the opinion of the Investigator, the subject was able to communicate effectively with study personnel, and was considered reliable, willing and likely to be cooperative with protocol requirements, including attending all study visits. 8. Subjects with connective tissue disease (CTD) had a Baseline forced vital capacity (FVC) of \<70%.
Exclusion criteria
1. The subject had a diagnosis of PAH or PH for reasons other than WHO Group 3 PH ILD as outlined in Inclusion Criterion 3. 2. The subject showed intolerance or significant lack of efficacy to a prostacyclin or prostacyclin analogue that resulted in discontinuation or inability to effectively titrate that therapy. 3. The subject received any PAH-approved therapy including: prostacyclin therapy (ie, epoprostenol, treprostinil, iloprost, or beraprost; except for acute vasoreactivity testing), prostacyclin (IP) receptor agonist (selexipag), endothelin receptor antagonist (ERA), phosphodiesterase type 5 inhibitor (PDE5-I), or soluble guanylate cyclase (sGC) stimulator within 60 days of randomization. 4. The subject had evidence of clinically significant left-sided heart disease as defined by: 1. PCWP \>15 mmHg 2. Left ventricular ejection fraction \<40%. Note: Subjects with abnormal left ventricular function attributable entirely to impaired left ventricular filling due to the effects of right ventricular overload (ie, right ventricular hypertrophy and/or dilatation) were not excluded. 5. The subject was receiving \>10 L/min of oxygen supplementation by any mode of delivery at rest at Baseline. 6. Current use of any inhaled tobacco/marijuana products or significant history of drug abuse at the time of informed consent. 7. Exacerbation of underlying lung disease or active pulmonary or upper respiratory infection within 30 days of randomization. 8. Initiation of pulmonary rehabilitation within 12 weeks prior to randomization. 9. In the opinion of the Investigator, the subject had any condition that would interfere with the interpretation of study assessments or has any disease or condition (ie, peripheral vascular disease, musculoskeletal disorder, morbid obesity) that would likely be the primary limit to ambulation (as opposed to PH). 10. Use of any investigational drug/device, or participation in any investigational study with therapeutic intent within 30 days prior to randomization. 11. Severe concomitant illness limiting life expectancy (\<6 months). 12. Acute pulmonary embolism within 90 days of randomization.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in 6-minute Walk Distance (6MWD) Measured at Peak Exposure From Baseline to Week 16 | Baseline and Week 16 | The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline to Week 16, 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 six minutes. Peak exposure 6MWD will occur by conducting 6-minute walk test (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 to Week 16 | Baseline and Week 16 | The 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 Week 16. Blood for NT-proBNP assessment must be drawn prior to conducting the 6MWT. |
| Incidence of Clinical Worsening | Baseline to Week 16 | Subjects were monitored for clinical worsening from the time of randomization until 1 of the following criteria were met: hospitalization due to a cardiopulmonary indication; decrease in 6MWD \>15% from Baseline directly related to the disease under study, at 2 consecutive visits and at least 24 hours apart; death (all causes); or lung transplantation. |
| Change in Peak 6-minute Walk Distance (6MWD) From Baseline to Week 12 | Baseline and Week 12 | The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline to Week 12, 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 six minutes. Peak exposure 6MWD will occur by conducting 6MWT within 10 to 60 minutes after the most recent dose of study drug dose. |
| Change in Trough 6-minute Walk Distance (6MWD) From Baseline to Week 15 | Baseline and Week 15 | The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline to Week 15, 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 six 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. Trough exposure 6MWD will occur by conducting 6-minute walk test (6MWT) at least four hours after the most recent study drug dose. |
Countries
Puerto Rico, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Matching placebo inhaled using an ultrasonic nebulizer four times daily
Placebo: Placebo administered four times daily | 163 |
| Inhaled Treprostinil Active Treprostinil for inhalation solution (0.6 mg/mL) delivered via an ultrasonic nebulizer which emits a dose of approximately 6 mcg per breath. Inhaled four times daily and titrated up to a maximum of 12 breaths four times daily
Inhaled Treprostinil: Inhaled treprostinil (6 mcg/breath) administered four times daily | 163 |
| Total | 326 |
Baseline characteristics
| Characteristic | Placebo | Inhaled Treprostinil | Total |
|---|---|---|---|
| 10 mmHg decrease in PAPm during Confirmatory RHC? No | 35 Participants | 37 Participants | 72 Participants |
| 10 mmHg decrease in PAPm during Confirmatory RHC? Not tested | 120 Participants | 120 Participants | 240 Participants |
| 10 mmHg decrease in PAPm during Confirmatory RHC? Yes | 8 Participants | 6 Participants | 14 Participants |
| 6 Minute Walk Distance | 265.1 meters STANDARD_DEVIATION 93.1 | 254.1 meters STANDARD_DEVIATION 102.4 | 259.6 meters STANDARD_DEVIATION 97.9 |
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 115 Participants | 99 Participants | 214 Participants |
| Age, Categorical Between 18 and 65 years | 48 Participants | 64 Participants | 112 Participants |
| Age, Continuous | 67.4 years STANDARD_DEVIATION 11.2 | 65.6 years STANDARD_DEVIATION 12.7 | 66.5 years STANDARD_DEVIATION 12 |
| BMI | 29.0 kg/m^2 STANDARD_DEVIATION 5.9 | 30.0 kg/m^2 STANDARD_DEVIATION 6.6 | 29.5 kg/m^2 STANDARD_DEVIATION 6.3 |
| Height | 169.0 cm STANDARD_DEVIATION 9.4 | 167.5 cm STANDARD_DEVIATION 10.3 | 168.2 cm STANDARD_DEVIATION 9.9 |
| Mean pulmonary arterial pressure (PAPm) | 36.0 mmHg STANDARD_DEVIATION 8.4 | 37.2 mmHg STANDARD_DEVIATION 8.6 | 36.6 mmHg STANDARD_DEVIATION 8.5 |
| N-terminal prohormone brain natriuretic peptide (NT-proBNP) | 210.9 pg/mL STANDARD_DEVIATION 370.7 | 223.5 pg/mL STANDARD_DEVIATION 378.5 | 217.1 pg/mL STANDARD_DEVIATION 374 |
| Pulmonary Capillary Wedge Pressure (PCWP) | 9.6 mmHg STANDARD_DEVIATION 3.5 | 10.1 mmHg STANDARD_DEVIATION 3.4 | 9.8 mmHg STANDARD_DEVIATION 3.5 |
| Pulmonary Vascular Resistance (PVR) | 6.0 Wood Units (WU) STANDARD_DEVIATION 2.7 | 6.4 Wood Units (WU) STANDARD_DEVIATION 2.9 | 6.2 Wood Units (WU) STANDARD_DEVIATION 2.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 5 Participants | 7 Participants | 12 Participants |
| Race (NIH/OMB) Black or African American | 30 Participants | 41 Participants | 71 Participants |
| Race (NIH/OMB) More than one race | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 126 Participants | 112 Participants | 238 Participants |
| Region of Enrollment Puerto Rico | 2 participants | 0 participants | 2 participants |
| Region of Enrollment United States | 161 participants | 163 participants | 324 participants |
| Sex: Female, Male Female | 68 Participants | 85 Participants | 153 Participants |
| Sex: Female, Male Male | 95 Participants | 78 Participants | 173 Participants |
| Vasodilator medications used during Confirmatory RHC? Adenosine | 2 Participants | 1 Participants | 3 Participants |
| Vasodilator medications used during Confirmatory RHC? Inhaled Nitrous Oxide | 43 Participants | 39 Participants | 82 Participants |
| Vasodilator medications used during Confirmatory RHC? No medication | 118 Participants | 121 Participants | 239 Participants |
| Vasodilator medications used during Confirmatory RHC? Other | 0 Participants | 2 Participants | 2 Participants |
| Vasodilator testing during confirmatory right heart catheterization (RHC)? No | 118 Participants | 121 Participants | 239 Participants |
| Vasodilator testing during confirmatory right heart catheterization (RHC)? Yes | 45 Participants | 42 Participants | 87 Participants |
| Weight | 83.5 kg STANDARD_DEVIATION 20.6 | 83.9 kg STANDARD_DEVIATION 20.5 | 83.7 kg STANDARD_DEVIATION 20.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 12 / 163 | 10 / 163 |
| other Total, other adverse events | 149 / 163 | 152 / 163 |
| serious Total, serious adverse events | 42 / 163 | 38 / 163 |
Outcome results
Primary
Change in 6-minute Walk Distance (6MWD) Measured at Peak Exposure From Baseline to Week 16
The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline to Week 16, 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 six minutes. Peak exposure 6MWD will occur by conducting 6-minute walk test (6MWT) within 10 to 60 minutes after the most recent dose of study drug dose.
Time frame: Baseline and Week 16
Population: All Subjects Dosed
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in 6-minute Walk Distance (6MWD) Measured at Peak Exposure From Baseline to Week 16 | -9.0 meters |
| Inhaled Treprostinil | Change in 6-minute Walk Distance (6MWD) Measured at Peak Exposure From Baseline to Week 16 | 6.0 meters |
p-value: 0.004395% CI: [7, 37]ANCOVA
Secondary
Change in Peak 6-minute Walk Distance (6MWD) From Baseline to Week 12
The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline to Week 12, 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 six minutes. 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 and Week 12
Population: For those subjects who withdrew early due to death, were too ill to walk, or had no 6MWD measure due to clinical worsening event, the 6MWD is set to 0, for all other withdrawals without Week 12 measurement, last observation carried forward (LOCF) is used for imputation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in Peak 6-minute Walk Distance (6MWD) From Baseline to Week 12 | -3.0 meters |
| Inhaled Treprostinil | Change in Peak 6-minute Walk Distance (6MWD) From Baseline to Week 12 | 8.0 meters |
p-value: 0.004195% CI: [7, 34]ANCOVA
Secondary
Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 16
The 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 Week 16. Blood for NT-proBNP assessment must be drawn prior to conducting the 6MWT.
Time frame: Baseline and Week 16
Population: Only subjects with Baseline NT-proBNP are included. For subjects who do not have Week 16 measure, the last observation carried forward imputation is used.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 16 | 20.65 pg/mL |
| Inhaled Treprostinil | Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 16 | -22.65 pg/mL |
p-value: <0.0001ANCOVA
Secondary
Change in Trough 6-minute Walk Distance (6MWD) From Baseline to Week 15
The intent of the 6MWD test is to evaluate exercise capacity associated with carrying out activities of daily living. Change in 6MWD from Baseline to Week 15, 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 six 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. Trough exposure 6MWD will occur by conducting 6-minute walk test (6MWT) at least four hours after the most recent study drug dose.
Time frame: Baseline and Week 15
Population: For those subjects who withdrew early due to death, were too ill to walk, or had no 6MWD measure due to clinical worsening event, the 6MWD is set to 0, for all other withdrawals without Week 15 measurement, baseline observation carried forward is used for imputation.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo | Change in Trough 6-minute Walk Distance (6MWD) From Baseline to Week 15 | -9.0 meter |
| Inhaled Treprostinil | Change in Trough 6-minute Walk Distance (6MWD) From Baseline to Week 15 | 0.0 meter |
p-value: 0.043295% CI: [0, 29]ANCOVA
Secondary
Incidence of Clinical Worsening
Subjects were monitored for clinical worsening from the time of randomization until 1 of the following criteria were met: hospitalization due to a cardiopulmonary indication; decrease in 6MWD \>15% from Baseline directly related to the disease under study, at 2 consecutive visits and at least 24 hours apart; death (all causes); or lung transplantation.
Time frame: Baseline to Week 16
Population: All Subjects with Clinical Worsening Events
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Incidence of Clinical Worsening | 54 Participants |
| Inhaled Treprostinil | Incidence of Clinical Worsening | 37 Participants |
p-value: 0.04195% CI: [0.4, 0.92]Log Rank