Chronic Obstructive Pulmonary Disease, Pulmonary Hypertension
Conditions
Keywords
Pulmonary Hypertension, COPD, Inhaled Treprostinil, 6-Minute Walk Test, Tyvaso
Brief summary
The primary objective of this study is to demonstrate the efficacy of inhaled treprostinil compared to placebo in improving exercise ability as measured by change from baseline in 6-Minute Walk Distance (6MWD) following 12 weeks of active treatment in participants with PH-COPD.
Detailed description
This is a multicenter, randomized, double-blind, placebo-controlled, 34-week, cross-over study, with a Treatment Period of approximately 26 weeks under the Original Crossover Design or, if applicable, a 21-week parallel study, with a Treatment Period of approximately 14 weeks under the Contingent Parallel Design.
Interventions
Treprostinil inhalation solution
DRUGPlacebo solution
Placebo solution
Sponsors
United Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
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
Participants who meet the following criteria may be included in the study: 1. Participant voluntarily gives informed consent to participate in the study. 2. Males and females 18 years of age and above at the time of informed consent. 1. Women of childbearing potential (defined as less than 1 year post-menopausal and not surgically sterile) must agree to practice abstinence or use 2 highly effective methods of contraception (defined as a method of birth control that results in a low failure rate, \[\<1% per year\], such as approved hormonal contraceptives, barrier methods \[such as condom or diaphragm\] used with a spermicide, or an intrauterine device) for the duration of study treatment and for 48 hours after discontinuing study drug. Participants must have a negative pregnancy test at the Screening Visit 1 (urine \[prior to the first dose of study medication\] and serum) and Baseline Visit (Study Week 1) (urine). 2. Males with a partner of childbearing potential must agree to use a barrier method (condom) with a spermicide for the duration of treatment and for at least 48 hours after discontinuing study drug. 3. Diagnosis of PH-COPD (World Heath Organization \[WHO\] Group 3). 4. Clinical diagnosis of COPD will be made using the Global Initiative for Chronic Obstructive Lung Disease (GOLD) diagnostic criteria (GOLD Criteria 2020) and spirometry with the following documented parameters measured during Screening Visit 1 (prior to start of low-dose inhaled treprostinil): 1. Forced expiratory volume in 1 second (FEV1) \<80% predicted 2. FEV1/Forced vital capacity (FVC) \<70 5. The participant has a resting saturation peripheral capillary oxygenation (SpO2) greater than or equal to 90%, with or without supplemental oxygen, but not to exceed 10 liters (L)/min oxygen supplementation by any mode of delivery during Screening Visit 1. 6. During Screening Visit 1 prior to start of low-dose inhaled treprostinil, a 6MWD greater than or equal to 100 meters. 7. Have a right heart catheterization (RHC) performed during Screening Visit 1. (A previous RHC obtained within 12 months prior to the start of Screening Visit 1 is acceptable for determining eligibility, even if done without oxygen or vasodilator challenge, and a repeat RHC is not required.) The following parameters must be documented for eligibility: 1. Pulmonary vascular resistance (PVR) greater than or equal to 4 Wood units 2. A pulmonary artery wedge pressure (PAWP) or left ventricular end-diastolic pressure (LVEDP) of less than or equal to 15 millimeters of mercury (mmHg) 3. A Pulmonary artery pressure mean (PAPm) of greater than or equal to 30 mmHg 8. Participants must be on a stable and optimized dose of chronic COPD medications for greater than or equal to 30 days prior to start of Screening Visit 1 and remain on the same dose throughout the Screening Period. 9. In the opinion of the Investigator, the participant can communicate effectively with study personnel and is considered reliable, willing, and likely to be cooperative with protocol requirements, including attending all study visits.
Exclusion criteria
The following will exclude participants from the study: 1. The participant has a diagnosis of either pulmonary arterial hypertension (PAH) or pulmonary hypertension (PH) due to reasons other than COPD. This would include, but is not limited to, chronic thromboembolic PH or acute/recent deep vein thrombosis or pulmonary embolism, untreated or inadequately treated obstructive sleep apnea, connective tissue disease (including but not limited to systemic sclerosis/scleroderma or systemic lupus erythematosus), sarcoidosis, human immunodeficiency virus-1 infection, and other conditions under WHO Group 1, 2, 4, and 5 classifications. 2. Based on chest computed tomography (CT) imaging during Screening Visit 1, the participant has a confirmed diagnosis of WHO Group 3 PH, other than COPD, such as idiopathic pulmonary fibrosis, combined pulmonary fibrosis and emphysema, diffuse parenchymal lung disease or interstitial lung disease. A previous chest CT scan performed within the 6 months prior to the start of Screening Visit 1 is also acceptable, and a repeat assessment is not required. A redacted CT scan report (from Screening Visit 1 or dated within prior 6 months) should be provided to the Medical Monitor with the Pre-Baseline Review Form to confirm eligibility. 3. The participant has received any Food and Drug Administration (FDA)-approved medication for the treatment of PAH (that is, prostacyclin, prostacyclin receptor agonist, endothelin receptor antagonist \[ERA\], phosphodiesterase type 5 inhibitor \[PDE5-I\], or soluble guanylate cyclase \[sGC\] stimulator) at Screening Visit 1 and thereafter, except if received for acute vasoreactivity testing. 4. The participant has a previous diagnosis of homozygous alpha-1 antitrypsin deficiency. 5. The participant has any prior intolerance to inhaled prostanoid therapy. 6. Inability to tolerate low-dose (3 breaths, 18 mcg) study drug and/or inability to follow dosing regimen during the Screening Period (pre-randomization). 7. Unwilling or unable to use Sponsor-provided devices (actigraph, spirometer, or smart device). 8. The participant has evidence of clinically significant left-sided heart disease (including but not limited to left ventricular ejection fraction \<40%, left ventricular hypertrophy,) or clinically significant cardiologic conditions, such as congestive heart failure, coronary artery disease, or valvular heart disease. Note: Participants with abnormal left ventricular function attributable to the effects of right ventricular overload will not be excluded, but a discussion with and approval by the Sponsor Medical Monitor is needed. 9. Any exacerbation of COPD (including hospitalization or outpatient therapy) or active pulmonary or upper respiratory infection 60 days prior to start of Screening Visit 1 through the Baseline Visit. This is defined as worsening of respiratory symptoms that required treatment with corticosteroids and/or antibiotics. 10. Initiation of pulmonary rehabilitation within 12 weeks prior to start of Screening Visit 1 or, in the opinion of the Investigator, pulmonary rehabilitation is likely to be needed during the study Treatment Period. 11. The participant has any form of congenital heart disease (repaired or unrepaired; other than a patent foramen ovale). 12. The participant has any musculoskeletal disorder (severe arthritis of the lower limbs which limits ambulation, recent hip or knee joint replacement, artificial leg) or any other condition that would likely be the primary limitation to ambulation. 13. Use of any other investigational drug or device within 30 days prior to the start of Screening Visit 1. 14. Any other clinically significant illness or abnormal laboratory value(s) measured during the Screening Period that, in the opinion of the Investigator, might adversely affect the interpretation of the study data or safety of the participant.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD) | Baseline, Week 12 | 6 MWD was calculated at peak exposure (10 to 60 minutes after dosing). 6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course for 6 minutes (timed) and the distance walked (in meters) was recorded. Statistical analyses were not performed due to lack of appropriate sample size. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline to Week 12 in Overall Activity | Baseline, Week 12 | Overall activity was defined as the number of minutes spent in overall activity (non-sedentary activity) as measured via a wrist-worn medical grade physical activity monitor. The screening data will be used to establish a baseline level of physical activity. |
| Change From Baseline to Week 12 in Borg Dyspnea Score | Baseline, Week 12 | The Borg Dyspnea Score was a 11-point scale rating the maximum level of dyspnea experienced during the 6-minute walking test (6MWT). Scores range from 0 (no dyspnea at all) to 10 (very, very severe dyspnea), with lower scores indicating a less exertion (a better outcome). The Borg Dyspnea Score was to be evaluated immediately after the 6MWT. |
| Change From Baseline to Week 12 in 6MWD/Borg Dyspnea Composite Score | Baseline, Week 12 | 6MWD was calculated at peak exposure (10 to 60 minutes after dosing). 6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course for 6 minutes (timed) and the distance walked (in meters) was recorded. The Borg Dyspnea Score was an 11-point scale rating the maximum level of dyspnea experienced during the 6MWT. Scores range from 0 (no dyspnea at all) to 10 (very, very severe dyspnea), with lower scores indicating less exertion (a better outcome). The Borg Dyspnea Score was to be evaluated immediately after the 6MWT. The average 6WMWD data and the average Borg Dyspnea Composite Score data were summed and reported as the composite score. |
| Change From Baseline to Week 12 in Moderate to Vigorous Physical Activity (MVPA) | Baseline, Week 12 | MVPA was defined as the number of minutes spent in moderate to vigorous physical activity as measured via a wrist-worn medical grade physical activity monitor. The screening data were used to establish a baseline level of physical activity. |
| Change From Baseline to Week 12 in QOL Measured by the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) | Baseline, Week 12 | The UCSD SOBQ is a self-administered rating of dyspnea associated with activities of daily living. The questionnaire uses a 6-point scale where 0 = not at all and 5 = maximal or unable to do because of breathlessness. Lower scores indicate a better QoL. |
| Change From Baseline to Week 12 in Plasma Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Levels | Baseline, Week 12 | The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function. Improvement is defined as a decrease in the NT-proBNP plasma concentration. |
| Change From Baseline to Week 12 in Patient Global Assessment (PGA) | Baseline, Week 12 | The PGA is used to rate participant fatigue and shortness of breath. Participants will use the Sponsor-provided smart device for at-home capture of PGA data. The PGA used a 5-point response scale of: never, rarely, sometimes, often, or always with higher scores indicating a worse symptom rating. |
| Change From Baseline to Week 12 in Quality of Life (QOL) Measured by St. George's Respiratory Questionnaire (SGRQ) | Baseline, Week 12 | The SGRQ is a designed to measure how breathing impacts overall health, daily life, and perceived well-being in participants with obstructive airways disease. Scores range from 0 to 100, with lower scores indicating a better QoL. |
Countries
Argentina, Israel, Puerto Rico, United States
Participant flow
Recruitment details
188 participants were enrolled; 80 of the 188 enrolled participants were screen failures prior to the Run-In Period. Per prespecified analysis, data were not collected for the participants who were screen failures.
Pre-assignment details
In the Original Crossover Design, a total of 64 participants were randomized to 1 of 2 treatment sequences (treprostinil-placebo) or (placebo-treprostinil) in a crossover study design for 12 weeks during 2 dosing periods. There was a washout of at least 7 days between the dosing periods. 12 participants were randomized to receive either treprostinil or placebo during the single treatment period in Contingent Parallel Design.
Participants by arm
| Arm | Count |
|---|---|
| Original Crossover Design Participants were randomized to one of two treatment sequences: treprostinil-placebo, or placebo-treprostinil during two dosing periods, each up to 12 weeks | 64 |
| Contingent Parallel Design - Treprostinil Participants received up to 72 μg of treprostinil for inhalation QID, for up to 12 weeks | 6 |
| Contingent Parallel Design - Placebo Participants received placebo to match treprostinil QID, for up to 12 weeks | 6 |
| Total | 76 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Period 1 (12 Weeks) | Death | 0 | 3 | 0 | 0 | 0 |
| Period 1 (12 Weeks) | Study Terminated by Sponsor | 0 | 0 | 0 | 1 | 2 |
| Period 1 (12 Weeks) | Withdrawal by Subject | 0 | 3 | 3 | 0 | 0 |
| Period 2 (12 Weeks) | COVID-19 Pandemic Impact | 0 | 4 | 5 | 0 | 0 |
| Period 2 (12 Weeks) | Lost to Follow-up | 0 | 0 | 1 | 0 | 0 |
| Period 2 (12 Weeks) | Study Terminated by Sponsor | 0 | 0 | 1 | 0 | 0 |
| Period 2 (12 Weeks) | Withdrawal by Subject | 0 | 3 | 1 | 0 | 0 |
| Run-In Period (2 Weeks) | Death | 1 | 0 | 0 | 0 | 0 |
| Run-In Period (2 Weeks) | Discontinued Prior to Randomization | 31 | 0 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Original Crossover Design | Contingent Parallel Design - Treprostinil | Contingent Parallel Design - Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 67.6 years STANDARD_DEVIATION 7.83 | 70.3 years STANDARD_DEVIATION 6.71 | 73.3 years STANDARD_DEVIATION 2.16 | 69.7 years STANDARD_DEVIATION 8.01 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 0 Participants | 2 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 62 Participants | 6 Participants | 4 Participants | 72 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 1 Participants | 2 Participants | 18 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 47 Participants | 5 Participants | 4 Participants | 56 Participants |
| Sex: Female, Male Female | 31 Participants | 0 Participants | 2 Participants | 33 Participants |
| Sex: Female, Male Male | 33 Participants | 6 Participants | 4 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 108 | 5 / 66 | 0 / 58 |
| other Total, other adverse events | 50 / 108 | 36 / 66 | 25 / 58 |
| serious Total, serious adverse events | 9 / 108 | 17 / 66 | 6 / 58 |
Outcome results
Primary
Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD)
6 MWD was calculated at peak exposure (10 to 60 minutes after dosing). 6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course for 6 minutes (timed) and the distance walked (in meters) was recorded. Statistical analyses were not performed due to lack of appropriate sample size.
Time frame: Baseline, Week 12
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug. Here, 'Overall number of participants analyzed' = participants evaluable for this outcome measure and 'Number analyzed' = participants evaluable at the specified timeframe.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Original Crossover Design - Treprostinil | Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD) | Baseline | 225.07 meters | Standard Deviation 77.41 |
| Original Crossover Design - Treprostinil | Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD) | Change at Week 12 | -4.47 meters | Standard Deviation 39.01 |
| Original Crossover Design - Placebo | Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD) | Change at Week 12 | -5.14 meters | Standard Deviation 50.71 |
| Original Crossover Design - Placebo | Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD) | Baseline | 220.47 meters | Standard Deviation 77.64 |
| Contingent Parallel Design - Treprostinil | Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD) | Baseline | 231.50 meters | Standard Deviation 60.77 |
| Contingent Parallel Design - Treprostinil | Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD) | Change at Week 12 | 20.33 meters | Standard Deviation 116.99 |
| Contingent Parallel Design - Placebo | Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD) | Baseline | 283.00 meters | Standard Deviation 67.78 |
| Contingent Parallel Design - Placebo | Change From Baseline to Week 12 in 6-Minute Walk Distance (6MWD) | Change at Week 12 | 18.5 meters | Standard Deviation 42.49 |
Secondary
Change From Baseline to Week 12 in 6MWD/Borg Dyspnea Composite Score
6MWD was calculated at peak exposure (10 to 60 minutes after dosing). 6MWT was performed by standardized procedures for all participants. Participants were asked to walk a set course for 6 minutes (timed) and the distance walked (in meters) was recorded. The Borg Dyspnea Score was an 11-point scale rating the maximum level of dyspnea experienced during the 6MWT. Scores range from 0 (no dyspnea at all) to 10 (very, very severe dyspnea), with lower scores indicating less exertion (a better outcome). The Borg Dyspnea Score was to be evaluated immediately after the 6MWT. The average 6WMWD data and the average Borg Dyspnea Composite Score data were summed and reported as the composite score.
Time frame: Baseline, Week 12
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug. Data were not collected for this outcome measure due to study termination and lack of appropriate sample size.
Secondary
Change From Baseline to Week 12 in Borg Dyspnea Score
The Borg Dyspnea Score was a 11-point scale rating the maximum level of dyspnea experienced during the 6-minute walking test (6MWT). Scores range from 0 (no dyspnea at all) to 10 (very, very severe dyspnea), with lower scores indicating a less exertion (a better outcome). The Borg Dyspnea Score was to be evaluated immediately after the 6MWT.
Time frame: Baseline, Week 12
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug. Data were not collected for this outcome measure due to study termination and lack of appropriate sample size.
Secondary
Change From Baseline to Week 12 in Moderate to Vigorous Physical Activity (MVPA)
MVPA was defined as the number of minutes spent in moderate to vigorous physical activity as measured via a wrist-worn medical grade physical activity monitor. The screening data were used to establish a baseline level of physical activity.
Time frame: Baseline, Week 12
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug. Data were not collected for this outcome measure due to study termination and lack of appropriate sample size.
Secondary
Change From Baseline to Week 12 in Overall Activity
Overall activity was defined as the number of minutes spent in overall activity (non-sedentary activity) as measured via a wrist-worn medical grade physical activity monitor. The screening data will be used to establish a baseline level of physical activity.
Time frame: Baseline, Week 12
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug. Data were not collected for this outcome measure due to study termination and lack of appropriate sample size.
Secondary
Change From Baseline to Week 12 in Patient Global Assessment (PGA)
The PGA is used to rate participant fatigue and shortness of breath. Participants will use the Sponsor-provided smart device for at-home capture of PGA data. The PGA used a 5-point response scale of: never, rarely, sometimes, often, or always with higher scores indicating a worse symptom rating.
Time frame: Baseline, Week 12
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug. Data were not collected for this outcome measure due to study termination and lack of appropriate sample size.
Secondary
Change From Baseline to Week 12 in Plasma Concentration of N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Levels
The NT-proBNP concentration is a biomarker associated with changes in right heart morphology and function. Improvement is defined as a decrease in the NT-proBNP plasma concentration.
Time frame: Baseline, Week 12
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug. Data were not collected for this outcome measure due to study termination and lack of appropriate sample size.
Secondary
Change From Baseline to Week 12 in QOL Measured by the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ)
The UCSD SOBQ is a self-administered rating of dyspnea associated with activities of daily living. The questionnaire uses a 6-point scale where 0 = not at all and 5 = maximal or unable to do because of breathlessness. Lower scores indicate a better QoL.
Time frame: Baseline, Week 12
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug. Data were not collected for this outcome measure due to study termination and lack of appropriate sample size.
Secondary
Change From Baseline to Week 12 in Quality of Life (QOL) Measured by St. George's Respiratory Questionnaire (SGRQ)
The SGRQ is a designed to measure how breathing impacts overall health, daily life, and perceived well-being in participants with obstructive airways disease. Scores range from 0 to 100, with lower scores indicating a better QoL.
Time frame: Baseline, Week 12
Population: Full Analysis Set included all participants who were randomized and received at least one dose of study drug. Data were not collected for this outcome measure due to study termination and lack of appropriate sample size.