Safety and Efficacy of Inhaled Treprostinil in Adult PH With ILD Including CPFE
Study Details
Study Description
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).
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
|
Phase 2/Phase 3 |
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.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
---|---|
Placebo Comparator: Placebo Matching placebo inhaled using an ultrasonic nebulizer four times daily |
Drug: Placebo
Placebo administered four times daily
|
Active Comparator: 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 |
Drug: Inhaled Treprostinil
Inhaled treprostinil (6 mcg/breath) administered four times daily
Other Names:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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.
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Subject voluntarily gave informed consent to participate in the study.
-
Males and females aged 18 years or older at the time of informed consent.
-
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.
-
Males with a partner of childbearing potential used condoms for the duration of treatment and for at least 48 hours after discontinuing study drug.
-
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.
-
Subjects were required to have a right heart catheterization (RHC) within 1 year prior to randomization with the following documented parameters:
-
Pulmonary vascular resistance (PVR) >3 Wood Units (WU) and
-
A pulmonary capillary wedge pressure (PCWP) of <15 mmHg and
-
A mean pulmonary arterial pressure (mPAP) of >25 mmHg
-
Baseline 6MWD ≥100 m.
-
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.
-
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.
-
Subjects with connective tissue disease (CTD) had a Baseline forced vital capacity (FVC) of <70%.
Exclusion criteria:
-
The subject had a diagnosis of PAH or PH for reasons other than WHO Group 3 PH ILD as outlined in Inclusion Criterion 3.
-
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.
-
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.
-
The subject had evidence of clinically significant left-sided heart disease as defined by:
-
PCWP >15 mmHg
-
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.
-
The subject was receiving >10 L/min of oxygen supplementation by any mode of delivery at rest at Baseline.
-
Current use of any inhaled tobacco/marijuana products or significant history of drug abuse at the time of informed consent.
-
Exacerbation of underlying lung disease or active pulmonary or upper respiratory infection within 30 days of randomization.
-
Initiation of pulmonary rehabilitation within 12 weeks prior to randomization.
-
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).
-
Use of any investigational drug/device, or participation in any investigational study with therapeutic intent within 30 days prior to randomization.
-
Severe concomitant illness limiting life expectancy (<6 months).
-
Acute pulmonary embolism within 90 days of randomization.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | University of Alabama at Birmingham | Birmingham | Alabama | United States | 35294 |
2 | IMC-Diagnostic & Medical Clinic | Mobile | Alabama | United States | 36604 |
3 | Arizona Pulmonary Specialists, Ltd. | Phoenix | Arizona | United States | 85012 |
4 | St. Joseph's Hospital and Medical Center | Phoenix | Arizona | United States | 85013 |
5 | University of Arizona | Tucson | Arizona | United States | 85724 |
6 | Cedars-Sinai Medical Center, Advanced Health Sciences Pavilion | Beverly Hills | California | United States | 90211 |
7 | University of California San Francisco - Fresno | Fresno | California | United States | 93701 |
8 | University of California San Diego | La Jolla | California | United States | 92093 |
9 | VA Long Beach Healthcare System | Long Beach | California | United States | 90822 |
10 | University of Southern California Health Sciences | Los Angeles | California | United States | 90033 |
11 | Department of Veterans Affairs Greater Los Angeles Healthcare System | Los Angeles | California | United States | 90073 |
12 | Pacific Pulmonary Medical Group | Riverside | California | United States | 92505 |
13 | Kaiser Permanente - Roseville | Roseville | California | United States | 95825 |
14 | University of California Davis Medical Center | Sacramento | California | United States | 95817 |
15 | Kaiser Permanente | San Francisco | California | United States | 94115 |
16 | University of Colorado Hospital - Cardiac and Vascular Center | Aurora | Colorado | United States | 80045 |
17 | National Jewish Health | Denver | Colorado | United States | 80206 |
18 | Yale New Haven Hospital | New Haven | Connecticut | United States | 06510 |
19 | Medstar Georgetown University Hospital | Washington | District of Columbia | United States | 20007 |
20 | MedStar Washington Hospital Center | Washington | District of Columbia | United States | 20010 |
21 | Florida Lung, Asthma & Sleep Specialists, P.A. | Celebration | Florida | United States | 34747 |
22 | St. Francis Sleep, Allergy and Lung Institute | Clearwater | Florida | United States | 33765 |
23 | University of Florida Clinical Research Center | Gainesville | Florida | United States | 32610 |
24 | University of Florida College of Medicine, Jacksonville | Jacksonville | Florida | United States | 32209 |
25 | Mayo Clinic Jacksonville | Jacksonville | Florida | United States | 32224 |
26 | St. Vincent's Health System | Jacksonville | Florida | United States | 33204 |
27 | University of Miami | Miami | Florida | United States | 33136 |
28 | Florida Hospital | Orlando | Florida | United States | 32804 |
29 | South Miami Heart Specialists | South Miami | Florida | United States | 33143 |
30 | Tampa General Hospital Center of Research Excellence | Tampa | Florida | United States | 33606 |
31 | Cleveland Clinic Florida | Weston | Florida | United States | 33331 |
32 | The Emory Clinic | Atlanta | Georgia | United States | 30322 |
33 | Piedmont - Georgia Lung Associates | Austell | Georgia | United States | 30106 |
34 | Wellstar Medical Group - Pulmonary Medicine | Marietta | Georgia | United States | 30060 |
35 | Northwestern University School of Medicine | Chicago | Illinois | United States | 60611 |
36 | Rush University Medical Center | Chicago | Illinois | United States | 60612 |
37 | University of Illinois at Chicago Hospital | Chicago | Illinois | United States | 60612 |
38 | University of Chicago Medical Center | Chicago | Illinois | United States | 60637 |
39 | Loyola University Medical Center | Maywood | Illinois | United States | 60153 |
40 | U Health Physicians Advanced Heart and Lung Clinic | Indianapolis | Indiana | United States | 46202 |
41 | Community Heart and Vascular Hospital East | Indianapolis | Indiana | United States | 46250 |
42 | St. Vincent Medical Group, Inc. | Indianapolis | Indiana | United States | 46260 |
43 | University of Iowa Hospitals & Clinics | Iowa City | Iowa | United States | 52242 |
44 | University of Kansas Medical Center | Kansas City | Kansas | United States | 66160 |
45 | University of Kentucky Medical Center | Lexington | Kentucky | United States | 40536 |
46 | University of Louisville Clinical Trials Unit | Louisville | Kentucky | United States | 40202 |
47 | Louisiana State University Health Sciences Center New Orleans | New Orleans | Louisiana | United States | 70112 |
48 | Chest Medicine Associates | South Portland | Maine | United States | 04106 |
49 | University of Maryland Medical Center | Baltimore | Maryland | United States | 21201 |
50 | Johns Hopkins University Pulmonary and Critical Care Medicine | Baltimore | Maryland | United States | 21205 |
51 | Tufts Medical Center | Boston | Massachusetts | United States | 02111 |
52 | Massachusetts General Hospital | Boston | Massachusetts | United States | 02114 |
53 | Brigham & Women's Hospital | Boston | Massachusetts | United States | 02115 |
54 | Spectrum Health Heart and Lung Specialized Care Clinic | Grand Rapids | Michigan | United States | 49503 |
55 | University of Minnesota | Minneapolis | Minnesota | United States | 55455 |
56 | Mayo Clinic | Rochester | Minnesota | United States | 55905 |
57 | University of Mississippi Medical Center | Jackson | Mississippi | United States | 39216 |
58 | Saint Luke's Hospital of Kansas City | Kansas City | Missouri | United States | 64111 |
59 | Washington University School of Medicine | Saint Louis | Missouri | United States | 63110 |
60 | The University of New Mexico Clinical and Translational Science Center | Albuquerque | New Mexico | United States | 87131 |
61 | Albany Medical College | Albany | New York | United States | 12208 |
62 | New York Methodist Hospital | Brooklyn | New York | United States | 11215 |
63 | Northwell Health | New Hyde Park | New York | United States | 11040 |
64 | NYU Langone Medical Center | New York | New York | United States | 10016 |
65 | Mount Sinai Medical Center | New York | New York | United States | 10029 |
66 | New York Presbyterian - Weill Cornell Medical Center | New York | New York | United States | 10065 |
67 | University of North Carolina at Chapel Hill | Chapel Hill | North Carolina | United States | 27599 |
68 | Duke University Medical Center-Duke South Clinic | Durham | North Carolina | United States | 27710 |
69 | Pinehurst Medical Clinic, Inc. | Pinehurst | North Carolina | United States | 28374 |
70 | The Lindner Research Center at The Christ Hospital | Cincinnati | Ohio | United States | 45219 |
71 | University of Cincinnati Health | Cincinnati | Ohio | United States | 45267 |
72 | University Hospitals Cleveland Medical Center | Cleveland | Ohio | United States | 44106 |
73 | Cleveland Clinic | Cleveland | Ohio | United States | 44195 |
74 | The Ohio State University Medical Center | Columbus | Ohio | United States | 43221 |
75 | INTEGRIS Baptist Medical Center | Oklahoma City | Oklahoma | United States | 73112 |
76 | Penn Medicine University City | Philadelphia | Pennsylvania | United States | 19104 |
77 | Allegheny General Hospital | Pittsburgh | Pennsylvania | United States | 15212 |
78 | UPMC Montifiore University Hospital | Pittsburgh | Pennsylvania | United States | 15213 |
79 | AnMed Health Medical Center | Anderson | South Carolina | United States | 29621 |
80 | Medical University of South Carolina | Charleston | South Carolina | United States | 29425 |
81 | Statcare Pulmonary Consultants | Knoxville | Tennessee | United States | 37919 |
82 | Baylor University Medical Center | Dallas | Texas | United States | 75246 |
83 | UT Southwestern Medical Center | Dallas | Texas | United States | 75390 |
84 | Texas Tech University Health Sciences Center | El Paso | Texas | United States | 79905 |
85 | Houston Methodist | Houston | Texas | United States | 77030 |
86 | Memoral Hermann Hospital - Texas Medical Center | Houston | Texas | United States | 77030 |
87 | Michael E. DeBakey VA Medical Center | Houston | Texas | United States | 77030 |
88 | The University of Texas Health Science Center at San Antonio | San Antonio | Texas | United States | 78229 |
89 | Vermont Lung Center | Colchester | Vermont | United States | 05446 |
90 | Inova Fairfax Medical Campus | Fairfax | Virginia | United States | 22042 |
91 | Sentara Norfolk General Hospital | Norfolk | Virginia | United States | 23507 |
92 | Pulmonary Associates of Richmond | Richmond | Virginia | United States | 23229 |
93 | University of Washington Medical Center | Seattle | Washington | United States | 98195 |
94 | University of Wisconsin School of Medicine and Public Health | Madison | Wisconsin | United States | 53792 |
95 | Aurora St. Luke's Medical Center | Milwaukee | Wisconsin | United States | 53215 |
96 | Medical College of Wisconsin/Froedtert Hospital | Milwaukee | Wisconsin | United States | 53226 |
97 | Auxilio Mutuo Hospital | Guaynabo | Puerto Rico | 00968 |
Sponsors and Collaborators
- United Therapeutics
Investigators
None specified.Study Documents (Full-Text)
More Information
Publications
None provided.- RIN-PH-201
Study Results
Participant Flow
Recruitment Details | |
---|---|
Pre-assignment Detail |
Arm/Group Title | Placebo | Inhaled Treprostinil |
---|---|---|
Arm/Group Description | Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily | 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 |
Period Title: Overall Study | ||
STARTED | 163 | 163 |
COMPLETED | 128 | 130 |
NOT COMPLETED | 35 | 33 |
Baseline Characteristics
Arm/Group Title | Placebo | Inhaled Treprostinil | Total |
---|---|---|---|
Arm/Group Description | Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily | 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 | Total of all reporting groups |
Overall Participants | 163 | 163 | 326 |
Age (Count of Participants) | |||
<=18 years |
0
0%
|
0
0%
|
0
0%
|
Between 18 and 65 years |
48
29.4%
|
64
39.3%
|
112
34.4%
|
>=65 years |
115
70.6%
|
99
60.7%
|
214
65.6%
|
Age (years) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [years] |
67.4
(11.2)
|
65.6
(12.7)
|
66.5
(12.0)
|
Sex: Female, Male (Count of Participants) | |||
Female |
68
41.7%
|
85
52.1%
|
153
46.9%
|
Male |
95
58.3%
|
78
47.9%
|
173
53.1%
|
Race (NIH/OMB) (Count of Participants) | |||
American Indian or Alaska Native |
1
0.6%
|
2
1.2%
|
3
0.9%
|
Asian |
5
3.1%
|
7
4.3%
|
12
3.7%
|
Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
Black or African American |
30
18.4%
|
41
25.2%
|
71
21.8%
|
White |
126
77.3%
|
112
68.7%
|
238
73%
|
More than one race |
1
0.6%
|
0
0%
|
1
0.3%
|
Unknown or Not Reported |
0
0%
|
1
0.6%
|
1
0.3%
|
Region of Enrollment (participants) [Number] | |||
Puerto Rico |
2
1.2%
|
0
0%
|
2
0.6%
|
United States |
161
98.8%
|
163
100%
|
324
99.4%
|
Weight (kg) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [kg] |
83.5
(20.6)
|
83.9
(20.5)
|
83.7
(20.5)
|
Height (cm) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [cm] |
169.0
(9.4)
|
167.5
(10.3)
|
168.2
(9.9)
|
BMI (kg/m^2) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [kg/m^2] |
29.0
(5.9)
|
30.0
(6.6)
|
29.5
(6.3)
|
6 Minute Walk Distance (meters) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [meters] |
265.1
(93.1)
|
254.1
(102.4)
|
259.6
(97.9)
|
N-terminal prohormone brain natriuretic peptide (NT-proBNP) (pg/mL) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [pg/mL] |
210.9
(370.7)
|
223.5
(378.5)
|
217.1
(374.0)
|
Pulmonary Vascular Resistance (PVR) (Wood Units (WU)) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [Wood Units (WU)] |
6.0
(2.7)
|
6.4
(2.9)
|
6.2
(2.8)
|
Mean pulmonary arterial pressure (PAPm) (mmHg) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [mmHg] |
36.0
(8.4)
|
37.2
(8.6)
|
36.6
(8.5)
|
Pulmonary Capillary Wedge Pressure (PCWP) (mmHg) [Mean (Standard Deviation) ] | |||
Mean (Standard Deviation) [mmHg] |
9.6
(3.5)
|
10.1
(3.4)
|
9.8
(3.5)
|
Vasodilator testing during confirmatory right heart catheterization (RHC)? (Count of Participants) | |||
Yes |
45
27.6%
|
42
25.8%
|
87
26.7%
|
No |
118
72.4%
|
121
74.2%
|
239
73.3%
|
10 mmHg decrease in PAPm during Confirmatory RHC? (Count of Participants) | |||
Yes |
8
4.9%
|
6
3.7%
|
14
4.3%
|
No |
35
21.5%
|
37
22.7%
|
72
22.1%
|
Not tested |
120
73.6%
|
120
73.6%
|
240
73.6%
|
Vasodilator medications used during Confirmatory RHC? (Count of Participants) | |||
Inhaled Nitrous Oxide |
43
26.4%
|
39
23.9%
|
82
25.2%
|
Adenosine |
2
1.2%
|
1
0.6%
|
3
0.9%
|
Other |
0
0%
|
2
1.2%
|
2
0.6%
|
No medication |
118
72.4%
|
121
74.2%
|
239
73.3%
|
Outcome Measures
Title | Change in 6-minute Walk Distance (6MWD) Measured at Peak Exposure From Baseline to Week 16 |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
All Subjects Dosed |
Arm/Group Title | Placebo | Inhaled Treprostinil |
---|---|---|
Arm/Group Description | Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily | 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 |
Measure Participants | 163 | 163 |
Median (Full Range) [meters] |
-9.0
|
6.0
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Placebo, Inhaled Treprostinil |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0043 |
Comments | p-value is obtained from nonparametric ANCOVA adjusted for Baseline 6MWD category. | |
Method | ANCOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Hodges-Lehmann |
Estimated Value | 21.0 | |
Confidence Interval |
(2-Sided) 95% 7.0 to 37.0 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Change in Plasma Concentration of N-terminal Pro-Brain Natriuretic Peptide (NT-proBNP) From Baseline to Week 16 |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
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/Group Title | Placebo | Inhaled Treprostinil |
---|---|---|
Arm/Group Description | Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily | 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 |
Measure Participants | 160 | 156 |
Median (Full Range) [pg/mL] |
20.65
|
-22.65
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Placebo, Inhaled Treprostinil |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | <0.0001 |
Comments | ||
Method | ANCOVA | |
Comments |
Title | Incidence of Clinical Worsening |
---|---|
Description | 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 |
Outcome Measure Data
Analysis Population Description |
---|
All Subjects with Clinical Worsening Events |
Arm/Group Title | Placebo | Inhaled Treprostinil |
---|---|---|
Arm/Group Description | Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily | 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 |
Measure Participants | 163 | 163 |
Count of Participants [Participants] |
54
33.1%
|
37
22.7%
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Placebo, Inhaled Treprostinil |
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Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0410 |
Comments | p-value is calculated with log-rank test stratified by baseline 6MWD category. | |
Method | Log Rank | |
Comments | ||
Method of Estimation | Estimation Parameter | Hazard Ratio (HR) |
Estimated Value | 0.61 | |
Confidence Interval |
(2-Sided) 95% 0.40 to 0.92 |
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Parameter Dispersion |
Type: Value: |
|
Estimation Comments | p-value was 0.0202 for the proportional hazard model. Hazard ratio, 95% confidence interval (CI), and p-values are calculated with proportional hazards model with treatment and Baseline 6MWD (continuous) as explanatory variables. |
Title | Change in Peak 6-minute Walk Distance (6MWD) From Baseline to Week 12 |
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Description | 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 |
Outcome Measure Data
Analysis Population Description |
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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/Group Title | Placebo | Inhaled Treprostinil |
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Arm/Group Description | Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily | 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 |
Measure Participants | 163 | 163 |
Median (Full Range) [meters] |
-3.0
|
8.0
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Placebo, Inhaled Treprostinil |
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Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0041 |
Comments | p-value is obtained from nonparametric ANCOVA adjusted for Baseline 6MWD category | |
Method | ANCOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Hodges-Lehmann |
Estimated Value | 20.0 | |
Confidence Interval |
(2-Sided) 95% 7.0 to 34.0 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Title | Change in Trough 6-minute Walk Distance (6MWD) From Baseline to Week 15 |
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Description | 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 |
Outcome Measure Data
Analysis Population Description |
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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/Group Title | Placebo | Inhaled Treprostinil |
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Arm/Group Description | Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily | 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 |
Measure Participants | 163 | 163 |
Median (Full Range) [meter] |
-9.0
|
0.0
|
Statistical Analysis 1
Statistical Analysis Overview | Comparison Group Selection | Placebo, Inhaled Treprostinil |
---|---|---|
Comments | ||
Type of Statistical Test | Superiority | |
Comments | ||
Statistical Test of Hypothesis | p-Value | 0.0432 |
Comments | p-value is obtained from nonparametric ANCOVA adjusted for Baseline 6MWD category. | |
Method | ANCOVA | |
Comments | ||
Method of Estimation | Estimation Parameter | Hodges-Lehmann |
Estimated Value | 15.0 | |
Confidence Interval |
(2-Sided) 95% 0.0 to 29.0 |
|
Parameter Dispersion |
Type: Value: |
|
Estimation Comments |
Adverse Events
Time Frame | AEs were recorded throughout the course of the study from the time that each subject signed the ICF until all study assessments were completed (16 weeks). | |||
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Adverse Event Reporting Description | All AEs were followed until either resolution (or return to normal or baseline values), until they were judged by the Investigator to no longer be clinically significant, or for at least 30 days if the AE extended beyond the final study visit. All AEs which met the criteria for serious (ie, SAEs) were followed until resolution, death, or the subject was lost to follow-up even if they were ongoing more than 30 days after completion of the final study visit (Week 16 or early termination Visit). | |||
Arm/Group Title | Placebo | Active Inhaled Treprostinil | ||
Arm/Group Description | Matching placebo inhaled using an ultrasonic nebulizer four times daily Placebo: Placebo administered four times daily | 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 | ||
All Cause Mortality |
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Placebo | Active Inhaled Treprostinil | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 12/163 (7.4%) | 10/163 (6.1%) | ||
Serious Adverse Events |
||||
Placebo | Active Inhaled Treprostinil | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 42/163 (25.8%) | 38/163 (23.3%) | ||
Blood and lymphatic system disorders | ||||
Coagulopathy | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Cardiac disorders | ||||
Acute myocardial infarction | 2/163 (1.2%) | 2 | 1/163 (0.6%) | 1 |
Acute right ventricular failure | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Arrythmia | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Cardiac arrest | 2/163 (1.2%) | 2 | 1/163 (0.6%) | 1 |
Cardiac failure congestive | 2/163 (1.2%) | 2 | 1/163 (0.6%) | 1 |
Cardiopulmonary failure | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Cor pulmonale | 0/163 (0%) | 0 | 1/163 (0.6%) | 2 |
Left ventricular failure | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Right ventricular failure | 2/163 (1.2%) | 2 | 1/163 (0.6%) | 1 |
Tachycardia | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Atrial fibrillation | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Bradycardia | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Cardiac failure | 2/163 (1.2%) | 2 | 0/163 (0%) | 0 |
Cardiac failure acute | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Cardiogenic shock | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Chronic right ventricular failure | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Cor pulmonale acute | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Coronary artery disease | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Gastrointestinal disorders | ||||
Abdominal pain | 2/163 (1.2%) | 2 | 0/163 (0%) | 0 |
Haematochezia | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
General disorders | ||||
Death | 1/163 (0.6%) | 1 | 3/163 (1.8%) | 3 |
Chest pain | 1/163 (0.6%) | 1 | 1/163 (0.6%) | 1 |
Disease progression | 2/163 (1.2%) | 2 | 0/163 (0%) | 0 |
Pain | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Infections and infestations | ||||
Bronchitis | 1/163 (0.6%) | 1 | 2/163 (1.2%) | 2 |
Upper respiratory tract infection | 1/163 (0.6%) | 1 | 2/163 (1.2%) | 2 |
Bronchopulmonary aspergillosis | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Cellulitis | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Influenza | 1/163 (0.6%) | 1 | 1/163 (0.6%) | 1 |
Pneumonia | 9/163 (5.5%) | 9 | 1/163 (0.6%) | 1 |
Rhinovirus infetion | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Pneumonia influenzal | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Post procedural infection | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Sepsis | 2/163 (1.2%) | 2 | 1/163 (0.6%) | 1 |
Urosepsis | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Injury, poisoning and procedural complications | ||||
Lumbar vertebral fracture | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Transplant dysfunction | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Metabolism and nutrition disorders | ||||
Hyperglycaemia | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Hypervolaemia | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Fluid overload | 4/163 (2.5%) | 5 | 0/163 (0%) | 0 |
Musculoskeletal and connective tissue disorders | ||||
Pain in extremity | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Scleroderma | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||
B-cell lymphoma | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Nervous system disorders | ||||
Cerebral haemorrhage | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Syncope | 1/163 (0.6%) | 1 | 1/163 (0.6%) | 1 |
Metabolic encephalopathy | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Presyncope | 2/163 (1.2%) | 2 | 0/163 (0%) | 0 |
Renal and urinary disorders | ||||
Acute kidney injury | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Respiratory, thoracic and mediastinal disorders | ||||
Acute respiratory failure | 5/163 (3.1%) | 5 | 4/163 (2.5%) | 4 |
Dyspnoea | 7/163 (4.3%) | 7 | 3/163 (1.8%) | 3 |
Interstitial lung disease | 2/163 (1.2%) | 2 | 3/163 (1.8%) | 3 |
Chronic obstructive pulmonary disease | 2/163 (1.2%) | 2 | 2/163 (1.2%) | 2 |
Chronic respiratory failure | 0/163 (0%) | 0 | 2/163 (1.2%) | 2 |
Respiratory failure | 5/163 (3.1%) | 5 | 2/163 (1.2%) | 2 |
Combined pulmonary fibrosis and emphysema | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Haemoptysis | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Hypoxia | 0/163 (0%) | 0 | 1/163 (0.6%) | 1 |
Idiopathic pulmonary fibrosis | 4/163 (2.5%) | 4 | 1/163 (0.6%) | 1 |
Pneumothorax | 1/163 (0.6%) | 11 | 1/163 (0.6%) | 1 |
Pulmonary hypertension | 1/163 (0.6%) | 1 | 1/163 (0.6%) | 1 |
Pulmonary oedema | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Aspiration | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Epistaxis | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Pulmonary congestion | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Respiratory distress | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Vascular disorders | ||||
Hypertension | 1/163 (0.6%) | 1 | 0/163 (0%) | 0 |
Other (Not Including Serious) Adverse Events |
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Placebo | Active Inhaled Treprostinil | |||
Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
Total | 149/163 (91.4%) | 152/163 (93.3%) | ||
Gastrointestinal disorders | ||||
Nausea | 26/163 (16%) | 27 | 25/163 (15.3%) | 26 |
Diarrhea | 19/163 (11.7%) | 19 | 22/163 (13.5%) | 24 |
General disorders | ||||
Fatigue | 23/163 (14.1%) | 24 | 23/163 (14.1%) | 24 |
Chest pain | 5/163 (3.1%) | 5 | 14/163 (8.6%) | 14 |
Oedema peripheral | 10/163 (6.1%) | 11 | 13/163 (8%) | 13 |
Chest discomfort | 4/163 (2.5%) | 4 | 8/163 (4.9%) | 9 |
Infections and infestations | ||||
Upper respiratory tract infection | 11/163 (6.7%) | 11 | 11/163 (6.7%) | 12 |
Pneumonia | 11/163 (6.7%) | 12 | 2/163 (1.2%) | 2 |
Injury, poisoning and procedural complications | ||||
Fall | 3/163 (1.8%) | 3 | 8/163 (4.9%) | 8 |
Investigations | ||||
N-terminal prohormone brain natriuretic peptide increased | 25/163 (15.3%) | 25 | 9/163 (5.5%) | 9 |
Metabolism and nutrition disorders | ||||
Decreased appetite | 8/163 (4.9%) | 8 | 7/163 (4.3%) | 7 |
Nervous system disorders | ||||
Headache | 32/163 (19.6%) | 34 | 45/163 (27.6%) | 49 |
Dizziness | 23/163 (14.1%) | 23 | 30/163 (18.4%) | 31 |
Respiratory, thoracic and mediastinal disorders | ||||
Cough | 54/163 (33.1%) | 56 | 71/163 (43.6%) | 76 |
Dyspnoea | 51/163 (31.3%) | 56 | 41/163 (25.2%) | 46 |
Throat irritation | 6/163 (3.7%) | 6 | 20/163 (12.3%) | 20 |
Oropharyngeal pain | 4/163 (2.5%) | 4 | 18/163 (11%) | 18 |
Epistaxis | 7/163 (4.3%) | 7 | 9/163 (5.5%) | 9 |
Rhinorrhoea | 4/163 (2.5%) | 4 | 8/163 (4.9%) | 8 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
Institution and/or Principal Investigator agree not to publish or publicly present any results of the Study without the prior written consent of Sponsor, not to be unreasonably withheld or delayed. Institution and/or Principal Investigator further agree to provide Sponsor with drafts of any such publication or presentation for review and approval no less than 30 days prior to submission for publication or the date of public presentation.
Results Point of Contact
Name/Title | United Therapeutics Global Medical Information |
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Organization | United Therapeutics |
Phone | 919-485-8350 |
clinicaltrials@unither.com |
- RIN-PH-201