Safety and Efficacy of Inhaled Treprostinil in Adult PH With ILD Including CPFE

Sponsor
United Therapeutics (Industry)
Overall Status
Completed
CT.gov ID
NCT02630316
Collaborator
(none)
326
97
2
34.7
3.4
0.1

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
  • Drug: Inhaled Treprostinil
  • Drug: Placebo
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

Study Type:
Interventional
Actual Enrollment :
326 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Safety and Efficacy of Inhaled Treprostinil in Subjects With Pulmonary Hypertension Due to Parenchymal Lung Disease
Actual Study Start Date :
Feb 3, 2017
Actual Primary Completion Date :
Dec 26, 2019
Actual Study Completion Date :
Dec 26, 2019

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:
  • Tyvaso
  • Outcome Measures

    Primary Outcome Measures

    1. 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

    1. 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.

    2. 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.

    3. 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.

    4. 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

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts 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.

    1. 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.

    2. Males with a partner of childbearing potential used condoms for the duration of treatment and for at least 48 hours after discontinuing study drug.

    1. 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.

    2. Subjects were required to have a right heart catheterization (RHC) within 1 year prior to randomization with the following documented parameters:

    3. Pulmonary vascular resistance (PVR) >3 Wood Units (WU) and

    4. A pulmonary capillary wedge pressure (PCWP) of <15 mmHg and

    5. A mean pulmonary arterial pressure (mPAP) of >25 mmHg

    6. Baseline 6MWD ≥100 m.

    7. 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.

    8. 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.

    9. 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:

    5. PCWP >15 mmHg

    6. 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.

    7. The subject was receiving >10 L/min of oxygen supplementation by any mode of delivery at rest at Baseline.

    8. Current use of any inhaled tobacco/marijuana products or significant history of drug abuse at the time of informed consent.

    9. Exacerbation of underlying lung disease or active pulmonary or upper respiratory infection within 30 days of randomization.

    10. Initiation of pulmonary rehabilitation within 12 weeks prior to randomization.

    11. 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).

    12. Use of any investigational drug/device, or participation in any investigational study with therapeutic intent within 30 days prior to randomization.

    13. Severe concomitant illness limiting life expectancy (<6 months).

    14. 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.
    Responsible Party:
    United Therapeutics
    ClinicalTrials.gov Identifier:
    NCT02630316
    Other Study ID Numbers:
    • RIN-PH-201
    First Posted:
    Dec 15, 2015
    Last Update Posted:
    Jul 27, 2022
    Last Verified:
    Jul 1, 2022
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by United Therapeutics
    Additional relevant MeSH terms:

    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

    1. Primary Outcome
    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
    2. Secondary Outcome
    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
    3. Secondary Outcome
    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
    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
    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.
    4. Secondary Outcome
    Title Change in Peak 6-minute Walk Distance (6MWD) From Baseline to Week 12
    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
    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
    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
    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
    5. Secondary Outcome
    Title Change in Trough 6-minute Walk Distance (6MWD) From Baseline to Week 15
    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
    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
    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).
    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
    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
    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

    [Not Specified]

    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
    Organization United Therapeutics
    Phone 919-485-8350
    Email clinicaltrials@unither.com
    Responsible Party:
    United Therapeutics
    ClinicalTrials.gov Identifier:
    NCT02630316
    Other Study ID Numbers:
    • RIN-PH-201
    First Posted:
    Dec 15, 2015
    Last Update Posted:
    Jul 27, 2022
    Last Verified:
    Jul 1, 2022