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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Multicenter, Placebo-Controlled Study to Evaluate the Safety and Tolerability of Treprostinil Palmitil Inhalation Powder in Participants with Pulmonary Hypertension Associated with Interstitial Lung Disease

    Summary
    EudraCT number
    		 2021-003294-66
    Trial protocol
    		 ES   DE   BE   IT  
    Global end of trial date
    13 Mar 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2025
    First version publication date
    29 Mar 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    INS1009-211
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05176951
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Insmed Incorporated
    Sponsor organisation address
    700 US Highway 202/206, Bridgewater, United States, 08807-1704
    Public contact
    Insmed Medical Information, Insmed Incorporated, +1 1-844-446-7633, medicalinformation@insmed.com
    Scientific contact
    Insmed Medical Information, Insmed Incorporated, +1 1-844-446-7633, medicalinformation@insmed.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Mar 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this study was to evaluate the safety and tolerability of Treprostinil Palmitil Inhalation Powder (TPIP) compared with placebo in participants with Pulmonary Hypertension with Interstitial Lung Disease.
    Protection of trial subjects
    This study was conducted in compliance with International Council for Harmonisation (ICH) Good Clinical Practice (GCP), including the archiving of essential documents.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Dec 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 4
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    United Kingdom: 3
    Worldwide total number of subjects
    39
    EEA total number of subjects
    30
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    17
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in this multi-centre study at different investigative sites from 22 December 2022 to 14 March 2024.

    Pre-assignment
    Screening details
    		 A total of 39 participants with pulmonary hypertension associated with interstitial lung disease were enrolled in the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treprostinil Palmitil
    Arm description
    		 Participants received TPIP once daily (QD) at a starting dose of 80 micrograms (mcg), followed by dose titration from 80 mcg to maximum tolerated dose up to 640 mcg during the initial 3 weeks of dose-titration period. Additional up-titration was allowed at the Week 5 visit if the participant did not reach the target dose of 640 mcg. The participant's highest dose tolerated was continued for the remainder of the study until Week 16.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treprostinil Palmitil
    Investigational medicinal product code
    Other name
    INS1009
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received inhalation dry powder capsules containing 80 mcg, 160 mcg, 240 mcg, 320 mcg, 400 mcg, 480 mcg or 640 mcg of TPIP, QD.

    Arm title
    		 Placebo
    Arm description
    		 Participants received placebo matching TPIP QD until Week 16.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Inhalation powder
    Routes of administration
    Inhalation use
    Dosage and administration details
    Participants received placebo matching TPIP QD until Week 16.

    Number of subjects in period 1
    		Treprostinil Palmitil Placebo
    Started
    29
    10
    Completed
    24
    8
    Not completed
    5
    2
         Adverse event, serious fatal
    1
    2
         Physician decision
    1
    -
         Adverse event, non-fatal
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treprostinil Palmitil
    Reporting group description
    		 Participants received TPIP once daily (QD) at a starting dose of 80 micrograms (mcg), followed by dose titration from 80 mcg to maximum tolerated dose up to 640 mcg during the initial 3 weeks of dose-titration period. Additional up-titration was allowed at the Week 5 visit if the participant did not reach the target dose of 640 mcg. The participant's highest dose tolerated was continued for the remainder of the study until Week 16.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matching TPIP QD until Week 16.

    Reporting group values
    		 Treprostinil Palmitil Placebo Total
    Number of subjects
    		 29 10
    Age Categorical
    Units: Subjects
    Age continuous
    Units:
        arithmetic mean (standard deviation)
    		 65.7 ( 7.65 ) 63.8 ( 10.55 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 2 11
        Male
    		 20 8 28
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 7 2 9
        Not Hispanic or Latino
    		 19 8 27
        Unknown or Not Reported
    		 3 0 3
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 24 9 33
        More than one race
    		 1 1 2
        Unknown or Not Reported
    		 4 0 4

    End points

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    End points reporting groups
    Reporting group title
    Treprostinil Palmitil
    Reporting group description
    		 Participants received TPIP once daily (QD) at a starting dose of 80 micrograms (mcg), followed by dose titration from 80 mcg to maximum tolerated dose up to 640 mcg during the initial 3 weeks of dose-titration period. Additional up-titration was allowed at the Week 5 visit if the participant did not reach the target dose of 640 mcg. The participant's highest dose tolerated was continued for the remainder of the study until Week 16.

    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matching TPIP QD until Week 16.

    Subject analysis set title
    TPIP 80 mcg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received TPIP 80 mcg QD until week 16.

    Subject analysis set title
    TPIP 400 mcg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received TPIP 400 mcg QD until week 16.

    Subject analysis set title
    TPIP 480 mcg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received TPIP 480 mcg QD until week 16.

    Subject analysis set title
    TPIP 640 mcg
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants received TPIP 640 mcg QD until week 16.

    Primary: Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    		 Number of Participants Who Experienced Treatment Emergent Adverse Events (TEAEs) and Serious TEAEs [1]
    End point description
    An AE is defined as any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. A TEAE is defined as any AE that occurs after the first dose of study drug and within 30 days after the last dose of study drug. TEAEs included both serious and non-serious TEAEs. Safety analysis set included all randomised participants who had received at least 1 dose of study drug in the double-blind treatment period.
    End point type
    Primary
    End point timeframe
    From signing the informed consent form up to Week 20
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Treprostinil Palmitil Placebo
    Number of subjects analysed
    29
    10
    Units: participants
        TEAEs
    27
    9
        Serious TEAEs
    6
    4
    No statistical analyses for this end point

    Primary: Change From Baseline in Supplemental Oxygen Used During the 6-Minute Walk Test (6MWT) at Week 5, Week 10, and Week 16

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    End point title
    		 Change From Baseline in Supplemental Oxygen Used During the 6-Minute Walk Test (6MWT) at Week 5, Week 10, and Week 16 [2]
    End point description
    Safety analysis set included all randomised participants who had received at least 1 dose of study drug in the double-blind treatment period. 'n’ signifies number of participants analysed at the specified timepoint in this endpoint.
    End point type
    Primary
    End point timeframe
    At Baseline, Week 5, Week 10, and Week 16
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Treprostinil Palmitil Placebo
    Number of subjects analysed
    29
    10
    Units: litres per minute (L/min)
    arithmetic mean (standard deviation)
        Baseline (n=29,10)
    3.3 ( 2.17 )
    2.3 ( 2.16 )
        Change at Week 5 (n=25,9)
    0.1 ( 1.19 )
    -0.4 ( 1.01 )
        Change at Week 10 (n=25,8)
    0.5 ( 1.69 )
    0.1 ( 0.83 )
        Change at Week 16 (n=24,8)
    0.0 ( 0.91 )
    0.6 ( 2.20 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Peripheral Capillary Oxygen Saturation Measured by Pulse Oximetry (SpO2) Levels

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    End point title
    		 Change from Baseline in Peripheral Capillary Oxygen Saturation Measured by Pulse Oximetry (SpO2) Levels [3]
    End point description
    Lowest SpO2 was defined as the lowest SpO2 value during or after the 6MWT. Safety analysis set included all randomised participants who had received at least 1 dose of study drug in the double-blind treatment period. 'n’ signifies number of participants analysed at the specified timepoint in this endpoint.
    End point type
    Primary
    End point timeframe
    Pre, during, and post 6-minute walk test (6MWT) at Baseline, Week 5, Week 10, and Week 16
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned for this endpoint.
    End point values
    		 Treprostinil Palmitil Placebo
    Number of subjects analysed
    29
    10
    Units: percentage of oxygen saturation
    arithmetic mean (standard deviation)
        Baseline: Pre-test SpO2 (n=29,10)
    94.6 ( 4.17 )
    96.1 ( 2.51 )
        Baseline: Lowest SpO2 (n=29,10)
    76.7 ( 11.71 )
    80.9 ( 9.96 )
        Change at Week 5: Pre-test SpO2 (n=25,9)
    0.1 ( 4.31 )
    -2.9 ( 7.79 )
        Change at Week 5: Lowest SpO2 (n=25,9)
    -2.7 ( 7.42 )
    -3.6 ( 5.17 )
        Change at Week 10: Pre-test SpO2 (n=25,8)
    0.7 ( 3.84 )
    -2.6 ( 5.60 )
        Change at Week 10: Lowest SpO2 (n=25,8)
    -3.5 ( 8.76 )
    -1.6 ( 6.19 )
        Change at Week 16: Pre-test SpO2 (n=24,8)
    -0.3 ( 5.64 )
    -0.9 ( 3.04 )
        Change at Week 16: Lowest SpO2 (n=22,8)
    -4.6 ( 11.65 )
    -1.3 ( 7.03 )
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of Treprostinil Palmitil (TP)

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Treprostinil Palmitil (TP)
    End point description
    Pharmacokinetic (PK) analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 99999 indicates that coefficient of variation (CV) was not estimable as there was only 1 participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 640 mcg
    Number of subjects analysed
    1
    8
    Units: picogram per millilitre (pg/mL)
        geometric mean (geometric coefficient of variation)
    13.40 ( 99999 )
    20.10 ( 45.9 )
    No statistical analyses for this end point

    Secondary: Cmax of Treprostinil (TRE)

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    End point title
    		 Cmax of Treprostinil (TRE)
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 99999 indicates that CV was not estimable as there was only 1 participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 400 mcg TPIP 480 mcg TPIP 640 mcg
    Number of subjects analysed
    28
    1
    3
    20
    Units: pg/mL
        geometric mean (geometric coefficient of variation)
    107.3 ( 97.4 )
    535.0 ( 99999 )
    1129 ( 56.8 )
    1361 ( 60.2 )
    No statistical analyses for this end point

    Secondary: Time to Reach Cmax (Tmax) of TP

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    End point title
    		 Time to Reach Cmax (Tmax) of TP
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 640 mcg
    Number of subjects analysed
    1
    8
    Units: hours
        median (full range (min-max))
    4.33 (4.33 to 4.33)
    3.06 (1.47 to 6.30)
    No statistical analyses for this end point

    Secondary: Tmax of TRE

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    End point title
    		 Tmax of TRE
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 400 mcg TPIP 480 mcg TPIP 640 mcg
    Number of subjects analysed
    28
    1
    3
    20
    Units: hours
        median (full range (min-max))
    2.00 (0.47 to 6.00)
    2.00 (2.00 to 2.00)
    1.03 (0.50 to 2.00)
    1.46 (0.47 to 6.00)
    No statistical analyses for this end point

    Secondary: Area Under Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUCtau) of TP

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    End point title
    		 Area Under Concentration-time Curve From Time 0 to 24 Hours Post-dose (AUCtau) of TP
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 9999 indicates that geometric mean and CV were not estimable because all samples were below level of quantification (BLQ).
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 8 and 24 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 640 mcg
    Number of subjects analysed
    1
    4
    Units: picograms*hours per millilitre (pg*h/mL)
        geometric mean (geometric coefficient of variation)
    9999 ( 9999 )
    121.8 ( 48.1 )
    No statistical analyses for this end point

    Secondary: AUCtau of TRE

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    End point title
    		 AUCtau of TRE
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 9999 indicates that geometric mean and CV were not estimable because all samples were BLQ. 99999 indicates that CV was not estimable as there was only 1 participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 8 and 24 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 400 mcg TPIP 480 mcg TPIP 640 mcg
    Number of subjects analysed
    28
    1
    3
    17
    Units: pg*h/mL
        geometric mean (geometric coefficient of variation)
    9999 ( 9999 )
    2625 ( 99999 )
    4590 ( 23.6 )
    7111 ( 35.1 )
    No statistical analyses for this end point

    Secondary: Area Under Concentration-time Curve From 0 to Infinity (AUC0-inf) of TP

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    End point title
    		 Area Under Concentration-time Curve From 0 to Infinity (AUC0-inf) of TP
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 9999 indicates that geometric mean and CV were not estimable because all samples were BLQ.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 8 and 24 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 640 mcg
    Number of subjects analysed
    1
    4
    Units: pg*h/mL
        geometric mean (geometric coefficient of variation)
    9999 ( 9999 )
    121.8 ( 48.1 )
    No statistical analyses for this end point

    Secondary: AUC0-inf of TRE

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    End point title
    		 AUC0-inf of TRE
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 9999 indicates that geometric mean and CV were not estimable because all samples were BLQ. 99999 indicates that CV was not estimable as there was only 1 participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, 8 and 24 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 400 mcg TPIP 480 mcg TPIP 640 mcg
    Number of subjects analysed
    28
    1
    3
    17
    Units: pg*h/mL
        geometric mean (geometric coefficient of variation)
    9999 ( 9999 )
    2625 ( 99999 )
    4590 ( 23.6 )
    7111 ( 35.1 )
    No statistical analyses for this end point

    Secondary: Area Under Concentration-time Curve From Time 0 to Last Measurable Concentration (AUClast) of TP

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    End point title
    		 Area Under Concentration-time Curve From Time 0 to Last Measurable Concentration (AUClast) of TP
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 99999 indicates that CV was not estimable as there was only 1 participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and pre-dose and 0.5, 1, 2, 4, 8 and 24 hours post-dose at Week 10
    End point values
    		 TPIP 80 mcg TPIP 640 mcg
    Number of subjects analysed
    1
    8
    Units: pg*h/mL
        geometric mean (geometric coefficient of variation)
    39.44 ( 99999 )
    62.04 ( 70.3 )
    No statistical analyses for this end point

    Secondary: AUClast of TRE

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    End point title
    		 AUClast of TRE
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 99999 indicates that CV was not estimable as there was only 1 participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and pre-dose and 0.5, 1, 2, 4, 8 and 24 hours post-dose at Week 10
    End point values
    		 TPIP 80 mcg TPIP 400 mcg TPIP 480 mcg TPIP 640 mcg
    Number of subjects analysed
    28
    1
    3
    20
    Units: pg*h/mL
        geometric mean (geometric coefficient of variation)
    306.7 ( 77.1 )
    2568 ( 99999 )
    4552 ( 24.1 )
    6356 ( 45.3 )
    No statistical analyses for this end point

    Secondary: Apparent Total Clearance (CL/F) of TP

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    End point title
    		 Apparent Total Clearance (CL/F) of TP
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 9999 indicates that geometric mean and CV were not estimable because all samples were BLQ.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 640 mcg
    Number of subjects analysed
    1
    4
    Units: litres per hour (L/h)
        geometric mean (geometric coefficient of variation)
    9999 ( 9999 )
    5254 ( 48.1 )
    No statistical analyses for this end point

    Secondary: CL/F of TRE

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    End point title
    		 CL/F of TRE
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 9999 indicates that geometric mean and CV were not estimable because all samples were BLQ. 99999 indicates that CV was not estimable as there was only 1 participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 400 mcg TPIP 480 mcg TPIP 640 mcg
    Number of subjects analysed
    28
    1
    3
    17
    Units: L/h
        geometric mean (geometric coefficient of variation)
    9999 ( 9999 )
    152.4 ( 99999 )
    104.6 ( 23.6 )
    90.00 ( 35.1 )
    No statistical analyses for this end point

    Secondary: Elimination Half-life (t1/2) of TP

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    End point title
    		 Elimination Half-life (t1/2) of TP
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. 9999 indicates that geometric mean and CV were not estimable because all samples were BLQ.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 640 mcg
    Number of subjects analysed
    29
    29
    Units: hours
        geometric mean (geometric coefficient of variation)
    9999 ( 9999 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: t1/2 of TRE

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    End point title
    		 t1/2 of TRE
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 9999 indicates that geometric mean and CV were not estimable because all samples were BLQ. 99999 indicates that CV was not estimable as there was only 1 participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4, and 8 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 400 mcg TPIP 480 mcg TPIP 640 mcg
    Number of subjects analysed
    28
    1
    2
    15
    Units: hours
        geometric mean (geometric coefficient of variation)
    9999 ( 9999 )
    11.16 ( 99999 )
    6.991 ( 42.3 )
    6.747 ( 34.0 )
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution After Terminal Phase (Vd/F) of TP

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    End point title
    		 Apparent Volume of Distribution After Terminal Phase (Vd/F) of TP
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. 9999 indicates that geometric mean and CV were not estimable because all samples were BLQ.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 640 mcg
    Number of subjects analysed
    29
    29
    Units: litres
        geometric mean (geometric coefficient of variation)
    9999 ( 9999 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Secondary: Vd/F of TRE

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    End point title
    		 Vd/F of TRE
    End point description
    PK analysis set included all participants who received one dose of TPIP and had at least one post-dose PK concentration datum available. Here 'Number of subjects analysed' is the number of participants with data available for analyses. 9999 indicates that geometric mean and CV were not estimable because all samples were BLQ. 99999 indicates that CV was not estimable as there was only 1 participant.
    End point type
    Secondary
    End point timeframe
    Pre-dose and 0.5, 1, 2, 4 and 8 hours post-dose at Day 1 and Week 10
    End point values
    		 TPIP 80 mcg TPIP 400 mcg TPIP 480 mcg TPIP 640 mcg
    Number of subjects analysed
    28
    1
    2
    15
    Units: litres
        geometric mean (geometric coefficient of variation)
    9999 ( 9999 )
    2454 ( 99999 )
    1034 ( 84.2 )
    850.2 ( 50.8 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing the informed consent form up to Week 20
    Adverse event reporting additional description
    Safety analysis set included all randomised participants who had received at least 1 dose of study drug in the double-blind treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo matching TPIP QD until Week 16.

    Reporting group title
    Treprostinil Palmitil
    Reporting group description
    		 Participants received TPIP once daily QD at a starting dose of 80 mcg, followed by dose titration from 80 mcg to maximum tolerated dose up to 640 mcg during the initial 3 weeks of dose-titration period. Additional up-titration was allowed at the Week 5 visit if the participant did not reach the target dose of 640 mcg. The participant's highest dose tolerated was continued for the remainder of the study until Week 16.

    Serious adverse events
    		 Placebo Treprostinil Palmitil
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 10 (40.00%)
    6 / 29 (20.69%)
         number of deaths (all causes)
    2
    2
         number of deaths resulting from adverse events
    2
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac disorders
    Right ventricular failure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urosepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 29 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Treprostinil Palmitil
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    23 / 29 (79.31%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Hot flush
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Flushing
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 29 (10.34%)
         occurrences all number
    1
    9
    General disorders and administration site conditions
    Oedema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Asthenia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Chest pain
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cyanosis central
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Interstitial lung disease
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Productive cough
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    0
    4
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 29 (13.79%)
         occurrences all number
    2
    5
    Cough
         subjects affected / exposed
    2 / 10 (20.00%)
    15 / 29 (51.72%)
         occurrences all number
    5
    18
    Oropharyngeal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Psychiatric disorders
    Post-traumatic stress disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Liver function test increased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    3
    0
    Injury, poisoning and procedural complications
    Craniofacial fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    2
    0
    Headache
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 29 (10.34%)
         occurrences all number
    0
    3
    Dizziness
         subjects affected / exposed
    0 / 10 (0.00%)
    4 / 29 (13.79%)
         occurrences all number
    0
    6
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    7 / 29 (24.14%)
         occurrences all number
    2
    8
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    5
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Back pain
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 29 (10.34%)
         occurrences all number
    1
    3
    Pain in extremity
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Infections and infestations
    Pneumonia serratia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 29 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1
    COVID-19
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 29 (6.90%)
         occurrences all number
    0
    2
    Respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 29 (6.90%)
         occurrences all number
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 29 (10.34%)
         occurrences all number
    1
    3
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 29 (3.45%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Oct 2021
    The following changes were made as per Amendment 01 - 1. Updated the exclusion criteria. 2. Schedule of activities was updated. 3. Secondary objectives and endpoints were updated.
    22 Jun 2022
    The following changes were made as per Amendment 02 - 1. Updated inclusion and exclusion criteria. 2. Schedule of activities was updated.
    26 Apr 2023
    The following changes were made as per Amendment 03 - 1. Updated inclusion and exclusion criteria. 2. Schedule of activities was updated. 3. Secondary objectives and endpoints were updated.
    15 May 2023
    The following changes were made as per Amendment 04 - 1. Updated inclusion and exclusion criteria. 2. Schedule of activities was updated. 3. Secondary objectives and endpoints were updated.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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