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    Clinical Trial Results:
    Intravenous Remodulin (Treprostinil) as Add-on Therapy for the Treatment of Persistent Pulmonary Hypertension of the Newborn: A Randomized, Placebo-Controlled, Safety and Efficacy Study

    Summary
    EudraCT number
    		 2023-001028-40
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    17 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Feb 2024
    First version publication date
    17 Feb 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RIV-PN-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02261883
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    United Therapeutics Corp.
    Sponsor organisation address
    55 TW Alexander Drive, North Carolina, United States, 14186
    Public contact
    Clinical Trials Information, United Therapeutics Corp, +1 9014258167,
    Scientific contact
    Clinical Trials Information, United Therapeutics Corp, +1 9014258167,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000207-PIP01-08
    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
    25 Sep 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 May 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    17 May 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To explore the safety and treatment effect of intravenous (IV) Remodulin as add on therapy in neonates with PPHN compared to placebo. Efficacy will be assessed by a composite endpoint of clinical worsening through Day 14 as defined by one of the following: - Death - Initiation of extracorporeal mechanical oxygenation (ECMO) per institutional policies - Need for additional treatment (initiation of an additional targeted pulmonary vasodilator therapy [e.g., phosphodiesterase-5 inhibitor [PDE-5i], endothelin receptor antagonist [ERA], prostanoid, L-citrulline]).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and the ICH E6 GCP guidance. The parent(s) or legal guardian(s) of each subject enrolled in the study were provided with information related to the clinical study, including specifics related to subject participation. This was documented in a written ICF that was approved by the same IRB/IEC responsible for approval of the protocol at the clinical study site. Each ICF included the elements required by the FDA regulations in 21 CFR Part 50. Informed consent was obtained from each subject’s parent(s) or legal guardian(s) prior to initiating any study-specific procedures in accordance with Title 21 CFR, Part 50 and ICH GCP guidance. A copy of the signed ICF was given to the subject’s parent(s) or legal guardian(s), and the original was retained in the study site’s records. Subjects could have voluntarily withdrawn or been withdrawn from the study and/or study drug by the Investigator at any time for reasons including, but not limited to, the following: • The subject’s parent or legal guardian wished to withdraw the subject from further participation. • A serious or life-threatening adverse event (AE) occurred, or the Investigator considered it necessary to discontinue study drug to protect the safety of the subject. • The subject did not initiate study drug.
    Background therapy
    		 None.
    Evidence for comparator
    		 Placebo was the comparator in the Treatment period.
    Actual start date of recruitment
    29 Jul 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 42
    Worldwide total number of subjects
    42
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    42
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted at 23 centers in the US. 59 subjects were screened and 42 were enrolled in the study. 41 received study treatment: 20 subjects in the Remodulin group and 21 subjects in the placebo group. One subject assigned to Remodulin required ECMO prior to study drug administration and was not included in the ITT population.

    Pre-assignment
    Screening details
    		 Eligible subjects had 2 consecutive oxygenation indexes (OIs) of ≥15, separated by at least 30 minutes, after having received inhaled nitric oxide (iNO) for at least 3 hours. All neonates underwent a screening echocardiogram (ECHO) to confirm the presence of pulmonary hypertension (PH).

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    Investigators, research staff, attending clinicians, neonatal intensive care unit staff, parent(s)/guardian(s), and Sponsor were not aware of the treatment allocation. Once prepared, the appearance of active and placebo doses was identical. The site personnel were not unblinded to the treatment assignment of subjects unless required for safety reasons.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Remodulin
    Arm description
    		 Subjects received Remodulin as a continuous intravenous (IV) infusion. Venous access (preferred via central line [eg, umbilical venous catheter or peripherally inserted central venous catheter]) was required for the IV administration of study drug. Administration as a continuous subcutaneous (SC) infusion could be used in subjects when a dedicated central venous access could not be established, when subjects were too unstable to attempt to establish a dedicated central venous access line for IV administration of study drug, or for subjects initiated on an IV infusion of study drug who lost venous access.
    Arm type
    		 Experimental

    Investigational medicinal product name
    treprostinil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Remodulin was supplied as 20-mL clear glass multi-dose vials sealed with a rubber-coated stopper and fitted with a cap containing 20 mg (1 mg/mL) of treprostinil as sterile solutions in water for injection. Composition: 1 mg/mL treprostinil. Each mL also contains 5.3 mg sodium chloride, 3 mg metacresol, 6.3 mg sodium citrate, and water for injection. Sodium hydroxide and hydrochloric acid may be added to adjust pH between 6.0 and 7.2. Remodulin was delivered via continuous IV or SC infusion. Study drug was diluted to the appropriate concentration based upon the subject weight, dose, fluid constraints in this neonate patient population, and infusion pump flow rate capabilities. Study drug was diluted with 0.9% sodium chloride injection, sterile water for injection, or high-pH glycine diluent (sterile diluent for Flolan or sterile diluent for epoprostenol sodium) prior to IV administration as a continuous infusion using an infusion pump designed for IV drug delivery.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo as a continuous intravenous (IV) infusion. Venous access (preferred via central line [eg, umbilical venous catheter or peripherally inserted central venous catheter]) was required for the IV administration of study drug. Administration as a continuous subcutaneous (SC) infusion could be used in subjects when a dedicated central venous access could not be established, when subjects were too unstable to attempt to establish a dedicated central venous access line for IV administration of study drug, or for subjects initiated on an IV infusion of study drug who lost venous access.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo was supplied as 20-mL clear glass multi-dose vials sealed with a rubber-coated stopper and fitted with a cap containing 20 mg (1 mg/mL) of placebo as sterile solutions in water for injection. Composition: sodium citrate USP/EP/JP, sodium chloride USP/EP/JP, sodium hydroxide pellets, metacresol, and citric acid (anhydrous). The pH was adjusted, if needed, with 1M citric acid and 1N sodium hydroxide. Placebo was delivered via continuous IV or SC infusion. Study drug was diluted to the appropriate concentration based upon the subject weight, dose, fluid constraints (ie, flow rate/total daily volume) in this neonate patient population, and infusion pump flow rate capabilities. Study drug was diluted with 0.9% sodium chloride injection, sterile water for injection, or high-pH glycine diluent (sterile diluent for Flolan or sterile diluent for epoprostenol sodium) prior to IV administration as a continuous infusion using an infusion pump designed for IV drug delivery.

    Number of subjects in period 1 [1]
    		Remodulin Placebo
    Started
    20
    21
    Completed
    15
    18
    Not completed
    5
    3
         Physician decision
    1
    -
         Consent withdrawn by subject
    -
    1
         Death
    3
    2
         Visit completed out of window
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Subject 387001 was assigned to the Remodulin group but required ECMO prior to study drug administration. This subject was not included in the ITT Population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Remodulin
    Reporting group description
    		 Subjects received Remodulin as a continuous intravenous (IV) infusion. Venous access (preferred via central line [eg, umbilical venous catheter or peripherally inserted central venous catheter]) was required for the IV administration of study drug. Administration as a continuous subcutaneous (SC) infusion could be used in subjects when a dedicated central venous access could not be established, when subjects were too unstable to attempt to establish a dedicated central venous access line for IV administration of study drug, or for subjects initiated on an IV infusion of study drug who lost venous access.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo as a continuous intravenous (IV) infusion. Venous access (preferred via central line [eg, umbilical venous catheter or peripherally inserted central venous catheter]) was required for the IV administration of study drug. Administration as a continuous subcutaneous (SC) infusion could be used in subjects when a dedicated central venous access could not be established, when subjects were too unstable to attempt to establish a dedicated central venous access line for IV administration of study drug, or for subjects initiated on an IV infusion of study drug who lost venous access.

    Reporting group values
    		 Remodulin Placebo Total
    Number of subjects
    		 20 21 41
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 20 21 41
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: days
        median (full range (min-max))
    		 2.0 (1 to 6) 3.0 (1 to 6) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10 20
        Male
    		 10 11 21
    Baseline OI
    Units: unit(s)
        median (full range (min-max))
    		 25.5 (4 to 46) 22.0 (6 to 46) -
    Baseline FiO2
    Units: percent
        median (full range (min-max))
    		 100.0 (75 to 100) 100.0 (35 to 100) -
    Baseline PaO2 (mmHG)
    Units: millimetre(s)
        median (full range (min-max))
    		 51.0 (33 to 153) 57.0 (32 to 286) -
    Baseline PaO2/FiO2
    Units: unit(s)
        median (full range (min-max))
    		 0.57 (0.4 to 1.6) 0.69 (0.4 to 2.9) -
    Inhaled nitric oxide
    Units: part per million
        median (full range (min-max))
    		 20.0 (20 to 20) 20.0 (20 to 20) -
    Baseline NT-proBNP
    Units: unit(s)
        median (full range (min-max))
    		 11194.0 (792 to 31366) 16646.0 (1011 to 70000) -

    End points

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    End points reporting groups
    Reporting group title
    Remodulin
    Reporting group description
    		 Subjects received Remodulin as a continuous intravenous (IV) infusion. Venous access (preferred via central line [eg, umbilical venous catheter or peripherally inserted central venous catheter]) was required for the IV administration of study drug. Administration as a continuous subcutaneous (SC) infusion could be used in subjects when a dedicated central venous access could not be established, when subjects were too unstable to attempt to establish a dedicated central venous access line for IV administration of study drug, or for subjects initiated on an IV infusion of study drug who lost venous access.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo as a continuous intravenous (IV) infusion. Venous access (preferred via central line [eg, umbilical venous catheter or peripherally inserted central venous catheter]) was required for the IV administration of study drug. Administration as a continuous subcutaneous (SC) infusion could be used in subjects when a dedicated central venous access could not be established, when subjects were too unstable to attempt to establish a dedicated central venous access line for IV administration of study drug, or for subjects initiated on an IV infusion of study drug who lost venous access.

    Primary: Clinical Worsening from Baseline to Day 14

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    End point title
    		 Clinical Worsening from Baseline to Day 14
    End point description
    Due to the early termination of the study, interpretation of the efficacy endpoints was limited as the number of subjects analyzed was not sufficient to provide meaningful statistical analysis.
    End point type
    Primary
    End point timeframe
    The primary endpoint in this study was if Remodulin reduced the incidence of clinical worsening in subjects with PPHN from Baseline to Day 14 compared to placebo.
    End point values
    		 Remodulin Placebo
    Number of subjects analysed
    20
    21
    Units: Number
        Clinical worsening: Yes
    8
    12
        Clinical worsening: No
    12
    9
    Statistical analysis title
    		 Chi-square test
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2723 [1]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - Not statistically significant.

    Secondary: Change in Oxygenation Index (OI)

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    End point title
    		 Change in Oxygenation Index (OI)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in OI from Baseline to Hours 12, 24, and 72; Days 7 and 14; and/or prior to study drug discontinuation/weaning.
    End point values
    		 Remodulin Placebo
    Number of subjects analysed
    20 [2]
    21 [3]
    Units: unit(s)
    median (full range (min-max))
        12 hours
    -2.0 (-41 to 37)
    -3.5 (-29 to 34)
        24 hours
    -8.5 (-40 to 23)
    -5.5 (-30 to 58)
        72 hours
    -7.0 (-40 to 65)
    -10.0 (-41 to 83)
        Day 7
    -9.5 (-40 to 36)
    -11.0 (-43 to 42)
        Day 14
    -12.0 (-40 to 36)
    -14.0 (-35 to 42)
    Notes
    [2] - Corresponds to the ITT population.
    [3] - Corresponds to the ITT population. 12 hours: N=20 24 hours: N=20 72 hours: N=20 Day 7/14: N=21
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to 12 hours
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.9235 [4]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [4] - Not statistically significant
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to 24 hours
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5977 [5]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [5] - Not statistically significant.
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to 72 hours
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7643 [6]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [6] - Not statistically significant.
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to day 7
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7458 [7]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [7] - Not statistically significant.
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to day 14
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7795 [8]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [8] - Not statistically significant.

    Secondary: Change in PaO2/FiO2

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    End point title
    		 Change in PaO2/FiO2
    End point description
    End point type
    Secondary
    End point timeframe
    Change in PaO2/fraction of inspired oxygen (FiO2) (P/F ratio) from Baseline to Hours 12, 24, and 72.
    End point values
    		 Remodulin Placebo
    Number of subjects analysed
    20 [9]
    21 [10]
    Units: unit(s)
    median (full range (min-max))
        12 hours
    0.11 (-0.5 to 10.5)
    0.10 (-2.3 to 4.1)
        24 hours
    0.35 (-0.4 to 9.3)
    0.27 (-2.3 to 7.1)
        72 hours
    0.50 (-0.4 to 4.8)
    0.65 (-2.3 to 7.5)
    Notes
    [9] - Corresponds to the ITT population.
    [10] - Corresponds to the ITT population.
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to 12 hours
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1992 [11]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [11] - Not statistically significant
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to 24 hours
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.282 [12]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [12] - Not statistically significant
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to 72 hours
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.6955 [13]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [13] - Not statistically significant

    Secondary: Change in pre- and post-ductal SpO2

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    End point title
    		 Change in pre- and post-ductal SpO2
    End point description
    End point type
    Secondary
    End point timeframe
    Change in pre- and post-ductal oxygen saturation of peripheral capillary oxygenation (SpO2) from Baseline to Hours 6, 12, 24, and 72.
    End point values
    		 Remodulin Placebo
    Number of subjects analysed
    20 [14]
    21 [15]
    Units: unit(s)
    median (full range (min-max))
        6 hours
    3.0 (-6 to 13)
    1.0 (-10 to 7)
        12 hours
    3.0 (-7 to 17)
    0.5 (-7 to 12)
        24 hours
    3.0 (-12 to 15)
    1.0 (-17 to 11)
        72 hours
    0.0 (-4 to 16)
    1.5 (-21 to 8)
    Notes
    [14] - Corresponds to the ITT population. 6 hours: N=17 12 hours: N=17 24 hours: N=18 72 hours: N=18
    [15] - Corresponds to the ITT population. 6 hours: N=20 12 hours: N=20 24 hours: N=20 72 hours: N=20
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to 6 hours
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0247 [16]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [16] - Statistically significant
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to 12 hours
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0914 [17]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [17] - Not statistically significant
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to 24 hours
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1886 [18]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [18] - Not statistically significant
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to 72 hours
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1825 [19]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [19] - Not statistically significant

    Secondary: Change in NT-proBNP

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    End point title
    		 Change in NT-proBNP
    End point description
    End point type
    Secondary
    End point timeframe
    Change in N-terminal pro-brain natriuretic peptide (NT-proBNP) at day 1, day 2, day 3, day 7 and day 14.
    End point values
    		 Remodulin Placebo
    Number of subjects analysed
    20 [20]
    21 [21]
    Units: unit(s)
    median (full range (min-max))
        Day 1
    -1577.00 (-21322.0 to 43388.0)
    -1378.00 (-23203.0 to 17923.0)
        Day 2
    -1955.00 (-24637.0 to 34599.0)
    -4090.00 (-37390.0 to 14163.0)
        Day 3
    -252.00 (-24623.0 to 30629.0)
    -4090.00 (-49200.0 to 13550.0)
        Day 7
    484.00 (-24623.0 to 19970.0)
    -11312.00 (-65387.0 to 12299.0)
        Day 14
    -719.00 (-26283.0 to 56529.0)
    -9003.00 (-65387.0 to 12299.0)
    Notes
    [20] - Corresponds to the ITT population. Day 1: N=13 Day 2: N=15 Day 3: N=15 Day 7: N=15 Day 14: N=15
    [21] - Corresponds to the ITT population. Day 1: N=19 Day 2: N=21 Day 3: N=21 Day 7: N=21 Day 14: N=21
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to day 1
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3133 [22]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [22] - Not statistically significant
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to day 2
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.1244 [23]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [23] - Not statistically significant
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to day 3
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0378 [24]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [24] - Statistically significant
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to day 7
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0219 [25]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [25] - Statistically significant
    Statistical analysis title
    		 Group t-test comparing change from baseline values
    Statistical analysis description
    Change from baseline to day 14
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0483 [26]
    Method
    		 T-test comparing change from baseline
    Confidence interval
    Notes
    [26] - Statistically significant

    Secondary: Time to Clinical Worsening

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    End point title
    		 Time to Clinical Worsening
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to clinical worsening
    End point values
    		 Remodulin Placebo
    Number of subjects analysed
    8 [27]
    12 [28]
    Units: day
        median (full range (min-max))
    3.0 (1 to 8)
    3.0 (1 to 13)
    Notes
    [27] - Corresponds to the ITT population.
    [28] - Corresponds to the ITT population.
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3327 [29]
    Method
    		 Logrank
    Confidence interval
    Notes
    [29] - Not statistically significant

    Secondary: Time to initiation of ECMO

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    End point title
    		 Time to initiation of ECMO
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to ECMO initiation
    End point values
    		 Remodulin Placebo
    Number of subjects analysed
    6 [30]
    7 [31]
    Units: day
        median (full range (min-max))
    2.5 (1 to 8)
    3.0 (1 to 5)
    Notes
    [30] - Corresponds to the ITT population.
    [31] - Corresponds to the ITT population.
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    13
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.8894 [32]
    Method
    		 Logrank
    Confidence interval
    Notes
    [32] - Not statistically significant

    Secondary: Time to Discontinuation of iNO

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    End point title
    		 Time to Discontinuation of iNO
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to discontinuation of iNO
    End point values
    		 Remodulin Placebo
    Number of subjects analysed
    12 [33]
    15 [34]
    Units: day
        median (full range (min-max))
    7.5 (1 to 12)
    7.0 (1 to 11)
    Notes
    [33] - Corresponds to the ITT population.
    [34] - Corresponds to the ITT population.
    Statistical analysis title
    		 Log-rank test
    Comparison groups
    Remodulin v Placebo
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.4791
    Method
    		 Logrank
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Subjects with ongoing AEs at the time of hospital discharge were followed for their AEs until resolution. All SAEs were followed until resolution, death, or the subject was lost to followup, even if they were ongoing more than 4 weeks after last dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Remodulin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Remodulin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 20 (40.00%)
    3 / 21 (14.29%)
         number of deaths (all causes)
    3
    2
         number of deaths resulting from adverse events
    Congenital, familial and genetic disorders
    Congenital diaphragmatic hernia
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pyloric stenosis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Laryngeal stenosis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (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 / 20 (5.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Liver disorder
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (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
    Sepsis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Lactic acidosis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Remodulin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 20 (95.00%)
    17 / 21 (80.95%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 20 (15.00%)
    0 / 21 (0.00%)
         occurrences all number
    3
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    1
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Vascular disorders
    Hypotension
         subjects affected / exposed
    8 / 20 (40.00%)
    4 / 21 (19.05%)
         occurrences all number
    8
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 20 (25.00%)
    5 / 21 (23.81%)
         occurrences all number
    5
    5
    Thrombocytopenia
         subjects affected / exposed
    4 / 20 (20.00%)
    1 / 21 (4.76%)
         occurrences all number
    4
    1
    Gastrointestinal disorders
    Oedema
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Aug 2014
    The main changes implemented with this amendment were: • Revised study design from an uncontrolled, open-label, single arm design to a controlled, blinded, comparator study. • Clarified the maximum amount of time a subject randomized to study drug would be enrolled in the study was 56 days. • Increased number of centers from up to 20 to up to 30. • Revised secondary objectives to identify time points for comparison between treatment arms. • Added change in P/F ratio, change in pre- and post-ductal SpO2, and change in NT proBNP as secondary objectives. • Identified procedures for randomization and unblinding. • Revised safety sections to include definitions for unexpected AE, suspected adverse reaction, and disease-related AEs. • Updated the window for continued safety follow-up of subjects in the study to reflect the change in study duration.
    30 Oct 2015
    The main changes implemented with this amendment were: • Increased number of centers to approximately 40. • Updated study duration description to include time of study withdrawal as an end of study participation. • Clarified end of study participation for a subject continuing on commercial Remodulin beyond Day 28. • Clarified sample size of approximately 70 subjects to be randomized. • Increased allowed number of subjects with congenital diaphragmatic hernia. • Added Chi-square test to test for treatment differences. Added efficacy analyses in the ITT Population. Revised analysis plan to include Group t-test analysis of secondary endpoints, Kaplan Meier estimate for time to event variables, and log-rank tests of treatment differences. • Added a second pre-planned DSMB review. • Updated administration description to allow continuous SC infusion. Added dosing guidelines for initiation of study drug as a SC infusion. • Clarified text regarding dilution of study drug and added information regarding acceptable diluents. • Added language regarding management of subjects on active study drug who needed to continue therapy beyond Day 28. • Revised text to clarify blinding in the study. • Added clarification that subjects should not be automatically unblinded upon initiation of ECMO, unless required for purposes of medically managing the subject. • Clarified timing of Day 7 and Day 14 assessments. • Allowed use of a recently performed historic ECHO. • Added that study drug should be initiated as soon as possible after randomization. • Clarified timing of assessments in a subject who would be continuing on commercial Remodulin and not weaning prior to Day 28. • Clarified when End of Study assessments should be performed. • Added that if withdrawal from study drug was warranted, then the dose of study drug was to be weaned until discontinued. • Clarified timing of FiO2, NT-proBNP, and vital sign assessments. • Clarified AE reporting requirements.
    15 Apr 2016
    The main changes implemented with this amendment were: • Updated to identify the overall End of Study event. • Clarified access to treatment assignment. • Clarified that some Screening and Baseline assessments could be combined if conducted within 3 hours of randomization. • Added caution statements regarding use of Remodulin with CYP450 2C8 inhibitors/inducers, and other blood pressure lowering agents and anticoagulants. • Clarified that symptoms of the underlying disease under study were recorded in the eCRF and identified as disease-related events.

    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.
    Due to the early termination of the study, interpretation of the efficacy endpoints was limited as the number of subjects analyzed was not sufficient to provide meaningful statistical analysis.
    For support, Contact us.
    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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