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    Clinical Trial Results:
    A multicenter, open-label, single-sequence, cross-over study to assess safety, tolerability, and pharmacokinetics of intravenous selexipag in subjects with stable pulmonary arterial hypertension switching from an oral stable dose of selexipag

    Summary
    EudraCT number
    		 2016-004035-21
    Trial protocol
    		 DE  
    Global end of trial date
    29 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 May 2019
    First version publication date
    03 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-065A309
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03187678
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Clinical trial disclosure deck, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@its.jnj.com
    Scientific contact
    Clinical trial disclosure deck, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@its.jnj.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
    02 Jul 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    29 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess whether it was safe for patients with PAH to temporarily change from selexipag tablets (Uptravi®) to selexipag given intravenously, and then switching back to the initial oral dose of selexipag.
    Protection of trial subjects
    The study was designed and conducted in compliance with International Good clinical Practice (ICH-GCP) Guidelines, the ethical principles of the Declaration of Helsinki and with the laws and regulations of the countries in which the study was conducted.
    Background therapy
    		 PAH-specific therapies (i.e., ERA, PDE-5 inhibitor, or sGC stimulator) were allowed if subjects were on a stable dose. Uptravi was a mandatory background therapy for participation in this study. Uptravi was to be prescribed as part of the subjects standard therapy and had to be temporarily interrupted during intravenous (iv) selexipag administration.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Dec 2017
    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
    Germany: 13
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    20
    EEA total number of subjects
    13
    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)
    15
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Twenty-two patients treated with Uptravi for pulmonary arterial hypertension (PAH) were screened. Twenty of them were enrolled in the study.

    Period 1
    Period 1 title
    Period 1 (oral selexipag)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Selexipag
    Arm description
    		 Subjects treated with a stable dose of oral selexipag (Uptravi) between 200 and 1600 ug twice daily continued to take Uptravi at their prescribed dose during Period 1 (Day 1), then they were switched to intravenous (iv) selexipag during period 2 (3 doses, Day 2 & Day 3) and back to Uptravi during Period 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oral selexipag (Uptravi®)
    Investigational medicinal product code
    ACT-293987
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Uptravi was used as an auxiliary medicinal product, as part of the PAH standard treatment and according to the local prescribing information.

    Number of subjects in period 1
    		Selexipag
    Started
    20
    Completed
    20
    Period 2
    Period 2 title
    Period 2 (intravenous selexipag)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Selexipag
    Arm description
    		 Subjects treated with a stable dose of oral selexipag (Uptravi) between 200 and 1600 ug twice daily continued to take Uptravi at their prescribed dose during Period 1 (Day 1), then they were switched to intravenous (iv) selexipag during period 2 (3 doses, Day 2 & Day 3) and back to Uptravi during Period 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Intravenous selexipag
    Investigational medicinal product code
    ACT-293987
    Other name
    Pharmaceutical forms
    Powder for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The intravenous dose was individualized for each subject to correspond to his/her current oral dose of Uptravi® and infused over 87 min.

    Number of subjects in period 2
    		Selexipag
    Started
    20
    Completed
    20
    Period 3
    Period 3 title
    Period 3 (oral selexipag)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Selexipag
    Arm description
    		 Subjects treated with a stable dose of oral selexipag (Uptravi) between 200 and 1600 ug twice daily continued to take Uptravi at their prescribed dose during Period 1 (Day 1), then they were switched to intravenous (iv) selexipag during period 2 (3 doses, Day 2 & Day 3) and back to Uptravi during Period 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oral selexipag (Uptravi®)
    Investigational medicinal product code
    ACT-293987
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Uptravi was used as an auxiliary medicinal product, as part of the PAH standard treatment and according to the local prescribing information.

    Number of subjects in period 3
    		Selexipag
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    		 Subjects treated with a stable dose of oral selexipag (Uptravi) between 200 and 1600 ug twice daily continued to take Uptravi at their prescribed dose during Period 1 (Day 1), then they were switched to intravenous (iv) selexipag during period 2 (3 doses, Day 2 & Day 3) and back to Uptravi during Period 3.

    Reporting group values
    		 Selexipag Total
    Number of subjects
    		 20 20
    Title for AgeCategorical
    Units: subjects
        Adults (18-64 years)
    		 15 15
        From 65 to 84 years
    		 5 5
        85 years and over
    		 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.5 ± 9.43 -
    Title for Gender
    Units: subjects
        Female
    		 16 16
        Male
    		 4 4
    Race
    Units: Subjects
        Asian
    		 1 1
        Black or African American
    		 0 0
        American Indian or Alaska Native
    		 0 0
        Native Hawaiian or other Pacific Islander
    		 0 0
        White
    		 19 19
        Other
    		 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0
        Non Hispanic or Latino
    		 20 20
    World Health Organization Functional classes (WHO FC)
    Only subjects with WHO FC I, II or III at screening and baseline visits could be enrolled
    Units: Subjects
        FC I
    		 1 1
        FC II
    		 13 13
        FC III
    		 6 6
    PAH-specific therapies at baseline
    The following PAH-specific therapies were allowed on top of Uptravi at baseline: endothelin receptor antagonists (ERA), phosphodiesterase type-5 (PDE-5) inhibitors and soluble guanylate cyclase (sGC) stimulators.
    Units: Subjects
        PDE-5 inhibitors
    		 1 1
        sGC stimulator
    		 1 1
        ERA + sGC stimulator
    		 5 5
        ERA + PDE-5 inhibitor
    		 13 13
    PAH etiology at baseline
    Patients with the following types of pulmonary arterial hypertension (PAH) could be enrolled: idiopathic PAH, heritable PAH, PAH associated with another disease or condition, including connective tissue disease (CTD), congenital heart disease (CHD), HIV infection, portal hypertension, schistosomiasis.
    Units: Subjects
        Idiopathic PAH
    		 13 13
        Heritable PAH
    		 1 1
        Drug or toxin induced PAH
    		 0 0
        Associated with CTD
    		 4 4
        Associated with CHD
    		 1 1
        Associated with HIV
    		 0 0
        Associated with portal hypertension
    		 1 1
        Associated with schistosomiasis
    		 0 0
    Uptravi dose at screening
    Units: Subjects
        200 ug twice daily
    		 0 0
        400 ug twice daily
    		 1 1
        600 ug twice daily
    		 2 2
        800 ug twice daily
    		 2 2
        1000 ug twice daily
    		 3 3
        1200 ug twice daily
    		 2 2
        1400 ug twice daily
    		 1 1
        1600 ug twice daily
    		 9 9

    End points

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    End points reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    		 Subjects treated with a stable dose of oral selexipag (Uptravi) between 200 and 1600 ug twice daily continued to take Uptravi at their prescribed dose during Period 1 (Day 1), then they were switched to intravenous (iv) selexipag during period 2 (3 doses, Day 2 & Day 3) and back to Uptravi during Period 3.
    Reporting group title
    Selexipag
    Reporting group description
    		 Subjects treated with a stable dose of oral selexipag (Uptravi) between 200 and 1600 ug twice daily continued to take Uptravi at their prescribed dose during Period 1 (Day 1), then they were switched to intravenous (iv) selexipag during period 2 (3 doses, Day 2 & Day 3) and back to Uptravi during Period 3.
    Reporting group title
    Selexipag
    Reporting group description
    		 Subjects treated with a stable dose of oral selexipag (Uptravi) between 200 and 1600 ug twice daily continued to take Uptravi at their prescribed dose during Period 1 (Day 1), then they were switched to intravenous (iv) selexipag during period 2 (3 doses, Day 2 & Day 3) and back to Uptravi during Period 3.

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled subjects who received at least one dose of Uptravi or intravenous selexipag during any of the study periods

    Subject analysis set title
    iv safety analysis set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All enrolled subjects who received at least one dose of intravenous selexipag during period 2

    Primary: Number of participants with at least one adverse event (AE)

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    End point title
    		 Number of participants with at least one adverse event (AE) [1]
    End point description
    AE is any untoward medical event that occurs in a participant during the course of the study whether or not considered by the investigator as related to the study treatment.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 37
    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: No formal statistic analyses were performed on these safety data
    End point values
    		 Safety analysis set
    Number of subjects analysed
    20
    Units: Subjects
    15
    No statistical analyses for this end point

    Primary: Number of participants with prostacyclin-associated adverse events

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    End point title
    		 Number of participants with prostacyclin-associated adverse events [2]
    End point description
    Prostacyclin-associated AE include headache, diarrhea, nausea, vomiting, jaw pain, myalgia, pain in the extremity, flushing and arthralgia.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 37
    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: No formal statistic analyses were performed on these safety data.
    End point values
    		 Safety analysis set
    Number of subjects analysed
    20
    Units: Subjects
    7
    No statistical analyses for this end point

    Primary: Number of participants with adverse event related to injection site reactions

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    End point title
    		 Number of participants with adverse event related to injection site reactions [3]
    End point description
    This is the number of participants with at least one clinically significant reaction at the injection site (e.g., erythema/redness, tenderness, swelling, induration, hemorrhage at the injection site) occurring on the days of intravenous (iv) selexipag injection.
    End point type
    Primary
    End point timeframe
    Day 2 and Day 3
    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: No formal statistic analyses were performed on these safety data.
    End point values
    		 iv safety analysis set
    Number of subjects analysed
    20
    Units: Subjects
    2
    No statistical analyses for this end point

    Primary: Number of participants with prostacyclin-associated AEs leading to study treatment discontinuation

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    End point title
    		 Number of participants with prostacyclin-associated AEs leading to study treatment discontinuation [4]
    End point description
    This is the number of subjects who discontinued the i.v. selexipag treatment due to prostacyclin-associated adverse events (headache, diarrhea, nausea, vomiting, jaw pain, myalgia, pain in the extremity, flushing and arthralgia).
    End point type
    Primary
    End point timeframe
    Day 2 and Day 3
    Notes
    [4] - 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: No formal statistic analyses were performed on these safety data.
    End point values
    		 iv safety analysis set
    Number of subjects analysed
    20
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Number of participants with PAH-related adverse events

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    End point title
    		 Number of participants with PAH-related adverse events [5]
    End point description
    This is the number of participants with at least one AE considered to be related to pulmonary arterial hypertension during the course of the study.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 37
    Notes
    [5] - 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: No formal statistic analyses were performed on these safety data.
    End point values
    		 Safety analysis set
    Number of subjects analysed
    20
    Units: Subjects
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 2 to Day 37
    Adverse event reporting additional description
    Treatment-emergent AEs are reported, i.e. serious and non-serious AEs starting on or after the first iv infusion of selexipag, which is the investigational treatment.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Safety analysis set
    Reporting group description
    		 All enrolled subjects who received at least one dose of Uptravi or intravenous selexipag during any of the study periods

    Serious adverse events
    		 Safety analysis set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 20 (10.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Right Ventricular Failure
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Rhegmatogenous Retinal Detachment
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blindness Unilateral
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Safety analysis set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 20 (65.00%)
    Injury, poisoning and procedural complications
    Incorrect Drug Administration Rate
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vascular Access Complication
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    9
    Tension Headache
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Infusion Site Erythema
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Infusion Site Swelling
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Oedema Peripheral
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    2
    Flatulence
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nasal Congestion
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pain in Jaw
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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
    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
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