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    Clinical Trial Results:
    A 16 Week, Open Label, Multi-Centre, Study to Evaluate the Safety, Tolerability and Pharmacodynamic Effects of a Rapid Dose Titration Regimen of Subcutaneous Remodulin® Therapy in Subjects with Pulmonary Arterial Hypertension.

    Summary
    EudraCT number
    		 2011-004631-31
    Trial protocol
    		 DE  
    Global end of trial date
    20 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Oct 2016
    First version publication date
    21 Oct 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    REM-PH-416
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02847260
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    United Therapeutics Corporation
    Sponsor organisation address
    55 TW Alexander Drive, Research Triangle Park, United States, NC 27709
    Public contact
    Medical Information, United Therapeutics Corporation, +44 1932573848, druginfo@unither.com
    Scientific contact
    Medical Information, United Therapeutics Corporation, +44 1932573848, druginfo@unither.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
    22 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the safety and tolerability of a rapid dose titration regimen of subcutaneous (SC) Remodulin® therapy in patients with Pulmonary Arterial Hypertension (PAH). Safety and tolerability of the rapid dose titration regimen was considered to be demonstrated by those clinical trial subjects that completed the 16 week treatment period of the study without experiencing any serious adverse events (SAEs) considered by the investigator to be possibly related to Remodulin. The secondary objectives of the study were to assess the effect of SC Remodulin on exercise capacity using the six minute walk test (6MWT), N-terminal pro-brain natriuretic peptide (NT-proBNP), World Health Organisation (WHO) Functional Class, Borg dyspnoea score, quality of life (CAMPHOR), right ventricular function, haemodynamics, Patient Reported Site Pain Questionnaire (PRSPQ), symptoms of PAH and safety.
    Protection of trial subjects
    The objective of this study was to evaluate safety, tolerability and clinical effects of a rapid up-titration dosing regimen of SC treprostinil using pro-active infusion site pain management. > Subjects were hospitalised for a minimum of 72 hours upon initiation of SC Remodulin therapy. > Subjects were fully trained on self-administration of SC Remodulin during hospitalisation. Training included the preparation of Remodulin, the operation and programming of the micro infusion pump, the connection and care of the infusion system, and management of SC infusion site. > Subjects could not be discharged from hospital until fully competent with the infusion set and Remodulin dosing. > Subjects and Medical staff were provided with a site pain management brochure. This brochure was a guide for subjects to use if they experienced any site pain. It detailed techniques to limit site pain and provided information on changing the infusion site, canula and drug reservoir. > Every time a subject changed their infusion site they had to complete a PRSPQ. The PRSPQ was a self assessment and a means to measure the magnitude and longevity of the subject's site pain. The PRSPQ was reviewed at each study visit by trained site personnel with any persistent and untoward events recorded and managed by medics.
    Background therapy
    		 Subjects were either treatment naive or receiving approved therapy for PAH (endothelin receptor antagonist (ERA) and/or phosphodiesterase (PDE)-5 inhibitor) for a minimum duration of 60 days and on a stable dose for at least 30 days prior to screening. All subjects were to remain on the same medication and doses from screening until study completion at the week 16 visit, unless the subject's safety was a concern and events experienced by the subject were deemed causally related to the background therapy (e.g. liver function test abnormality due to Bosentan therapy). Conventional PAH therapies were permitted (e.g., oral vasodilators, digoxin and/or oxygen) provided the dose administered was stable at least 14 days before the start of the screening phase (i.e. date of obtaining written informed consent), with the exception of diuretics and anticoagulants which could be adjusted throughout the study as required. Unless they were considered essential to ensure subject safety, no dose adjustments or new vasodilator therapies were to be added to treatment of pulmonary hypertension during the course of the study. All conventional therapies were to remain constant for all study assessments.
    Evidence for comparator
    		 No comparators were used for this study.
    Actual start date of recruitment
    16 Apr 2012
    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: 39
    Worldwide total number of subjects
    39
    EEA total number of subjects
    39
    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)
    29
    From 65 to 84 years
    10
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Single territory (Germany), 10 centre study. First site initiation April 2012 and first patient recruited on the 16th April 2012. Enrollment ran for two years with the last patient/last visit on the 20th March 2014. 40 patients screened, 39 enrolled and 32 completed the 16 week study. 7 patients withdrew prematurely.

    Pre-assignment
    Screening details
    		 At screening, the following assessments were conducted: 6MWT, NT-proBNP, WHO Functional Class, Borg dyspnoea score, cardiopulmonary haemodynamics (RAP; mPAP; CI; PVR; PVRI; PCWP), TAPSE and TRJV, PAH symptoms and history, safety (vital signs, physical exam, local lab samples, medical history, serum pregnancy test, Adverse Events (AE))

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N/A Open Label

    Arms
    Arm title
    		 Overall Trial - Intent to treat
    Arm description
    		 The overall trial arm included all subjects enrolled to the study. As this was an open label study, all enrolled subjects received study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treprostinil
    Investigational medicinal product code
    Other name
    Remodulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Remodulin was administered by continuous SC infusion using an ambulatory micro infusion pump and microbore infusion tubing connected to a cannula. The treatment phase consisted of 16 weeks of SC Remodulin therapy, which was initiated at baseline whilst subjects were hospitalised (minimum of 72 hours) and under medical supervision. The dose of SC Remodulin was optimised prior to the subject’s discharge. Treatment was initiated at approximately 2.0 ng/kg/min with dose increments of 1-2 ng/kg/min applied approximately every 12 hours according to clinical response and tolerability. Following discharge, dose rate increments were permitted at 1-2 ng/kg/min with a minimum of 24 hours between each dose titration. Once a dose rate of 20 ng/kg/min was achieved the dose could be increased by 4 ng/kg/min again with each dose increment separated by at least 24 hours.

    Number of subjects in period 1
    		Overall Trial - Intent to treat
    Started
    39
    Completed
    39
    Period 2
    Period 2 title
    Week 4
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Overall Trial - Intent to treat
    Arm description
    		 The overall trial arm included all subjects enrolled to the study who completed all assessments up to and including Week 4. As this was an open label study, all enrolled subjects received study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treprostinil
    Investigational medicinal product code
    Other name
    Remodulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Treatment was continuous with up titrations made throughout the duration of the study. Dose rate increments were permitted at 1-2 ng/kg/min with a minimum of 24 hours between each dose titration. Once a dose rate of 20 ng/kg/min was achieved the dose could be increased by 4 ng/kg/min again with each dose increment separated by at least 24 hours.

    Number of subjects in period 2
    		Overall Trial - Intent to treat
    Started
    39
    Completed
    39
    Period 3
    Period 3 title
    Week 8
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Overall Trial - Intent to treat
    Arm description
    		 The overall trial arm included all subjects enrolled to the study who completed all assessments up to and including Week 8. As this was an open label study, all enrolled subjects received study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treprostinil
    Investigational medicinal product code
    Other name
    Remodulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Treatment was continuous with up titrations made throughout the duration of the study. Dose rate increments were permitted at 1-2 ng/kg/min with a minimum of 24 hours between each dose titration. Once a dose rate of 20 ng/kg/min was achieved the dose could be increased by 4 ng/kg/min again with each dose increment separated by at least 24 hours.

    Number of subjects in period 3
    		Overall Trial - Intent to treat
    Started
    39
    Completed
    35
    Not completed
    4
         Adverse event, non-fatal
    3
         Clinical deterioration
    1
    Period 4
    Period 4 title
    Week 12
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Overall Trial - Intent to treat
    Arm description
    		 The overall trial arm included all subjects enrolled to the study who completed all assessments up to and including Week 12. As this was an open label study, all enrolled subjects received study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treprostinil
    Investigational medicinal product code
    Other name
    Remodulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Treatment was continuous with up titrations made throughout the duration of the study. Dose rate increments were permitted at 1-2 ng/kg/min with a minimum of 24 hours between each dose titration. Once a dose rate of 20 ng/kg/min was achieved the dose could be increased by 4 ng/kg/min again with each dose increment separated by at least 24 hours.

    Number of subjects in period 4
    		Overall Trial - Intent to treat
    Started
    35
    Completed
    32
    Not completed
    3
         Consent withdrawn by subject
    2
         Implantable Pump
    1
    Period 5
    Period 5 title
    Week 16
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Overall Trial - Intent to treat
    Arm description
    		 The overall trial arm included all subjects enrolled to the study who completed all assessments up to and including Week 16. As this was an open label study, all enrolled subjects received study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Treprostinil
    Investigational medicinal product code
    Other name
    Remodulin
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Treatment was continuous with up titrations made throughout the duration of the study. Dose rate increments were permitted at 1-2 ng/kg/min with a minimum of 24 hours between each dose titration. Once a dose rate of 20 ng/kg/min was achieved the dose could be increased by 4 ng/kg/min again with each dose increment separated by at least 24 hours.

    Number of subjects in period 5
    		Overall Trial - Intent to treat
    Started
    32
    Completed
    32

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 The reporting group included the entire study population. This was all subjects enrolled into the study who received study drug. As this was an open label study, all study subjects enrolled were included in this group.

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 39 39
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 29 29
        85 years and over
    		 10 10
    Gender categorical
    Units: Subjects
        Female
    		 29 29
        Male
    		 10 10
    Race
    Units: Subjects
        Black or African American
    		 1 1
        White
    		 38 38
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0
        Non Hispanic or Latino
    		 39 39

    End points

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    End points reporting groups
    Reporting group title
    Overall Trial - Intent to treat
    Reporting group description
    		 The overall trial arm included all subjects enrolled to the study. As this was an open label study, all enrolled subjects received study drug.
    Reporting group title
    Overall Trial - Intent to treat
    Reporting group description
    		 The overall trial arm included all subjects enrolled to the study who completed all assessments up to and including Week 4. As this was an open label study, all enrolled subjects received study drug.
    Reporting group title
    Overall Trial - Intent to treat
    Reporting group description
    		 The overall trial arm included all subjects enrolled to the study who completed all assessments up to and including Week 8. As this was an open label study, all enrolled subjects received study drug.
    Reporting group title
    Overall Trial - Intent to treat
    Reporting group description
    		 The overall trial arm included all subjects enrolled to the study who completed all assessments up to and including Week 12. As this was an open label study, all enrolled subjects received study drug.
    Reporting group title
    Overall Trial - Intent to treat
    Reporting group description
    		 The overall trial arm included all subjects enrolled to the study who completed all assessments up to and including Week 16. As this was an open label study, all enrolled subjects received study drug.

    Primary: Number of subjects that tolerated the rapid dose titration

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    End point title
    		 Number of subjects that tolerated the rapid dose titration [1]
    End point description
    Patients were deemed to tolerate the dose if they completed the 16 week treatment phase without experiencing a study drug related SAE. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Primary
    End point timeframe
    Measured from initiation of study drug dose at baseline through to the Week 16 visit.
    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 analysis was conducted because the end point was qualitative not quantitative.
    End point values
    		 Overall Trial - Intent to treat Overall Trial - Intent to treat
    Number of subjects analysed
    39
    32
    Units: subjects
    39
    26
    No statistical analyses for this end point

    Secondary: Change in Six Minute Walk Test distance

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    End point title
    		 Change in Six Minute Walk Test distance
    End point description
    Comparison of Six Minute Walk Test distance after 16 weeks of Remodulin therapy. Subjects presented are those that completed the 6MWT at both the Baseline and Week 16 visits only. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Secondary
    End point timeframe
    Collected at Baseline and Week 16 visit.
    End point values
    		 Overall Trial - Intent to treat Overall Trial - Intent to treat
    Number of subjects analysed
    30
    30
    Units: metres
        median (inter-quartile range (Q1-Q3))
    351 (294 to 420)
    419 (309 to 468)
    No statistical analyses for this end point

    Secondary: Change in Borg Dyspnoea Score

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    End point title
    		 Change in Borg Dyspnoea Score
    End point description
    Comparison of Borg Dyspnoea Scores after 16 weeks of Remodulin therapy. Subjects presented are those that completed the Borg Dyspnoea assessment at both the Baseline and Week 16 visits only. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Secondary
    End point timeframe
    Borg Dyspnoea Score was measured at Baseline and Week 16.
    End point values
    		 Overall Trial - Intent to treat Overall Trial - Intent to treat
    Number of subjects analysed
    30
    30
    Units: Score
        median (inter-quartile range (Q1-Q3))
    4.5 (3 to 5)
    3.5 (3 to 5)
    No statistical analyses for this end point

    Secondary: Change in NT-proBNP

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    End point title
    		 Change in NT-proBNP
    End point description
    Comparison of NT-proBNP after 16 weeks of Remodulin therapy. Subjects presented are those that completed the NT-proBNP assessment at both the Baseline and Week 16 visits only. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Secondary
    End point timeframe
    Collected at Baseline and Week 16 visit.
    End point values
    		 Overall Trial - Intent to treat Overall Trial - Intent to treat
    Number of subjects analysed
    32
    32
    Units: pg/mL
        median (inter-quartile range (Q1-Q3))
    998.7 (521.5 to 2537.5)
    701.5 (375.5 to 1377)
    No statistical analyses for this end point

    Secondary: Change in WHO Functional Class

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    End point title
    		 Change in WHO Functional Class
    End point description
    Comparison of WHO Functional Class categorisation after 16 weeks of Remodulin therapy. Data presented is for those subjects that completed the 16 week study. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Secondary
    End point timeframe
    WHO Functional Class data was collected throughout the study and shift data from Baseline to Week 16 generated.
    End point values
    		 Overall Trial - Intent to treat
    Number of subjects analysed
    32
    Units: subjects
        WHO Functional Class II to II
    4
        WHO Functional Class II to III
    1
        WHO Functional Class III to II
    8
        WHO Functional Class III to III
    18
        WHO Functional Class III to IV
    1
    No statistical analyses for this end point

    Secondary: Change in Pulmonary Vascular Resistance Index (PVRI)

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    End point title
    		 Change in Pulmonary Vascular Resistance Index (PVRI)
    End point description
    Comparison of Pulmonary Vascular Resistance Index after 16 weeks of Remodulin therapy. Subjects presented are those that completed the PVRI assessment at both the Baseline and Week 16 visits only. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Secondary
    End point timeframe
    Collected at Baseline and Week 16 visit.
    End point values
    		 Overall Trial - Intent to treat Overall Trial - Intent to treat
    Number of subjects analysed
    29
    29
    Units: mmHg/min/m2/L
        median (inter-quartile range (Q1-Q3))
    20.7 (16.1 to 24.7)
    16.3 (12 to 21.5)
    No statistical analyses for this end point

    Secondary: Change in Systemic Vascular Resistance Index (SVRI)

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    End point title
    		 Change in Systemic Vascular Resistance Index (SVRI)
    End point description
    Comparison of Systemic Vascular Resistance Index after 16 weeks of Remodulin therapy. Subjects presented are those that completed the SVRI assessment at both the Baseline and Week 16 visits only. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Secondary
    End point timeframe
    Collected at Baseline and 16 Week visit.
    End point values
    		 Overall Trial - Intent to treat Overall Trial - Intent to treat
    Number of subjects analysed
    25
    27
    Units: mmHg/min/m2/L
        median (inter-quartile range (Q1-Q3))
    36.1 (30.8 to 42.1)
    29.7 (24.7 to 36.4)
    No statistical analyses for this end point

    Secondary: Change in Cardiac Index (CI)

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    End point title
    		 Change in Cardiac Index (CI)
    End point description
    Comparison of Cardiac Index after 16 weeks of Remodulin therapy. Subjects presented are those that completed the CI assessment at both the Baseline and Week 16 visits only. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Secondary
    End point timeframe
    Collected at Baseline and Week 16 visit.
    End point values
    		 Overall Trial - Intent to treat Overall Trial - Intent to treat
    Number of subjects analysed
    29
    29
    Units: L/min/m2
        median (inter-quartile range (Q1-Q3))
    2.2 (1.9 to 2.5)
    2.6 (2.2 to 2.9)
    No statistical analyses for this end point

    Secondary: Change in Pulmonary Artery Pressure (PAPm)

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    End point title
    		 Change in Pulmonary Artery Pressure (PAPm)
    End point description
    Comparison of Pulmonary Artery Pressure after 16 weeks of Remodulin therapy. Subjects presented are those that completed the PAPm assessment at both the Baseline and Week 16 visits only. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Secondary
    End point timeframe
    Collected at Baseline and Week 16 visit.
    End point values
    		 Overall Trial - Intent to treat Overall Trial - Intent to treat
    Number of subjects analysed
    29
    29
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    52 (47 to 62)
    49 (44 to 60)
    No statistical analyses for this end point

    Secondary: Change in Tricuspid Annular Plane Systolic Excursion (TAPSE)

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    End point title
    		 Change in Tricuspid Annular Plane Systolic Excursion (TAPSE)
    End point description
    Comparison of TAPSE after 16 weeks of Remodulin therapy. Subjects presented are those that completed the TAPSE assessment at both the Baseline and Week 16 visits only. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Secondary
    End point timeframe
    Collected at Baseline and Week 16
    End point values
    		 Overall Trial - Intent to treat Overall Trial - Intent to treat
    Number of subjects analysed
    31
    31
    Units: cm
        median (inter-quartile range (Q1-Q3))
    1.6 (1.3 to 1.8)
    1.8 (1.6 to 2)
    No statistical analyses for this end point

    Secondary: Change in Tricuspid Regurgitant Jet Velocity (TRJV)

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    End point title
    		 Change in Tricuspid Regurgitant Jet Velocity (TRJV)
    End point description
    Comparison of TRJV after 16 weeks of Remodulin therapy. Subjects presented are those that completed the TRJV assessment at both the Baseline and Week 16 visits only. No statistical analyses were performed, data were descriptively summarised.
    End point type
    Secondary
    End point timeframe
    Collected at Baseline and Week 16 visit.
    End point values
    		 Overall Trial - Intent to treat Overall Trial - Intent to treat
    Number of subjects analysed
    27
    27
    Units: m/sec
        median (inter-quartile range (Q1-Q3))
    4.33 (3.94 to 4.74)
    3.9 (3.4 to 4.53)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All serious adverse events (SAEs) were reported to the Sponsors Global Drug Safety department with a 24 hour reporting timeline & were coded according to MedDRA V.17.0. All SAEs were followed until resolution, death, or the subject was lost to follow up.
    Adverse event reporting additional description
    Disease related events were assessed at Baseline and throughout the treatment phase by means of a brief physical examination and vital signs assessment (weight, blood pressure, heart rate and respiratory rate) with the subjects PAH symptoms (fatigue, dyspnoea, oedema, dizziness, syncope, chest pain, orthopnoea) rated as mild, moderate or severe.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Overall Trial - Intent to treat
    Reporting group description
    		 The overall trial - Intent to treat group included all subjects enrolled to the study. As this was an open label study, all enrolled subjects received study drug and adverse events were reported for these subjects throughout the study.

    Serious adverse events
    		 Overall Trial - Intent to treat
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 39 (28.21%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Rib fracture
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Right ventricular failure
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Infusion site pain
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Renal Impairment
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia, bacterial
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Fluid overload
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall Trial - Intent to treat
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 39 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Flushing
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    General disorders and administration site conditions
    Infusion site pain
         subjects affected / exposed
    36 / 39 (92.31%)
         occurrences all number
    39
    Infusion site erythema
         subjects affected / exposed
    10 / 39 (25.64%)
         occurrences all number
    10
    Oedema peripheral
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Infusion site haemorrhage
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    6
    Fatigue
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Infusion site irritation
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Infusion site swelling
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Local swelling
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Injection site inflammation
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Oedema
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    8 / 39 (20.51%)
         occurrences all number
    8
    Cough
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Epistaxis
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Tachycardia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 39 (69.23%)
         occurrences all number
    28
    Dizziness
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    7
    Presyncope
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    4
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    8 / 39 (20.51%)
         occurrences all number
    8
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    28 / 39 (71.79%)
         occurrences all number
    28
    Nausea
         subjects affected / exposed
    18 / 39 (46.15%)
         occurrences all number
    18
    Vomiting
         subjects affected / exposed
    15 / 39 (38.46%)
         occurrences all number
    16
    Abdominal distension
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Abdominal pain upper
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Abdominal pain
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Pruritus
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Pain in jaw
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    9
    Rheumatic disorder
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    7
    Pain in extremity
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    7
    Myalgia
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Arthralgia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Back pain
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Bone pain
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Groin pain
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    8
    Infusion site infection
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Infusion site abscess
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Hypokalaemia
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Feb 2012
    Amendment 1: The following changes were made in line with Federal Institute for Drugs and Medical Devices (BfArM) request: 1)The trial phase was changed from IV to Phase III (b). 2)Exclusion criterion 8 was revised to include all contraindications listed in the product information for Remodulin. 3)Local blood sampling was added to the screening visit. 4)Section 3.3.2.3 of the protocol, was revised to include “new” events so these could be captured alongside those that were serious, unusual, or there was a reasonable possibility that the event was caused by Remodulin therapy. 5)Further findings from the paper Skoro-Sajer N et al, Clin Pharmacokinet; 2008; 47 (9) were added to the protocol to provide further information on the risk/benefit rationale of the study. 6)The word “approximately” was added ahead of the starting dose of 2.0 ng/kg/min of study medication due to study drug dose being dependent on the weight of the subject and the flow rate of the infusion pump. The following changes were made in line with Central Ethics Committee request: 1)The protocol was updated to prospectively define the criteria that will be considered to demonstrate safety and tolerability of the rapid dose titration regimen. 2)Descriptive statistics were more specifically defined. 3)The subject coding and identifiers were simplified and outlined. 4)The entry for Patient initials in the “Patient reported site pain questionnaire” was removed.
    11 Oct 2012
    Amendment 2: 1) Exclusion criterion 2 was changed to allow subjects on inhaled prostacyclins into the study, given that the wash out time for this route of administration is minimal. 2) The window for accepting right heart catheterisation (RHC) data obtained prior to screening was increased from 4 weeks to 8 weeks due to the invasive nature of the assessment.

    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.
    The main limitations of the study were the small sample size and the study duration of 16 weeks. The study was an investigation of the titration phase thus there was no long-term follow up conducted.
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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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