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    Clinical Trial Results:
    A Randomized, Double-blind, Parallel-group, Placebo-controlled Phase 2 Trial of Ralinepag, an Oral IP Receptor Agonist, in Patients with Pulmonary Arterial Hypertension

    Summary
    EudraCT number
    		 2014-000667-40
    Trial protocol
    		 CZ   HU   ES   PL   RO   SK  
    Global end of trial date
    22 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Sep 2024
    First version publication date
    05 Sep 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    APD811-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02279160
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    United Therapeutics Corp.
    Sponsor organisation address
    55 TW Alexander Drive, Durham, United States, 27709
    Public contact
    Global Medical Information, United Therapeutics Corp., +1 9194858350, clinicaltrials@unither.com
    Scientific contact
    Global Medical Information, United Therapeutics Corp., +1 9194858350, clinicaltrials@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
    04 Dec 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effects of ralinepag on hemodynamics and on 6-Minute Walk Distance (6MWD) in subjects with pulmonary arterial hypertension (PAH) after 22 weeks of treatment, including an initial dose titration period of up to 9 weeks.
    Protection of trial subjects
    A Safety Monitoring Committee (SMC) oversaw the safe conduct of the study, and in particular, the SMC monitored dose titration to achieve the optimal dose within the 9-week titration period while maintaining subject safety. Based on review of safety and tolerability information, the SMC was allowed to recommend a higher starting dose, different dose increments and/or time at each dose before escalation (escalation scheme), different dosage strengths, and even a higher final dose level than 0.3 mg twice daily (BID). The roles and responsibilities of the SMC were outlined in a separate charter. The SMC included at least 2 physicians, representing expertise in clinical care of subjects with PAH and expertise in drug development, and a biostatistician.
    Background therapy
    		 Subjects enrolled in the study were on stable oral disease-specific PAH therapy with either an endothelin receptor antagonist (ERA) and/or an agent acting on the nitric oxide (NO) pathway, phosphodiesterase type 5 inhibitor (PDE5-I), or as a soluble guanylate cyclase (sGC) stimulator. Stable was defined as no change in dose within 3 months of the start of screening and for the duration of the study. If the subject’s disease-specific PAH therapy did not include a PDE5-I, the use of a PDE5-I as needed for erectile dysfunction (ED) was permitted as long as the subject had not taken a dose within 48 hours of any baseline or study-related efficacy assessment. In addition, the subject must not have taken more than 8 sildenafil tablets, 6 vardenafil tablets, or 4 tadalafil tablets per month for ED. Subjects could have been on one agent active in the NO pathway, either a PDE5-I or a sGC stimulator at a stable dose (but not both).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Serbia: 11
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Romania: 6
    Country: Number of subjects enrolled
    Spain: 9
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Hungary: 3
    Worldwide total number of subjects
    61
    EEA total number of subjects
    28
    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)
    57
    From 65 to 84 years
    4
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 This study was conducted at 28 study sites in the US, Australia, Poland, Romania, Bulgaria, Serbia, Spain, Hungary, and Czech Republic. Approximately 60 subjects with PAH were planned to be enrolled.

    Pre-assignment
    Screening details
    		 The Screening Visit(s) began no more than 28 days prior to randomization. Each subject must have met all of the inclusion criteria and none of the exclusion criteria to have been eligible for enrollment in the study.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    The Sponsor, subjects, and personnel involved with the conduct of the study were blinded to the identity of study drug, with the exception of the independent statistician (Novella Clinical LLC) responsible for generating the randomization code and interacting with the SMC. The appearance of the ralinepag and matching placebo capsules was identical. Although the identity of study drug (ralinepag or placebo) was blinded, the dose level was not.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo tablets
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Study drug (ie, ralinepag or matching placebo) was supplied as 0.01, 0.02, 0.03, 0.04, and 0.10 mg capsules. Study drug was supplied as liquid-filled, size 4, hard-gelatin capsules. The starting dose was 0.01 mg BID. Dosage was then uptitrated, as tolerated, over the course of a 9-week dose-titration period. The dose was potentially escalated to a maximum total daily dose of 0.6 mg (0.3 mg BID). If the initial ralinepag dose of 0.01 mg BID was not tolerated, the dose was decreased to 0.01 mg once daily (QD). At any time point during the titration phase, if subsequent doses were not tolerated, the ralinepag dose was decreased to the previous dose level.

    Arm title
    		 Ralinepag
    Arm description
    		 Ralinepag capsules (oral) 0.01, 0.02, 0.03, 0.04, and 0.10 mg titrated to the individual maximum tolerated dose (maximum dose of 0.6 mg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ralinepag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Study drug (ie, ralinepag or matching placebo) was supplied as 0.01, 0.02, 0.03, 0.04, and 0.10 mg capsules. Study drug was supplied as liquid-filled, size 4, hard-gelatin capsules. The starting dose was 0.01 mg BID. Dosage was then uptitrated, as tolerated, over the course of a 9-week dose-titration period. The dose was potentially escalated to a maximum total daily dose of 0.6 mg (0.3 mg BID). If the initial ralinepag dose of 0.01 mg BID was not tolerated, the dose was decreased to 0.01 mg QD. At any time point during the titration phase, if subsequent doses were not tolerated, the ralinepag dose was decreased to the previous dose level.

    Number of subjects in period 1
    		Placebo Ralinepag
    Started
    21
    40
    Completed
    21
    40
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    The Sponsor, subjects, and personnel involved with the conduct of the study were blinded to the identity of study drug, with the exception of the independent statistician (Novella Clinical LLC) responsible for generating the randomization code and interacting with the SMC. The appearance of the ralinepag and matching placebo capsules was identical. Although the identity of study drug (ralinepag or placebo) was blinded, the dose level was not.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo tablets
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Study drug (ie, ralinepag or matching placebo) was supplied as 0.01, 0.02, 0.03, 0.04, and 0.10 mg capsules. Study drug was supplied as liquid-filled, size 4, hard-gelatin capsules. The starting dose was 0.01 mg BID. Dosage was then uptitrated, as tolerated, over the course of a 9-week dose-titration period. The dose was potentially escalated to a maximum total daily dose of 0.6 mg (0.3 mg BID). If the initial ralinepag dose of 0.01 mg BID was not tolerated, the dose was decreased to 0.01 mg QD. At any time point during the titration phase, if subsequent doses were not tolerated, the ralinepag dose was decreased to the previous dose level.

    Arm title
    		 Ralinepag
    Arm description
    		 Ralinepag capsules (oral) 0.01, 0.02, 0.03, 0.04, and 0.10 mg titrated to the individual maximum tolerated dose (maximum dose of 0.6 mg).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ralinepag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Study drug (ie, ralinepag or matching placebo) was supplied as 0.01, 0.02, 0.03, 0.04, and 0.10 mg capsules. Study drug was supplied as liquid-filled, size 4, hard-gelatin capsules. The starting dose was 0.01 mg BID. Dosage was then uptitrated, as tolerated, over the course of a 9-week dose-titration period. The dose was potentially escalated to a maximum total daily dose of 0.6 mg (0.3 mg BID). If the initial ralinepag dose of 0.01 mg BID was not tolerated, the dose was decreased to 0.01 mg QD. At any time point during the titration phase, if subsequent doses were not tolerated, the ralinepag dose was decreased to the previous dose level.

    Number of subjects in period 2
    		Placebo Ralinepag
    Started
    21
    40
    Completed
    19
    34
    Not completed
    2
    6
         Adverse event, serious fatal
    2
    -
         Physician decision
    -
    1
         Adverse event, non-fatal
    -
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 61 61
    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)
    		 57 57
        From 65-84 years
    		 4 4
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 51.0 (19 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 53 53
        Male
    		 8 8
    Race
    Units: Subjects
        White
    		 57 57
        Black or African American
    		 1 1
        Asian
    		 1 1
        Other
    		 2 2
    PAH Classification
    Units: Subjects
        Idiopathic PAH
    		 32 32
        Heritable PAH
    		 5 5
        Drugs or Toxin Induced
    		 4 4
        Associated PAH
    		 20 20
    PAH Disease Specific Concomitant Medication - ERA
    Units: Subjects
        Yes
    		 42 42
        No
    		 19 19
    PAH Monotherapy or Combination Therapy
    Units: Subjects
        ERA
    		 6 6
        PDE5-I
    		 19 19
        sGC Stimulator
    		 0 0
        ERA + PDE5-I
    		 34 34
        ERA + sGC Stimulator
    		 2 2
    Baseline WHO/NYHA Functional Classification
    Units: Subjects
        Class I
    		 0 0
        Class II
    		 34 34
        Class III
    		 26 26
        Class IV
    		 1 1
    PAH Disease Specific Concomitant Medication - PDE5-I
    Units: Subjects
        Yes
    		 53 53
        No
    		 8 8
    PAH Disease Specific Concomitant Medication - sGC stimulator
    Units: Subjects
        Yes
    		 2 2
        No
    		 59 59
    Weight
    Units: kilogram(s)
        median (full range (min-max))
    		 72.5 (43 to 122) -
    Height
    Units: centimetre
        median (full range (min-max))
    		 161.0 (145 to 182) -
    Body Mass Index
    Units: kilogram(s)/square metre
        median (full range (min-max))
    		 27.13 (18.1 to 43.8) -
    Duration of PAH
    Units: year
        median (full range (min-max))
    		 2.00 (0.3 to 27.0) -
    Baseline Pulmonary Vascular Resistance
    Units: dyn.sec/cm^5
        median (full range (min-max))
    		 575.70 (282.4 to 2119.4) -
    Baseline 6MWT
    Units: metre
        median (full range (min-max))
    		 400.0 (105 to 686) -
    Baseline BNP
    Units: pg/mL
        median (full range (min-max))
    		 58.0 (10 to 1359) -
    Baseline NT-proBNP
    Units: pg/mL
        median (full range (min-max))
    		 343.0 (50 to 8924) -
    Subject analysis sets

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All 61 subjects randomized into the study received at least 1 dose of study drug and were included in the Safety Population as part of this report.

    Subject analysis sets values
    		 Safety Population
    Number of subjects
    61
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    57
        From 65-84 years
    4
        85 years and over
    0
    Age continuous
    Units: years
        median (full range (min-max))
    51.0 (19 to 73)
    Gender categorical
    Units: Subjects
        Female
    53
        Male
    8
    Race
    Units: Subjects
        White
    57
        Black or African American
    1
        Asian
    1
        Other
    2
    PAH Classification
    Units: Subjects
        Idiopathic PAH
    32
        Heritable PAH
    5
        Drugs or Toxin Induced
    4
        Associated PAH
    20
    PAH Disease Specific Concomitant Medication - ERA
    Units: Subjects
        Yes
    42
        No
    19
    PAH Monotherapy or Combination Therapy
    Units: Subjects
        ERA
    6
        PDE5-I
    19
        sGC Stimulator
    0
        ERA + PDE5-I
    34
        ERA + sGC Stimulator
    2
    Baseline WHO/NYHA Functional Classification
    Units: Subjects
        Class I
    0
        Class II
    34
        Class III
    26
        Class IV
    1
    PAH Disease Specific Concomitant Medication - PDE5-I
    Units: Subjects
        Yes
    53
        No
    8
    PAH Disease Specific Concomitant Medication - sGC stimulator
    Units: Subjects
        Yes
    2
        No
    59
    Weight
    Units: kilogram(s)
        median (full range (min-max))
    72.5 (43 to 122)
    Height
    Units: centimetre
        median (full range (min-max))
    161.0 (145 to 182)
    Body Mass Index
    Units: kilogram(s)/square metre
        median (full range (min-max))
    27.13 (18.1 to 43.8)
    Duration of PAH
    Units: year
        median (full range (min-max))
    2.00 (0.3 to 27.0)
    Baseline Pulmonary Vascular Resistance
    Units: dyn.sec/cm^5
        median (full range (min-max))
    575.70 (282.4 to 2119.4)
    Baseline 6MWT
    Units: metre
        median (full range (min-max))
    400.0 (105 to 686)
    Baseline BNP
    Units: pg/mL
        median (full range (min-max))
    58.0 (10 to 1359)
    Baseline NT-proBNP
    Units: pg/mL
        median (full range (min-max))
    343.0 (50 to 8924)

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets

    Reporting group title
    Ralinepag
    Reporting group description
    		 Ralinepag capsules (oral) 0.01, 0.02, 0.03, 0.04, and 0.10 mg titrated to the individual maximum tolerated dose (maximum dose of 0.6 mg).
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets

    Reporting group title
    Ralinepag
    Reporting group description
    		 Ralinepag capsules (oral) 0.01, 0.02, 0.03, 0.04, and 0.10 mg titrated to the individual maximum tolerated dose (maximum dose of 0.6 mg).

    Subject analysis set title
    Safety Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All 61 subjects randomized into the study received at least 1 dose of study drug and were included in the Safety Population as part of this report.

    Primary: Change from baseline in PVR after 22 weeks of treatment

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    End point title
    		 Change from baseline in PVR after 22 weeks of treatment
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and 22 weeks
    End point values
    		 Placebo Ralinepag
    Number of subjects analysed
    19
    34
    Units: dyn.sec/cm^5
        geometric mean (standard deviation)
    512.0 ( 1.62 )
    514.6 ( 1.85 )
    Statistical analysis title
    		 Primary Endpoint Analysis of PVR by Point Estimate
    Comparison groups
    Ralinepag v Placebo
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.022
    Method
    		 ANCOVA
    Parameter type
    		 Multiple imputation
    Point estimate
    0.742
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.575
         upper limit
    		 0.958
    Notes
    [1] - GMR of PVR at Week 22 over Baseline comparing Ralinepag arm over Placebo arm.

    Primary: Change from baseline in 6MWD after 22 weeks of treatment

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    End point title
    		 Change from baseline in 6MWD after 22 weeks of treatment
    End point description
    End point type
    Primary
    End point timeframe
    Baseline and 22 weeks
    End point values
    		 Placebo Ralinepag
    Number of subjects analysed
    21
    38
    Units: meters
        least squares mean (standard error)
    29.4 ( 16.16 )
    36.2 ( 11.79 )
    Statistical analysis title
    		 Primary Endpoint Analysis of 6MWD
    Comparison groups
    Placebo v Ralinepag
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9002
    Method
    		 Stratified Wilcoxon
    Parameter type
    		 Hodges-Lehmann estimate
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28
         upper limit
    		 30

    Secondary: Percent change from baseline in PVR after 22 weeks of treatment

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    End point title
    		 Percent change from baseline in PVR after 22 weeks of treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 22 weeks
    End point values
    		 Placebo Ralinepag
    Number of subjects analysed
    21
    40
    Units: percent
        arithmetic mean (standard deviation)
    12.1 ( 50.98 )
    -19.7 ( 29.24 )
    No statistical analyses for this end point

    Secondary: Proportion of subjects who progress to clinical worsening

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    End point title
    		 Proportion of subjects who progress to clinical worsening
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 22 weeks
    End point values
    		 Placebo Ralinepag
    Number of subjects analysed
    21
    40
    Units: percent
        number (confidence interval 95%)
    2 (1.2 to 30.4)
    1 (0.1 to 13.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were assessed from the time the subject provided informed consent through the duration of the study (22 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo tablets

    Reporting group title
    Ralinepag
    Reporting group description
    		 Ralinepag capsules (oral) 0.01, 0.02, 0.03, 0.04, and 0.10 mg titrated to the individual maximum tolerated dose (maximum dose of 0.6 mg).

    Serious adverse events
    		 Placebo Ralinepag
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 21 (28.57%)
    4 / 40 (10.00%)
         number of deaths (all causes)
    2
    0
         number of deaths resulting from adverse events
    2
    0
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypovolaemic shock
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drug withdrawal syndrome
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Portal vein thrombosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Toxic skin eruption
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Haemarthrosis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Ralinepag
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 21 (90.48%)
    40 / 40 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 21 (4.76%)
    13 / 40 (32.50%)
         occurrences all number
    5
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 21 (28.57%)
    31 / 40 (77.50%)
         occurrences all number
    7
    67
    Dizziness
         subjects affected / exposed
    3 / 21 (14.29%)
    7 / 40 (17.50%)
         occurrences all number
    3
    11
    Syncope
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    3
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 21 (4.76%)
    6 / 40 (15.00%)
         occurrences all number
    2
    8
    Asthenia
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    5 / 21 (23.81%)
    20 / 40 (50.00%)
         occurrences all number
    9
    35
    Diarrhoea
         subjects affected / exposed
    3 / 21 (14.29%)
    19 / 40 (47.50%)
         occurrences all number
    5
    32
    Vomiting
         subjects affected / exposed
    3 / 21 (14.29%)
    10 / 40 (25.00%)
         occurrences all number
    5
    14
    Abdominal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    7 / 40 (17.50%)
         occurrences all number
    0
    10
    Abdominal pain upper
         subjects affected / exposed
    1 / 21 (4.76%)
    4 / 40 (10.00%)
         occurrences all number
    1
    9
    Abdominal discomfort
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 21 (4.76%)
    3 / 40 (7.50%)
         occurrences all number
    1
    4
    Cough
         subjects affected / exposed
    0 / 21 (0.00%)
    2 / 40 (5.00%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Pain in jaw
         subjects affected / exposed
    3 / 21 (14.29%)
    14 / 40 (35.00%)
         occurrences all number
    4
    18
    Myalgia
         subjects affected / exposed
    1 / 21 (4.76%)
    11 / 40 (27.50%)
         occurrences all number
    1
    20
    Pain in extremity
         subjects affected / exposed
    1 / 21 (4.76%)
    7 / 40 (17.50%)
         occurrences all number
    1
    13
    Neck pain
         subjects affected / exposed
    0 / 21 (0.00%)
    4 / 40 (10.00%)
         occurrences all number
    0
    4
    Muscle spasms
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 40 (7.50%)
         occurrences all number
    4
    5
    Musculoskeletal pain
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    4
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 40 (7.50%)
         occurrences all number
    3
    5
    Influenza
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 21 (9.52%)
    3 / 40 (7.50%)
         occurrences all number
    2
    3
    Metabolism and nutrition disorders
    Arthralgia
         subjects affected / exposed
    1 / 21 (4.76%)
    5 / 40 (12.50%)
         occurrences all number
    4
    14
    Decreased appetite
         subjects affected / exposed
    0 / 21 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    0
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2014
    The main changes to the protocol were as follows: • Removed Part A, open-label pilot study. • Revised study objectives, endpoints and analyses to reflect changes after Part A removal and to include a 22-week randomized, double-blind, treatment period. • Revised primary endpoint to include co-primary endpoint (6MWD). • Revised secondary and exploratory endpoints to include, but not be limited to, the effect on clinical worsening and assessment of WHO/NYHA functional class. • Reduced subject enrollment size from approximately 80 subjects total (Part A and Part B) to approximately 60 total enrolled. • Revised duration of study to include 3±1 week follow-up transition period to OLE Study APD811-007. • Revised end-of-study and exit visits to accommodate transition to OLE study while still allowing the Week 25 Follow-up Visit to serve as the Baseline Visit for the OLE study. • Removed 3x weekly visits with 6-hour postdose safety assessments and observation at 6 weeks of dose titration to 1x weekly visits with 4-hour postdose safety assessments and observation at 9 weeks, in-clinic titration. • Added the following assessments: VQ scan, echocardiogram, and optional DNA sample. • Revised storage and handling conditions for study material “bottles should be stored at room temperature (approximately 15ºC - 30ºC)” to “under refrigeration at 2ºC (36ºF) to 8ºC (46ºF)”.
    15 Aug 2014
    The main changes to the protocol were as follows: • Added ECG assessments to all dose-titration period visits (Weeks 1 through 9), to be completed predose and 2 hours postdose. • Corrected requirement for 6MWD distance at screening. − Previously: “Has a 6MWT distance of ≥50 meters and ≤500 meters, and within 15% of each other on 2 consecutive tests on different days during screening”. − Corrected: “Has a 6MWT distance of ≥100 meters and ≤500 meters, and within 15% of each other on 2 consecutive tests on different days during screening”. • Removed exclusion criteria of positive drug test at screening and added collection of history of alcohol or substance (drug/solvent) abuse per exclusion #21.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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