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    Clinical Trial Results:
    A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric Patients with Pulmonary Arterial Hypertension

    Summary
    EudraCT number
    		 2012-002354-23
    Trial protocol
    		 GB   DE   BE   IT   AT   NL   PL   ES   RO   FR  
    Global end of trial date

    Results information
    Results version number
    		 v3(current)
    This version publication date
    19 Nov 2021
    First version publication date
    22 Mar 2020
    Other versions
    		 v1 , v2
    Version creation reason
    • Correction of full data set
    Correction of full data set

    Trial information

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    Trial identification
    Sponsor protocol code
    H6D-MC-LVHV
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01824290
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 10609
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐CTLilly,
    Scientific contact
    Available Mon ‐ Fri 9 AM ‐ 5 PM EST, Eli Lilly and Company, 1 877‐285‐4559,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000452-PIP02-10
    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
    Interim
    Date of interim/final analysis
    18 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Mar 2019
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to evaluate the safety and efficacy of tadalafil in pediatric participants with pulmonary arterial hypertension. Participants will receive study treatment for 6 months in the double-blind period (Period 1), and then will be eligible to enroll into an open-label 2 year extension period (Period 2) during which participants will receive tadalafil.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 Some participants received endothelin receptor agonist (ERA) background therapy (bosentan or ambrisentan).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Feb 2014
    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
    Brazil: 15
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Japan: 2
    Country: Number of subjects enrolled
    Mexico: 5
    Country: Number of subjects enrolled
    Turkey: 3
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Poland: 1
    Worldwide total number of subjects
    35
    EEA total number of subjects
    4
    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)
    13
    Adolescents (12-17 years)
    22
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants who experienced clinical worsening during double-blind period were considered as completers.

    Pre-assignment
    Screening details
    		 Per protocol and statistical analysis plan (SAP), the primary and secondary analysis from period 1 were performed to compare all tadalafil participants together versus all placebo participants together.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Period 1: Participants received placebo orally by tablets once a day.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo orally by tablets once a day.

    Arm title
    		 Tadalafil
    Arm description
    		 Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tadalafil
    Investigational medicinal product code
    Other name
    LY450190
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tadalafil orally by tablets once a day.

    Number of subjects in period 1
    		Placebo Tadalafil
    Started
    18
    17
    Received at least one dose of study drug
    18
    17
    Received 20 mg
    0 [1]
    4 [2]
    Received 40 mg
    0 [3]
    13 [4]
    Completed
    16
    16
    Not completed
    2
    1
         Parent/Caregiver Decision
    1
    1
         Entry Criteria Not Met
    1
    -
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants in the milestones represent participants who received drug in each drug category (20 mg tadalafil, or 40 mg tadalafil).
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants in the milestones represent participants who received drug in each drug category (20 mg tadalafil, or 40 mg tadalafil).
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants in the milestones represent participants who received drug in each drug category (20 mg tadalafil, or 40 mg tadalafil).
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants in the milestones represent participants who received drug in each drug category (20 mg tadalafil, or 40 mg tadalafil).
    Period 2
    Period 2 title
    Open-Label Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tadalafil/Tadalafil
    Arm description
    		 Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day. Participants had received tadalafil during period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tadalafil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tadalafil orally by tablets once a day.

    Arm title
    		 Placebo/Tadalafil
    Arm description
    		 Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day. Participants had received placebo during period 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tadalafil
    Investigational medicinal product code
    Other name
    LY450190
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received tadalafil orally by tablets once a day.

    Number of subjects in period 2
    		Tadalafil/Tadalafil Placebo/Tadalafil
    Started
    16
    16
    Received 20 mg
    3 [5]
    3 [6]
    Received 40 mg
    13
    13
    Completed
    13
    13
    Not completed
    3
    3
         Consent withdrawn by subject
    1
    2
         Adverse Event
    1
    -
         Parent caregiver Decision
    1
    1
    Notes
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants in the milestones represent participants who received drug in each drug category (20 mg tadalafil, or 40 mg tadalafil).
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The number of participants in the milestones represent participants who received drug in each drug category (20 mg tadalafil, or 40 mg tadalafil).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Period 1: Participants received placebo orally by tablets once a day.

    Reporting group title
    Tadalafil
    Reporting group description
    		 Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day.

    Reporting group values
    		 Placebo Tadalafil Total
    Number of subjects
    		 18 17 35
    Age categorical
    Units: Subjects
    Age continuous
    All participants who received at least one dose. Per protocol and statistical analysis plan (SAP), the primary and secondary analysis were performed to compare all tadalafil participants together versus all placebo participants together.
    Units: years
        arithmetic mean (standard deviation)
    		 12.8 ± 3.39 14.1 ± 3.49 -
    Gender categorical
    Units: Subjects
        Female
    		 9 10 19
        Male
    		 9 7 16
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 7 8 15
        Not Hispanic or Latino
    		 6 4 10
        Unknown or Not Reported
    		 5 5 10
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 3 4
        Asian
    		 1 1 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 2 1 3
        White
    		 14 12 26
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        Japan
    		 1 1 2
        Turkey
    		 2 1 3
        Brazil
    		 9 6 15
        Mexico
    		 1 4 5
        Israel
    		 2 4 6
        France
    		 1 1 2
        Germany
    		 1 0 1
        Poland
    		 1 0 1
    6 Minute Walk Distance
    Units: Meters
        arithmetic mean (standard deviation)
    		 476.7 ± 105.11 485.8 ± 160.231 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Period 1: Participants received placebo orally by tablets once a day.

    Reporting group title
    Tadalafil
    Reporting group description
    		 Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day.
    Reporting group title
    Tadalafil/Tadalafil
    Reporting group description
    		 Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day. Participants had received tadalafil during period 1.

    Reporting group title
    Placebo/Tadalafil
    Reporting group description
    		 Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day. Participants had received placebo during period 1.

    Subject analysis set title
    20 mg Tadalafil
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Period 1: 20 mg tadalafil administered orally by tablets once a day with concomitant endothelin receptor antagonist (ERA).

    Subject analysis set title
    40 mg Tadalafil
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Period 1: 40 mg tadalafil administered orally by tablets once a day with concomitant endothelin receptor antagonist (ERA).

    Subject analysis set title
    Placebo/Tadalafil - Open-Label Treatment
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Period 1: Participants received placebo orally by tablets once a day. Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day.

    Subject analysis set title
    Tadalafil/Tadalafil - Open-Label Treatment
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day. Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered orally by tablets once a day.

    Primary: Period 1: Change from Baseline to Week 24 in a 6 Minute Walk (MW) Distance in Meters

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    End point title
    		 Period 1: Change from Baseline to Week 24 in a 6 Minute Walk (MW) Distance in Meters
    End point description
    6MWD in meters assessed in a subset of participants who are ≥6 to <18 years of age who are developmentally capable of performing a 6MW test. Change from baseline was derived using mixed model repeated measures (MMRM) with terms for treatment group, visit, baseline 6MWD, and treatment-by-visit interaction. Analysis Population Description: All participants who received at least one dose of study drug who were > = 6 to < 18 years of age and were capable of performing a 6MW test.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Placebo Tadalafil
    Number of subjects analysed
    15
    15
    Units: Meters
        least squares mean (standard error)
    36.60 ± 20.776
    60.48 ± 20.410
    Statistical analysis title
    		 6 Minute Walk (MW) Distance in Meters
    Comparison groups
    Tadalafil v Placebo
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    23.88
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -14.25
         upper limit
    		 62

    Secondary: Period 1: Time to Adjudicated Clinical Worsening (CW)

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    End point title
    		 Period 1: Time to Adjudicated Clinical Worsening (CW)
    End point description
    Clinical worsening was defined as any of the following: death,lung or heart transplantation,atrial septostomy or Potts' shunt,hospitalization for Pulmonary Arterial Hypertension(PAH) progression,new onset syncope,initiation of new PAH therapy(including increase in the dose of existing PAH specific concomitant therapy,such as endothelin receptor agonist or beraprost medication), or increase of 1 or more in World Health Organization(WHO) Functional Class(except for participants already in Class IV;only for participants unable to perform the 6 minute walk(6MW) test;worsening of WHO functional class by 1 or more for participants who can perform a 6 minute walk(6MW) test and who have a decrease of ≥ 20% in the 6 minute walk distance(for those participants who are ≥6 years of age). Criteria for CW(from Period 1) were adjudicated by an independent,blinded study-specific Clinical Endpoint Committee(CEC).This adjudication was used for data analysis, and was not used to guide subject treatment.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 24 Analysis Population Description: All participants who received at least one dose of study drug.
    End point values
    		 Placebo Tadalafil
    Number of subjects analysed
    18 [1]
    17 [2]
    Units: Weeks
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [1] - 9999=Data Not Available (NA). There was no confirmed adjudicated CW case to report.
    [2] - 9999=Data Not Available (NA). There was no confirmed adjudicated CW case to report.
    No statistical analyses for this end point

    Secondary: Period 1: Percentage of Participants Who Experience CW

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    End point title
    		 Period 1: Percentage of Participants Who Experience CW
    End point description
    Clinical worsening was defined as any of the following: death,lung or heart transplantation,atrial septostomy or Potts' shunt,hospitalization for Pulmonary Arterial Hypertension(PAH) progression,new onset syncope, initiation of new PAH therapy(including increase in the dose of existing PAH specific concomitant therapy,such as endothelin receptor agonist or beraprost medication),or increase of 1 or more in World Health Organization(WHO) Functional Class(except for participants already in Class IV; only for participants unable to perform the 6 minute walk(6MW) test;worsening of WHO functional class by 1 or more for participants who can perform a 6 minute walk(6MW) test and who have a decrease of ≥ 20% in the 6 minute walk distance(for those participants who are ≥6 years of age).Criteria for CW(from Period 1) were adjudicated by an independent,blinded study-specific Clinical Endpoint Committee(CEC).This adjudication was used for data analysis, and was not used to guide subject treatment.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 24 Analysis Population Description: All participants who received at least one dose of study drug.
    End point values
    		 Placebo Tadalafil
    Number of subjects analysed
    18
    17
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of tadalafil

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    End point title
    		 Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of tadalafil
    End point description
    Period 1: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil at Steady-state. Analysis Population Description: All participants who received at least one dose of study drug and had evaluable PK data. 9999= NA. For 20 mg tadalafil with concomitant bosentan, n=3. For 20 mg tadalafil no bosentan (ERA: macitentan), n = 1. For n = 1, geometric mean and geometric coefficient of variation could not be calculated. Individual value is 2.68. For 40 mg tadalafil No bosentan (ERA: Macitentan), n=0.
    End point type
    Secondary
    End point timeframe
    Week 2, Week 4, Week16 and Week 24
    End point values
    		 20 mg Tadalafil 40 mg Tadalafil
    Number of subjects analysed
    4 [3]
    13 [4]
    Units: Liter Per Hour (L/hr)
    geometric mean (geometric coefficient of variation)
        With concomitant bosentan
    3.63 ± 38.1
    4.49 ± 28.2
        No bosentan (ERA: Macitentan)
    9999 ± 9999
    9999 ± 9999
    Notes
    [3] - 9999= NA. For 20 mg tadalafil No bosentan (ERA: Macitentan), n = 1.
    [4] - 9999= NA. For 40 mg tadalafil No bosentan (ERA: Macitentan), n=0.
    No statistical analyses for this end point

    Secondary: Period 2: Time to First Occurrence of CW

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    End point title
    		 Period 2: Time to First Occurrence of CW
    End point description
    Clinical worsening was defined as any of the following: death, lung or heart transplantation, atrial septostomy or Potts' shunt, hospitalization for Pulmonary Arterial Hypertension (PAH) progression, new onset syncope, initiation of new PAH therapy (including increase in the dose of existing PAH specific concomitant therapy, such as endothelin receptor agonist or beraprost medication), or increase of 1 or more in World Health Organization(WHO) Functional Class (except for participants already in Class IV; only for participants unable to perform the 6 minute walk (6MW) test; worsening of WHO functional class by 1 or more for participants who can perform a 6 minute walk (6MW) test and who have a decrease of ≥ 20% in the 6 minute walk distance (for those participants who are ≥6 years of age). Median and CI are not estimable due to inadequate events of Clinical Worsening (CW) using Kaplan-Meier survival Estimates.
    End point type
    Secondary
    End point timeframe
    Baseline through Study Completion (Up to 24 Months) Analysis Population Description: Period 2: All participants who received at least one dose of study drug.
    End point values
    		 Placebo/Tadalafil - Open-Label Treatment Tadalafil/Tadalafil - Open-Label Treatment
    Number of subjects analysed
    16 [5]
    16 [6]
    Units: Months
        median (confidence interval 95%)
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    Notes
    [5] - 9999=NA.
    [6] - 9999=NA.
    No statistical analyses for this end point

    Secondary: Period 2: Percentage of Participants Who Experience CW

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    End point title
    		 Period 2: Percentage of Participants Who Experience CW
    End point description
    Clinical worsening was defined as any of the following: death, lung or heart transplantation, atrial septostomy or Potts' shunt, hospitalization for Pulmonary Arterial Hypertension (PAH) progression, new onset syncope, initiation of new PAH therapy (including increase in the dose of existing PAH specific concomitant therapy, such as endothelin receptor agonist or beraprost medication), or increase of 1 or more in World Health Organization(WHO) Functional Class (except for participants already in Class IV; only for participants unable to perform the 6 minute walk (6MW) test; worsening of WHO functional class by 1 or more for participants who can perform a 6 minute walk (6MW) test and who have a decrease of ≥ 20% in the 6 minute walk distance (for those participants who are ≥6 years of age).
    End point type
    Secondary
    End point timeframe
    Period 2 Baseline through Study Completion (Up to 24 Months) Analysis Population Description: Period 2: All participants who received at least one dose of study drug.
    End point values
    		 Placebo/Tadalafil - Open-Label Treatment Tadalafil/Tadalafil - Open-Label Treatment
    Number of subjects analysed
    16
    16
    Units: percentage of participants
        number (not applicable)
    12.5
    18.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline Up To 24 Months
    Adverse event reporting additional description
    All participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo - Double Blind
    Reporting group description
    		 Period 1: Participants received placebo orally by tablets once a day.

    Reporting group title
    Placebo/Tadalafil - Open-Label Treatment
    Reporting group description
    		 Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day. Participants had received placebo during period 1.

    Reporting group title
    Tadalafil/Tadalafil - Open-Label Treatment
    Reporting group description
    		 Period 2: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day. Participants had received tadalafil during period 1.

    Reporting group title
    Tadalafil - Double Blind
    Reporting group description
    		 Period 1: 20 mg middle weight cohort or 40 mg for heavy weight cohort administered tadalafil orally by tablets once a day.

    Serious adverse events
    		 Placebo - Double Blind Placebo/Tadalafil - Open-Label Treatment Tadalafil/Tadalafil - Open-Label Treatment Tadalafil - Double Blind
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    4 / 16 (25.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Cardiac disorders
    acute right ventricular failure
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    haemoptysis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    gastroenteritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo - Double Blind Placebo/Tadalafil - Open-Label Treatment Tadalafil/Tadalafil - Open-Label Treatment Tadalafil - Double Blind
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 18 (44.44%)
    11 / 16 (68.75%)
    12 / 16 (75.00%)
    15 / 17 (88.24%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    pharyngeal neoplasm
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular disorders
    deep vein thrombosis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    flushing
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    hypotension
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    asthenia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    exercise tolerance decreased
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    pyrexia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Immune system disorders
    hypersensitivity
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    seasonal allergy
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Social circumstances
    menarche
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [1]
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Reproductive system and breast disorders
    menorrhagia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [2]
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 10 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    2
    1
    metrorrhagia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [3]
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    penis disorder
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [4]
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    polymenorrhoea
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [5]
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 10 (10.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    spontaneous penile erection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [6]
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    2
    uterine haemorrhage
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [7]
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 10 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    dyspnoea
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    epistaxis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 16 (6.25%)
    1 / 16 (6.25%)
    2 / 17 (11.76%)
         occurrences all number
    1
    1
    1
    2
    oropharyngeal pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    1
    pulmonary arterial hypertension
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    respiratory distress
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    excessive masturbation
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    insomnia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Investigations
    blood creatine phosphokinase increased
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    hepatic enzyme increased
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    bone contusion
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    penis injury
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [8]
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    0 / 6 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    palpitations
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    supraventricular tachycardia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    tachycardia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    ventricular extrasystoles
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    dizziness
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    3 / 16 (18.75%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    3
    0
    headache
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 16 (12.50%)
    3 / 16 (18.75%)
    5 / 17 (29.41%)
         occurrences all number
    6
    2
    3
    5
    presyncope
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    1
    somnolence
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    syncope
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Blood and lymphatic system disorders
    anaemia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    0
    eosinophilia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ear and labyrinth disorders
    ear pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye disorders
    asthenopia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    photopsia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    abdominal pain upper
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    2
    0
    dental caries
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    enterocolitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    irritable bowel syndrome
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    nausea
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    plicated tongue
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    vomiting
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    3 / 16 (18.75%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Skin and subcutaneous tissue disorders
    dermatitis allergic
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    2
    0
    haemorrhage subcutaneous
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    3
    livedo reticularis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    photosensitivity reaction
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    pruritus
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    rash
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    swelling face
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    arthralgia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    2 / 17 (11.76%)
         occurrences all number
    1
    0
    2
    2
    back pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    pain in extremity
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    patellofemoral pain syndrome
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Infections and infestations
    acute sinusitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    0
    0
    ascariasis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    body tinea
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    bronchitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    ear infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    2
    0
    gastroenteritis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    impetigo
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    influenza
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    3 / 17 (17.65%)
         occurrences all number
    0
    0
    1
    3
    nasopharyngitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    3 / 16 (18.75%)
    0 / 17 (0.00%)
         occurrences all number
    0
    2
    4
    0
    otitis media acute
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    paronychia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    pharyngitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    4
    1
    rhinitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 16 (12.50%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    2
    0
    1
    sinusitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    2
    1
    tonsillitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    tracheobronchitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    2 / 16 (12.50%)
    3 / 17 (17.65%)
         occurrences all number
    1
    0
    2
    3
    urinary tract infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    1
    1
    vaginal infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed [9]
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 10 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    viral infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    viral tonsillitis
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    0
    viral upper respiratory tract infection
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    0 / 16 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    dyslipidaemia
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 16 (0.00%)
    1 / 16 (6.25%)
    0 / 17 (0.00%)
         occurrences all number
    0
    0
    1
    0
    vitamin b12 deficiency
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    vitamin d deficiency
    alternative dictionary used: MedDRA 24.0
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 16 (6.25%)
    0 / 16 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This event is gender specific, only occurring in male or female subjects. The number of subjects exposed has been adjusted accordingly

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Sep 2012
    Change of primary endpoint for US from right heart catheterization (RHC) to Cardiac Echo. Per requirement from FDA that RHC can no longer be used as primary endpoint in Pediatric PAH trials.
    14 Dec 2012
    Per FDA removal of Tricuspid Annular Plane Systolic Excursion (TAPSE) as primary endpoint for US. Change of primary endpoint for US to improving time of 6-minute walk (6MW) test from baseline to week 24.
    13 Dec 2018
    Change of primary endpoint and study sample size.

    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 study is mainly descriptive in a small number of children with PAH and there were no participants enrolled in the light weight cohort.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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