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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial of Tadalafil for Duchenne Muscular Dystrophy

    Summary
    EudraCT number
    		 2013-001194-25
    Trial protocol
    		 GB   IT   DE   ES   BE   NL  
    Global end of trial date
    31 Mar 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    15122
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01865084
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Alias: H6D-MC-LVJJ, Trial ID: 15122
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, 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)
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Mar 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main purpose of this study is to determine if tadalafil can slow the decline in walking ability of boys who have Duchenne muscular dystrophy (DMD). The study will also assess the safety of tadalafil and any side effects that might be associated with it in boys who have DMD. Participants will receive study treatment (tadalafil or placebo) for the first 48 weeks of the study, and can then continue into an open label extension (OLE) that consists of two periods during which all participants will receive tadalafil. In OLE period 1, all participants will receive tadalafil for 48 weeks. Participants completing OLE period 1 will continue into OLE period 2 and will receive tadalafil for at least another 48 weeks.
    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
    		 All the participants in the study were receiving corticosteroids.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 8 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 17
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    United States: 107
    Country: Number of subjects enrolled
    Japan: 17
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    Canada: 23
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    Turkey: 20
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Korea, Republic of: 12
    Worldwide total number of subjects
    331
    EEA total number of subjects
    105
    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)
    280
    Adolescents (12-17 years)
    51
    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
    		 The Long term follow-up duration of 8 months cited in the "Trial Information Section" reflects average actual follow-up duration and is shorter than the planned OLE duration because the study was stopped early.

    Pre-assignment
    Screening details
    		 No Text Entered

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo taken orally once daily.
    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
    Placebo taken orally once daily.

    Arm title
    		 0.3 mg/kg Tadalafil
    Arm description
    		 0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily.
    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
    0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily.

    Arm title
    		 0.6 mg/kg Tadalafil
    Arm description
    		 0.6 mg/kg tadalafil taken orally once daily.
    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
    0.6 mg/kg tadalafil taken orally once daily.

    Number of subjects in period 1
    		Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Started
    116
    102
    113
    Received at least one dose of study drug
    116
    102
    112
    Completed
    111
    98
    107
    Not completed
    5
    4
    6
         Consent withdrawn by subject
    1
    -
    -
         Adverse event, non-fatal
    2
    2
    1
         Withdrawal by Parent/Guardian
    2
    2
    4
         Protocol deviation
    -
    -
    1
    Period 2
    Period 2 title
    Open Label Extension (OLE) Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 0.3 mg/kg Tadalafil
    Arm description
    		 0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily. There was no control in the open label period. In period 2 the original placebo arm was randomised to one of the two tadalafil arms. The original tadalafil arms had no randomisation in period 2.
    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
    0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily.

    Arm title
    		 0.6 mg/kg Tadalafil
    Arm description
    		 0.6 mg/kg tadalafil taken orally once daily. There was no control in the open label period. In period 2 the original placebo arm was randomised to one of the two tadalafil arms. The original tadalafil arms had no randomisation in period 2.
    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
    0.6 mg/kg tadalafil taken orally once daily.

    Number of subjects in period 2 [1]
    		0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Started
    150
    165
    Completed
    139
    158
    Not completed
    11
    7
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    -
    1
         Withdrawal by Parent/Guardian
    8
    2
         Lost to follow-up
    1
    -
         Lack of efficacy
    -
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants who were on Placebo during the double blind period were assigned tadalafil during OLE.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo taken orally once daily.

    Reporting group title
    0.3 mg/kg Tadalafil
    Reporting group description
    		 0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily.

    Reporting group title
    0.6 mg/kg Tadalafil
    Reporting group description
    		 0.6 mg/kg tadalafil taken orally once daily.

    Reporting group values
    		 Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil Total
    Number of subjects
    		 116 102 113 331
    Age categorical
    Units: Subjects
    Age Continuous
    All participants who were randomized to study drug.
    Units: years
        arithmetic mean (standard deviation)
    		 9.4 ( 1.76 ) 9.9 ( 2.26 ) 9.5 ( 1.71 ) -
    Gender, Male/Female
    All participants who were randomized to study drug.
    Units: participants
        Female
    		 0 0 0 0
        Male
    		 116 102 113 331
    Race (NIH/OMB)
    All participants who were randomized to study drug.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 2 2
        Asian
    		 15 16 20 51
        Native Hawaiian or Other Pacific Islander
    		 3 1 3 7
        Black or African American
    		 0 0 1 1
        White
    		 96 82 84 262
        More than one race
    		 2 3 2 7
        Unknown or Not Reported
    		 0 0 1 1
    Region of Enrollment
    All participants who were randomized to study drug.
    Units: Subjects
        Argentina
    		 7 4 6 17
        Russian Federation
    		 4 4 4 12
        United States
    		 39 34 34 107
        Japan
    		 6 5 6 17
        Spain
    		 9 7 12 28
        Canada
    		 8 7 8 23
        Netherlands
    		 2 1 3 6
        Turkey
    		 5 7 8 20
        Belgium
    		 8 5 4 17
        Taiwan
    		 6 4 8 18
        Korea, Republic of
    		 3 4 5 12
        Italy
    		 8 8 8 24
        France
    		 3 2 2 7
        Germany
    		 8 10 5 23

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo taken orally once daily.

    Reporting group title
    0.3 mg/kg Tadalafil
    Reporting group description
    		 0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily.

    Reporting group title
    0.6 mg/kg Tadalafil
    Reporting group description
    		 0.6 mg/kg tadalafil taken orally once daily.
    Reporting group title
    0.3 mg/kg Tadalafil
    Reporting group description
    		 0.3 milligram per kilogram (mg/kg) tadalafil taken orally once daily. There was no control in the open label period. In period 2 the original placebo arm was randomised to one of the two tadalafil arms. The original tadalafil arms had no randomisation in period 2.

    Reporting group title
    0.6 mg/kg Tadalafil
    Reporting group description
    		 0.6 mg/kg tadalafil taken orally once daily. There was no control in the open label period. In period 2 the original placebo arm was randomised to one of the two tadalafil arms. The original tadalafil arms had no randomisation in period 2.

    Subject analysis set title
    0.3 mg/kg Tadalafil and 0.6 mg/kg Tadalafil
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    0.3 mg/kg tadalafil taken orally once daily. 0.6 mg/kg tadalafil taken orally once daily.

    Primary: Change from Baseline in Six Minute Walk Distance (6MWD) in Meters

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    End point title
    		 Change from Baseline in Six Minute Walk Distance (6MWD) in Meters
    End point description
    6MWD measured the distance in meters a participant was able to walk in 6 minutes. The study used 6MWD procedure modified specifically for use in boys with Duchenne muscular dystrophy (DMD), including standardized verbal encouragement at specific intervals to maintain attention to the test, and use of a "safety chaser" to walk behind the participant during testing (McDonald et al., 2010a). The LS mean (LSM) change from baseline, standard error was derived using mixed model repeated measures (MMRM) methodology with factors for pooled country, treatment, visit, treatment-by-visit interaction and baseline 6MWD as a covariate. Analysis Population Description: All randomized participants who received at least one dose of study drug who had a baseline and at least one post-baseline measurement.
    End point type
    Primary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Number of subjects analysed
    113
    101
    111
    Units: Meters
        least squares mean (standard error)
    -50.99 ( 9.316 )
    -64.71 ( 9.809 )
    -59.08 ( 9.397 )
    Statistical analysis title
    		 Six Minute Walk Distance (6MWD)
    Comparison groups
    Placebo v 0.3 mg/kg Tadalafil
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.307 [1]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - The p-value is based on the treatment difference LS Mean changes from baseline between tadalafil and placebo.
    Statistical analysis title
    		 Six Minute Walk Distance (6MWD)
    Comparison groups
    Placebo v 0.6 mg/kg Tadalafil
    Number of subjects included in analysis
    224
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.538 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [2] - The p-value is based on the treatment difference LS Mean changes from baseline between tadalafil and placebo.

    Secondary: Change from Baseline in the North Star Ambulatory Assessment (NSAA) Global Score

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    End point title
    		 Change from Baseline in the North Star Ambulatory Assessment (NSAA) Global Score
    End point description
    The NSAA is a functional scale specifically designed for ambulant boys with DMD that can provide additional information on motor functions important in maintaining normal ambulation and other activities important to everyday life. The NSAA is a 17-item evaluation of standing, ability to transition from lying to sitting,sitting to standing,and other mobility assessments.Each of the 17 items is evaluated on an ordinal scale of 0,1, or 2, with higher scores reflecting better performance on the assessment, for a total maximum score of 34.This score was transformed to a 0 to 100 scale for the key analysis (referred to as linearized).The LS mean(LSM) change from baseline standard error was derived using MMRM with factors for pooled country,treatment,visit, treatment-by-visit interaction and Day 1 value as baseline covariate. Analysis Population Description: All randomized participants who received at least 1 dose of study drug who had a baseline and at least 1 post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Number of subjects analysed
    116
    102
    112
    Units: Units on a scale
        least squares mean (standard error)
    -8.8 ( 1.104 )
    -9.31 ( 1.181 )
    -8.96 ( 1.115 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Timed Function Tests in Seconds

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    End point title
    		 Change from Baseline in Timed Function Tests in Seconds
    End point description
    Timed function tests included time it took to rise from floor, walk 10 meters, ascend 4 stairs, and descend 4 stairs.The lower the time in seconds taken, the better the performance. The LS mean change from baseline, standard error, was derived using mixed model repeated measures methodology (MMRM) with factors for pooled country, treatment, visit, treatment-by-visit interaction and Day 1 value as baseline covariate. Analysis Population Description : All randomized participants who received at least one dose of study drug who had a baseline and at least one post-baseline measurement.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Number of subjects analysed
    116
    96
    110
    Units: Seconds
    least squares mean (standard error)
        Rise from the Floor(n=92,75,89)
    4.16 ( 1.12 )
    3.6 ( 1.223 )
    4.81 ( 1.156 )
        10 Meter Walk/Run(n=105,90,100)
    1.11 ( 0.204 )
    0.95 ( 0.226 )
    1.12 ( 0.217 )
        Stair Climb (n=116,96,110)
    3.96 ( 1.041 )
    4.1 ( 1.154 )
    5.82 ( 1.072 )
        Stair Descend(n=115,95,110)
    3.19 ( 0.827 )
    2.07 ( 0.915 )
    3.27 ( 0.853 )
    No statistical analyses for this end point

    Secondary: Time to Persistent 10% Worsening in 6MWD

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    End point title
    		 Time to Persistent 10% Worsening in 6MWD
    End point description
    Time on study until the 6MWD becomes 10% less than the baseline 6MWD and continues at that level or lower until the end of study. Analysis Population Description: All randomized participants who received at least one dose of study drug who had complete evaluable data. Complete evaluable data was defined as having baseline measurement, complete dates at evaluable visits and a post-baseline measurement at each evaluable visit. Censored participants: placebo=71, 0.3 mg/kg=63, 0.6 mg/kg=61.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 48
    End point values
    		 Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Number of subjects analysed
    115 [3]
    101 [4]
    111 [5]
    Units: Days
        median (confidence interval 95%)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    Notes
    [3] - 999=These statistics were not estimable due to large number of participants who were censored.
    [4] - 999=These statistics were not estimable due to large number of participants who were censored.
    [5] - 999=These statistics were not estimable due to large number of participants who were censored.
    No statistical analyses for this end point

    Secondary: Time to Persistent 10% Worsening in Timed Function Tests (TFT)

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    End point title
    		 Time to Persistent 10% Worsening in Timed Function Tests (TFT)
    End point description
    Time on study until the TFT becomes 10% worse than the baseline TFT and continues at that level or lower until the end of study. The time to persistent 10% worsening is the observed time after baseline( until the first observed timepoint where their time used for the TFTs is >110% of the baseline time and all the time values observed afterward are also >110% of baseline. If the participant discontinues prior to experiencing persistent worsening, this outcome for the participant is censored at the date of discontinuation of the double-blind period. Analysis Population Description: All randomized participants who received at least 1 dose of study drug who had complete evaluable data. Censored participants:Rise from Floor;placebo (pl)=40,0.3 mg/kg=39,0.6 mg/kg=43;Stair Climb;pl=55,0.3 mg/kg=45,0.6 mg/kg=52;10 Meter Walk/Run pl=61,0.3 mg/kg=65,0.6 mg/kg=58,Stair Descend;pl=63,0.3 mg/kg=60,0.6 mg/kg=59.
    End point type
    Secondary
    End point timeframe
    Baseline through Week 48
    End point values
    		 Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Number of subjects analysed
    116 [6]
    102 [7]
    113 [8]
    Units: Days
    median (confidence interval 95%)
        Rise from the Floor (n=81,67,77)
    253 (170 to 999)
    999 (999 to 999)
    999 (999 to 999)
        Stair Climb (n=112,91,107)
    255 (252 to 999)
    259 (176 to 999)
    253 (185 to 999)
        10 Meter Walk/Run (n=98,83,91)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
        Stair Descend (n=110,91,108)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    Notes
    [6] - 999=These statistics were not estimable due to large number of participants who were censored.
    [7] - 999=These statistics were not estimable due to large number of participants who were censored.
    [8] - 999=These statistics were not estimable due to large number of participants who were censored.
    No statistical analyses for this end point

    Secondary: Change from Baseline in Pediatric Outcomes Data Collection Instrument (PODCI) Scores

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    End point title
    		 Change from Baseline in Pediatric Outcomes Data Collection Instrument (PODCI) Scores
    End point description
    The global functioning score is the mean of the mean scores from 4 of the 5 core scales (all except the happiness core scale). The scores were standardized so that a score of “0” represents a poor outcome/worse health, while “100” is the best possible outcome/best health. The LS mean (LSM) change from baseline, standard error was derived using mixed model repeated measures methodology (MMRM) with factors for pooled country, treatment, visit, treatment-by-visit interaction and baseline PODCI scale as covariate. Analysis Population Description: All randomized participants who received at least one dose of study drug who had a baseline and at least one post-baseline measurement. The reason the number of participants analyzed is significantly less than the total number of randomized participants is because PODCI was administered only in English.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Placebo 0.3 mg/kg Tadalafil 0.6 mg/kg Tadalafil
    Number of subjects analysed
    41
    35
    34
    Units: Units on a scale
    least squares mean (standard error)
        Global Functioning Scale (n=41,34,34)
    -8.81 ( 1.77 )
    -7.36 ( 1.929 )
    -7.34 ( 1.888 )
        Upper Extremity & Physical Function
    -5.47 ( 1.901 )
    -3.73 ( 2.06 )
    -2.47 ( 2.042 )
        Transfer/Basic Mobility Core Scale
    -14.26 ( 3.037 )
    -12.5 ( 3.26 )
    -12.78 ( 3.279 )
        Sports/Physical Functioning Core Scale
    -12.47 ( 2.362 )
    -11.98 ( 2.552 )
    -7.88 ( 2.537 )
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil

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    End point title
    		 Pharmacokinetics (PK): Apparent Clearance (CL/F) of Tadalafil
    End point description
    The data reported are the population estimate (geometric mean) and the inter-patient variability (geometric coefficient of variation (%)). Analysis Population Description : All randomized participants who received at least one dose of study drug and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12, 24 and 36: -1 Hour up to 24 Hours Postdose
    End point values
    		 0.3 mg/kg Tadalafil and 0.6 mg/kg Tadalafil
    Number of subjects analysed
    210
    Units: Liter per hour (L/hr)
        geometric mean (geometric coefficient of variation)
    1.79 ( 29.6 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Double-Blind and Open-Label Treatment Periods
    Adverse event reporting additional description
    All randomized participants who received at least one dose of study drug for Placebo - DB, 0.3 mg/kg tadalafil -DB and 0.6 mg/kg tadalafil -DB arms during the DB period. All randomized participants who received at least one dose of study drug for 0.3 mg/kg tadalafil - OLE and 0.6 mg/kg tadalafil - OLE arms during the OLE period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Placebo-DB
    Reporting group description
    		 -

    Reporting group title
    Tadalafil 0.3mg/Kg-DB
    Reporting group description
    		 -

    Reporting group title
    Tadalafil 0.6mg/Kg-DB
    Reporting group description
    		 -

    Reporting group title
    Tadalafil 0.3mg/Kg-OLE
    Reporting group description
    		 -

    Reporting group title
    Tadalafil 0.6mg/Kg-OLE
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo-DB Tadalafil 0.3mg/Kg-DB Tadalafil 0.6mg/Kg-DB Tadalafil 0.3mg/Kg-OLE Tadalafil 0.6mg/Kg-OLE
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 116 (4.31%)
    4 / 102 (3.92%)
    6 / 112 (5.36%)
    6 / 150 (4.00%)
    9 / 165 (5.45%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    ankle fracture
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    1 / 150 (0.67%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    fall
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 102 (0.00%)
    2 / 112 (1.79%)
    1 / 150 (0.67%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    femoral neck fracture
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    femur fracture
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    2 / 112 (1.79%)
    1 / 150 (0.67%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    lower limb fracture
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    spinal fracture
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    myocarditis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 102 (0.98%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    extrapyramidal disorder
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    1 / 150 (0.67%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    abasia
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    1 / 150 (0.67%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    vomiting
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    self injurious behaviour
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    suicidal ideation
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    muscle contracture
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 102 (0.98%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    tendinous contracture
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 102 (0.00%)
    1 / 112 (0.89%)
    1 / 150 (0.67%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    tendon disorder
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    appendicitis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    bronchitis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    gastroenteritis viral
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    gastrointestinal infection
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 102 (0.98%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    influenza
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pharyngotonsillitis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    1 / 112 (0.89%)
    0 / 150 (0.00%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 102 (0.98%)
    0 / 112 (0.00%)
    0 / 150 (0.00%)
    1 / 165 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    pneumonia adenoviral
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    1 / 112 (0.89%)
    0 / 150 (0.00%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    varicella
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    1 / 112 (0.89%)
    0 / 150 (0.00%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 102 (0.00%)
    0 / 112 (0.00%)
    1 / 150 (0.67%)
    0 / 165 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo-DB Tadalafil 0.3mg/Kg-DB Tadalafil 0.6mg/Kg-DB Tadalafil 0.3mg/Kg-OLE Tadalafil 0.6mg/Kg-OLE
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 116 (71.55%)
    82 / 102 (80.39%)
    92 / 112 (82.14%)
    68 / 150 (45.33%)
    84 / 165 (50.91%)
    Injury, poisoning and procedural complications
    fall
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    24 / 116 (20.69%)
    18 / 102 (17.65%)
    22 / 112 (19.64%)
    16 / 150 (10.67%)
    15 / 165 (9.09%)
         occurrences all number
    41
    30
    41
    22
    18
    Vascular disorders
    flushing
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    3 / 116 (2.59%)
    8 / 102 (7.84%)
    8 / 112 (7.14%)
    2 / 150 (1.33%)
    2 / 165 (1.21%)
         occurrences all number
    3
    8
    9
    2
    2
    Nervous system disorders
    headache
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    36 / 116 (31.03%)
    40 / 102 (39.22%)
    43 / 112 (38.39%)
    8 / 150 (5.33%)
    14 / 165 (8.48%)
         occurrences all number
    92
    57
    68
    12
    19
    General disorders and administration site conditions
    abasia
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    6 / 116 (5.17%)
    14 / 102 (13.73%)
    9 / 112 (8.04%)
    12 / 150 (8.00%)
    16 / 165 (9.70%)
         occurrences all number
    6
    14
    9
    12
    16
    pyrexia
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    4 / 116 (3.45%)
    11 / 102 (10.78%)
    9 / 112 (8.04%)
    7 / 150 (4.67%)
    6 / 165 (3.64%)
         occurrences all number
    4
    11
    10
    8
    6
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    6 / 116 (5.17%)
    4 / 102 (3.92%)
    9 / 112 (8.04%)
    2 / 150 (1.33%)
    3 / 165 (1.82%)
         occurrences all number
    7
    4
    9
    2
    3
    abdominal pain upper
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    7 / 116 (6.03%)
    5 / 102 (4.90%)
    8 / 112 (7.14%)
    4 / 150 (2.67%)
    2 / 165 (1.21%)
         occurrences all number
    7
    6
    8
    5
    2
    diarrhoea
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    10 / 116 (8.62%)
    6 / 102 (5.88%)
    10 / 112 (8.93%)
    9 / 150 (6.00%)
    7 / 165 (4.24%)
         occurrences all number
    10
    9
    19
    13
    7
    nausea
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    2 / 116 (1.72%)
    7 / 102 (6.86%)
    3 / 112 (2.68%)
    1 / 150 (0.67%)
    1 / 165 (0.61%)
         occurrences all number
    2
    8
    3
    1
    1
    vomiting
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    14 / 116 (12.07%)
    6 / 102 (5.88%)
    17 / 112 (15.18%)
    9 / 150 (6.00%)
    10 / 165 (6.06%)
         occurrences all number
    20
    6
    25
    12
    11
    Reproductive system and breast disorders
    erection increased
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    3 / 116 (2.59%)
    10 / 102 (9.80%)
    17 / 112 (15.18%)
    2 / 150 (1.33%)
    4 / 165 (2.42%)
         occurrences all number
    3
    11
    18
    2
    4
    spontaneous penile erection
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    4 / 116 (3.45%)
    13 / 102 (12.75%)
    13 / 112 (11.61%)
    3 / 150 (2.00%)
    4 / 165 (2.42%)
         occurrences all number
    6
    13
    14
    3
    4
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    10 / 116 (8.62%)
    4 / 102 (3.92%)
    5 / 112 (4.46%)
    4 / 150 (2.67%)
    5 / 165 (3.03%)
         occurrences all number
    11
    4
    5
    5
    5
    epistaxis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    5 / 116 (4.31%)
    10 / 102 (9.80%)
    6 / 112 (5.36%)
    4 / 150 (2.67%)
    3 / 165 (1.82%)
         occurrences all number
    11
    15
    8
    6
    5
    Skin and subcutaneous tissue disorders
    rash
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    7 / 116 (6.03%)
    3 / 102 (2.94%)
    5 / 112 (4.46%)
    3 / 150 (2.00%)
    1 / 165 (0.61%)
         occurrences all number
    7
    3
    5
    3
    1
    Musculoskeletal and connective tissue disorders
    back pain
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    9 / 116 (7.76%)
    11 / 102 (10.78%)
    7 / 112 (6.25%)
    7 / 150 (4.67%)
    9 / 165 (5.45%)
         occurrences all number
    15
    12
    7
    7
    9
    muscle spasms
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    7 / 116 (6.03%)
    3 / 102 (2.94%)
    3 / 112 (2.68%)
    0 / 150 (0.00%)
    2 / 165 (1.21%)
         occurrences all number
    9
    3
    4
    0
    2
    pain in extremity
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    8 / 116 (6.90%)
    6 / 102 (5.88%)
    10 / 112 (8.93%)
    2 / 150 (1.33%)
    4 / 165 (2.42%)
         occurrences all number
    14
    6
    11
    2
    4
    Infections and infestations
    gastroenteritis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    6 / 116 (5.17%)
    4 / 102 (3.92%)
    3 / 112 (2.68%)
    3 / 150 (2.00%)
    2 / 165 (1.21%)
         occurrences all number
    6
    4
    3
    3
    2
    influenza
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    9 / 116 (7.76%)
    8 / 102 (7.84%)
    5 / 112 (4.46%)
    3 / 150 (2.00%)
    2 / 165 (1.21%)
         occurrences all number
    9
    9
    5
    3
    2
    nasopharyngitis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    16 / 116 (13.79%)
    8 / 102 (7.84%)
    18 / 112 (16.07%)
    8 / 150 (5.33%)
    12 / 165 (7.27%)
         occurrences all number
    26
    10
    24
    10
    12
    sinusitis
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    6 / 116 (5.17%)
    4 / 102 (3.92%)
    3 / 112 (2.68%)
    1 / 150 (0.67%)
    0 / 165 (0.00%)
         occurrences all number
    11
    5
    3
    1
    0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 18.1
         subjects affected / exposed
    10 / 116 (8.62%)
    10 / 102 (9.80%)
    12 / 112 (10.71%)
    6 / 150 (4.00%)
    8 / 165 (4.85%)
         occurrences all number
    18
    21
    16
    15
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Sep 2013
    Updated information brochure (IB) to include a warning about the use of tadalafil with guanylate cyclase stimulators such as riociguat due to the risk of hypotension.
    29 Apr 2015
    Adding an additional open label extension phase to the study.

    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 Sponsor concluded that the efficacy results do not provide sufficient justification for continuance of the open-label extension (OLE) period of the study, where all participants were receiving daily treatment with tadalafil.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/19941337
    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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