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    Clinical Trial Results:
    A multiple ascending dose study of Tadalafil to assess the pharmacokinetics and safety in a pediatric population with Pulmonary Arterial Hypertension

    Summary
    EudraCT number
    		 2011-001873-24
    Trial protocol
    		 ES   GB   PL  
    Global end of trial date
    03 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Oct 2019
    First version publication date
    13 Oct 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    H6D-MC-LVIG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01484431
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number: 12917
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to see how much study drug is in the blood of children with pulmonary arterial hypertension (PAH) after dosing to establish the correct dose for further clinical research.
    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
    17 Jul 2012
    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
    Canada: 5
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Spain: 2
    Worldwide total number of subjects
    19
    EEA total number of subjects
    12
    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)
    6
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Per protocol, the summary was based on weight cohorts.

    Pre-assignment
    Screening details
    		 This study contains 2 periods: Pharmacokinetics(PK)/safety Period 1 and an open-label safety extension Period 2. Period 1 is approximately 10 weeks (that is, approximately 5 consecutive weeks for each dose [low and high]). Period 2 is at least 2 years after participating in Period 1. Period 2 final data will be reported after study completion.

    Period 1
    Period 1 title
    Period 1: Low Dose and High Dose
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Light Weight: <25 kg
    Arm description
    		 Period 1: 2 milligram (mg) or 4 mg tadalafil administered once daily (QD) in oral suspension formulation for 5 weeks then 8 mg,10 mg,15 mg or 20 mg tadalafil was administered QD in oral suspension formulation for 5 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tadalafil
    Investigational medicinal product code
    Other name
    LY450190
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Period 1: 2 milligram (mg) or 4 mg tadalafil administered once daily (QD) in oral suspension formulation for 5 weeks then 8 mg,10 mg,15 mg or 20 mg tadalafil was administered QD in oral suspension formulation for 5 weeks.

    Arm title
    		 Middle Weight: 25 kg to <40 kg
    Arm description
    		 Period 1: 5 mg tadalafil tablet administered QD for 5 weeks then 10 mg, 15 mg or 20 mg tablet tadalafil administered QD for 5 weeks.
    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
    Period 1: 5 mg tadalafil tablet administered QD for 5 weeks then 10 mg, 15 mg or 20 mg tablet tadalafil administered QD for 5 weeks.

    Arm title
    		 Heavy Weight: ≥40 kg
    Arm description
    		 Period 1: 10 mg tadalafil tablet administered QD for 5 weeks then 20 mg or 40 mg tablet tadalafil administered QD for 5 weeks.
    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
    Period 1: 10 mg tadalafil tablet administered QD for 5 weeks then 20 mg or 40 mg tablet tadalafil administered QD for 5 weeks.

    Number of subjects in period 1
    		Light Weight: <25 kg Middle Weight: 25 kg to <40 kg Heavy Weight: ≥40 kg
    Started
    6
    7
    6
    Received 2 mg Low Dose
    1 [1]
    0 [2]
    0 [3]
    Received 4 mg Low Dose
    5 [4]
    0 [5]
    0 [6]
    Received 5 mg Low Dose
    0 [7]
    7
    0 [8]
    Received 10 mg Low Dose
    0 [9]
    0 [10]
    6
    Received 8 mg High Dose
    1 [11]
    0 [12]
    0 [13]
    Received 10 mg High Dose
    1 [14]
    1 [15]
    0 [16]
    Received 15 mg High Dose
    1 [17]
    1 [18]
    0 [19]
    Received 20 mg High Dose
    3 [20]
    5 [21]
    1 [22]
    Received 40 mg High Dose
    0 [23]
    0 [24]
    5 [25]
    Completed
    6
    6
    6
    Not completed
    0
    1
    0
         Physician decision
    -
    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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [7] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [8] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [9] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [10] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [11] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [12] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [13] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [14] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [15] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [16] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [17] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [18] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [19] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [20] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [21] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [22] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [23] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [24] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [25] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Light Weight: <25 kg
    Arm description
    		 Period 2: Open Label Extension for 2 years. 7 mg, 8 mg, 15 mg or 20 mg tadalafil administered once daily (QD) in oral suspension formulation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tadalafil
    Investigational medicinal product code
    Other name
    LY450190
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Period 2: Open Label Extension for 2 years. 7 mg, 8 mg, 15 mg or 20 mg tadalafil administered once daily (QD) in oral suspension formulation.

    Arm title
    		 Middle Weight: 25 kg to <40 kg
    Arm description
    		 Period 2: Open Label Extension for 2 years. 7.5 mg, 10 mg, 15 mg or 20 mg tadalafil administered once daily (QD) in oral tablet.
    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
    Period 2: Open Label Extension for 2 years. 7.5 mg, 10 mg, 15 mg or 20 mg tadalafil administered once daily (QD) in oral tablet.

    Arm title
    		 Heavy Weight: ≥40 kg
    Arm description
    		 Period 2: Open Label Extension for 2 years. 15 mg, 20 mg or 40 mg tadalafil administered once daily (QD) in oral tablet.
    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
    Period 2: Open Label Extension for 2 years. 15 mg, 20 mg or 40 mg tadalafil administered once daily (QD) in oral tablet.

    Number of subjects in period 2
    		Light Weight: <25 kg Middle Weight: 25 kg to <40 kg Heavy Weight: ≥40 kg
    Started
    6
    6
    6
    Received 7 mg
    1 [26]
    0 [27]
    0 [28]
    Received 7.5 mg
    0 [29]
    2 [30]
    0 [31]
    Received 8 mg
    1 [32]
    0 [33]
    0 [34]
    Received 10 mg
    0 [35]
    1 [36]
    0 [37]
    Received 15 mg
    1 [38]
    2 [39]
    1 [40]
    Received 20 mg
    3 [41]
    1 [42]
    4
    Receceived 40 mg
    0 [43]
    0 [44]
    1 [45]
    Completed
    5
    5
    4
    Not completed
    1
    1
    2
         Physician decision
    -
    -
    1
         Non-Compliance with Study Drug
    1
    -
    -
         Death
    -
    1
    1
    Notes
    [26] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [27] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [28] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [29] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [30] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [31] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [32] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [33] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [34] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [35] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [36] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [37] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [38] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [39] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [40] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [41] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [42] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [43] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [44] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.
    [45] - 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: Participants in each of the three arms (Light Weight: <25 kg , Middle Weight: 25 kg to <40 kg and Heavy Weight: ≥40 kg ) received different doses of drug during Low dose period 1, high dose period 1 and Period 2 therefore the numbers in the milestones individually do not add up to number started.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Light Weight: <25 kg
    Reporting group description
    		 Period 1: 2 milligram (mg) or 4 mg tadalafil administered once daily (QD) in oral suspension formulation for 5 weeks then 8 mg,10 mg,15 mg or 20 mg tadalafil was administered QD in oral suspension formulation for 5 weeks.

    Reporting group title
    Middle Weight: 25 kg to <40 kg
    Reporting group description
    		 Period 1: 5 mg tadalafil tablet administered QD for 5 weeks then 10 mg, 15 mg or 20 mg tablet tadalafil administered QD for 5 weeks.

    Reporting group title
    Heavy Weight: ≥40 kg
    Reporting group description
    		 Period 1: 10 mg tadalafil tablet administered QD for 5 weeks then 20 mg or 40 mg tablet tadalafil administered QD for 5 weeks.

    Reporting group values
    		 Light Weight: <25 kg Middle Weight: 25 kg to <40 kg Heavy Weight: ≥40 kg Total
    Number of subjects
    		 6 7 6 19
    Age categorical
    Units: Subjects
    Age continuous
    Participants who received at least one dose of study drug. Participants were first administered a low dose to explore PK of tadalafil and determine a high dose within the weight cohort. Per protocol, the summary was based on weight cohorts.
    Units: years
        arithmetic mean (full range (min-max))
    		 5.00 (2.5 to 8.0) 10.91 (7.3 to 17.9) 14.45 (11.3 to 17.6) -
    Gender categorical
    Units: Subjects
        Female
    		 4 5 4 13
        Male
    		 2 2 2 6
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 0 1
        Asian
    		 0 2 1 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 1 0 0 1
        White
    		 4 5 5 14
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0
    Region of Enrollment
    Units: Subjects
        Canada
    		 3 1 1 5
        United States
    		 1 0 1 2
        Poland
    		 1 2 2 5
        United Kingdom
    		 0 3 0 3
        France
    		 0 1 1 2
        Spain
    		 1 0 1 2

    End points

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    End points reporting groups
    Reporting group title
    Light Weight: <25 kg
    Reporting group description
    		 Period 1: 2 milligram (mg) or 4 mg tadalafil administered once daily (QD) in oral suspension formulation for 5 weeks then 8 mg,10 mg,15 mg or 20 mg tadalafil was administered QD in oral suspension formulation for 5 weeks.

    Reporting group title
    Middle Weight: 25 kg to <40 kg
    Reporting group description
    		 Period 1: 5 mg tadalafil tablet administered QD for 5 weeks then 10 mg, 15 mg or 20 mg tablet tadalafil administered QD for 5 weeks.

    Reporting group title
    Heavy Weight: ≥40 kg
    Reporting group description
    		 Period 1: 10 mg tadalafil tablet administered QD for 5 weeks then 20 mg or 40 mg tablet tadalafil administered QD for 5 weeks.
    Reporting group title
    Light Weight: <25 kg
    Reporting group description
    		 Period 2: Open Label Extension for 2 years. 7 mg, 8 mg, 15 mg or 20 mg tadalafil administered once daily (QD) in oral suspension formulation.

    Reporting group title
    Middle Weight: 25 kg to <40 kg
    Reporting group description
    		 Period 2: Open Label Extension for 2 years. 7.5 mg, 10 mg, 15 mg or 20 mg tadalafil administered once daily (QD) in oral tablet.

    Reporting group title
    Heavy Weight: ≥40 kg
    Reporting group description
    		 Period 2: Open Label Extension for 2 years. 15 mg, 20 mg or 40 mg tadalafil administered once daily (QD) in oral tablet.

    Primary: Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil

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    End point title
    		 Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil [1]
    End point description
    Population Pharmacokinetics: Area Under the Concentration Curve Versus Time at a Dosing Interval at Steady State (AUCtau) for Tadalafil . Analysis Population Description: All participants who received at least one dose of study drug and had evaluable PK data including all dose levels on Day 1, 14 and 49. Per protocol, the summary reflects potential exposure of the high dose within each weight cohort
    End point type
    Primary
    End point timeframe
    Period 1: Pre Dose and 2, 4, 8, 12, and 24 Hours Post Dose on Days 1, 14 and 49; with single dose measures on Day 1 and steady-state measurements on Days 14 and 49.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, statistical analysis were not planned for this outcome measure.
    End point values
    		 Light Weight: <25 kg Middle Weight: 25 kg to <40 kg Heavy Weight: ≥40 kg
    Number of subjects analysed
    6
    7
    6
    Units: nanograms* hour per milliliter(ng*hr/mL)
    median (confidence interval 90%)
        Not Taking Bosentan
    8170 (3850 to 16700)
    8390 (4130 to 18400)
    15200 (6980 to 31100)
        Taking Concomitant Bosentan
    4550 (2170 to 9450)
    5000 (2440 to 10600)
    8990 (4270 to 19500)
    No statistical analyses for this end point

    Primary: Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State

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    End point title
    		 Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State [2]
    End point description
    Population Pharmacokinetics: Average Concentration (Cmean,ss) of for Tadalafil at Steady-State. Analysis Population Description: All participants who received at least one dose of study drug and had evaluable PK data including all dose levels on Day 1, 14 and 49. Per protocol, the summary reflects potential exposure of the high dose within each weight cohort.
    End point type
    Primary
    End point timeframe
    Period 1: Pre Dose and 2, 4, 8, 12, and 24 Hours Post Dose on Days 1, 14 and 49; with single dose measures on Day 1 and steady-state measurements on Days 14 and 49.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, statistical analysis were not planned for this outcome measure.
    End point values
    		 Light Weight: <25 kg Middle Weight: 25 kg to <40 kg Heavy Weight: ≥40 kg
    Number of subjects analysed
    6
    7
    6
    Units: nanograms per milliliter (ng/mL)
    median (confidence interval 90%)
        Not Taking Bosentan
    340 (161 to 694)
    350 (172 to 767)
    633 (291 to 1300)
        Taking Concomitant Bosentan
    190 (90.4 to 394)
    209 (102 to 440)
    375 (178 to 815)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Clinical Worsening

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    End point title
    		 Percentage of Participants With Clinical Worsening
    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, 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) and an increase in the dose of endothelin receptor agonist (ERA) medication. Analysis Population Description: All participants who received at least one dose of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline Up to 27 Months
    End point values
    		 Light Weight: <25 kg Middle Weight: 25 kg to <40 kg Heavy Weight: ≥40 kg
    Number of subjects analysed
    6
    7
    6
    Units: percentage of participants
        number (not applicable)
    50.00
    28.57
    33.33
    No statistical analyses for this end point

    Secondary: Number of Participants With Palatability of the Tadalafil Suspension

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    End point title
    		 Number of Participants With Palatability of the Tadalafil Suspension [3]
    End point description
    The Taste Assessment Questionnaire (TAQ) questions were: TAQRES1: Please rate the bitterness level. TAQRES2: Please rate the sweetness level. TAQRES3: Please rate the aftertaste. TAQRES4: Please rate the overall acceptability of the taste for daily use. Analysis Population Description: Participants who received at least one oral suspension dose of study drug in the Light-weight cohort (≥2 years of age). Per protocol, palatability of the tadalafil suspension was evaluated in the Light-weight cohort only.
    End point type
    Secondary
    End point timeframe
    Day 35 (high dose)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Per protocol, only participants in Light Weight: <25 kg were analyzed for this outcome measure.
    End point values
    		 Light Weight: <25 kg
    Number of subjects analysed
    3
    Units: Count of Participants
        TAQRES1: Extremely bitter
    0
        TAQRES1: Very bitter
    0
        TAQRES1: Moderately bitter
    0
        TAQRES1: Slightly bitter
    0
        TAQRES1: Not bitter
    3
        TAQRES2: Extremely sweet
    1
        TAQRES2: Very sweet
    0
        TAQRES2: Moderately sweet
    1
        TAQRES2: Slightly sweet
    1
        TAQRES2: Not sweet
    0
        TAQRES3: Extreme aftertaste
    0
        TAQRES3: Strong aftertaste
    1
        TAQRES3: Moderate aftertaste
    0
        TAQRES3:Slight aftertaste
    0
        TAQRES3:No aftertaste
    2
        TAQRES4: Not acceptable
    0
        TAQRES4: Slightly acceptable
    0
        TAQRES4: Acceptable
    2
        TAQRES4: Very acceptable
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up To 27 Months
    Adverse event reporting additional description
    All participants who received at least one dose of study drug. Participants were first administered a low dose to explore PK of tadalafil and determine a high dose within the weight cohort. Per protocol, the summary was based on weight cohorts.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Light Weight Cohort
    Reporting group description
    		 Period 1: 2 milligram (mg) or 4 mg tadalafil administered once daily (QD) in oral suspension formulation for 5 weeks then 8 mg,10 mg,15 mg or 20 mg tadalafil was administered QD in oral suspension formulation for 5 weeks. Period 2: Open Label Extension for 2 years. 7 mg, 8 mg, 15 mg or 20 mg tadalafil administered once daily (QD) in oral suspension formulation.

    Reporting group title
    Middle Weight Cohort
    Reporting group description
    		 Period 1: 5 mg tadalafil tablet administered QD for 5 weeks then 10 mg, 15 mg or 20 mg tablet tadalafil administered QD for 5 weeks. Period 2: Open Label Extension for 2 years. 7.5 mg, 10 mg, 15 mg or 20 mg tadalafil administered once daily (QD) in oral tablet.

    Reporting group title
    Heavy Weight Cohort
    Reporting group description
    		 Period 1: 10 mg tadalafil tablet administered QD for 5 weeks then 20 mg or 40 mg tablet tadalafil administered QD for 5 weeks. Period 2: Open Label Extension for 2 years. 15 mg, 20 mg or 40 mg tadalafil administered once daily (QD) in oral tablet.

    Serious adverse events
    		 Light Weight Cohort Middle Weight Cohort Heavy Weight Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 7 (57.14%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    cardiac failure
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    febrile convulsion
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    presyncope
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    seizure
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    syncope
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    pyrexia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    ovarian cyst
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [1]
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    pulmonary arterial hypertension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Infections and infestations
    pneumonia viral
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    viral infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    type 1 diabetes mellitus
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
    Justification: Gender specific event
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Light Weight Cohort Middle Weight Cohort Heavy Weight Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    skin papilloma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    flushing
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    haematoma
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    hypertension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    orthostatic hypotension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    vasodilatation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    catheter site pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    chest discomfort
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    disease progression
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    face oedema
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    puncture site pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    4
    pyrexia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    7
    1
    1
    thirst
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Immune system disorders
    allergy to arthropod sting
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    dysmenorrhoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [2]
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    menorrhagia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [3]
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    ovarian cyst
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed [4]
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    bronchospasm
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    3
    catarrh
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    cough
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    1
    dyspnoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    epistaxis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    oropharyngeal pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 7 (42.86%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    productive cough
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    pulmonary arterial hypertension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    rhinitis allergic
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    rhinorrhoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    1
    Psychiatric disorders
    abnormal behaviour
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    agitation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    anxiety
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Investigations
    cytogenetic analysis abnormal
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    electrocardiogram qt prolonged
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    exercise test abnormal
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    oxygen saturation decreased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    serum ferritin decreased
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    arthropod bite
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    radius fracture
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Congenital, familial and genetic disorders
    dermoid cyst
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    angina pectoris
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    2
    cyanosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    palpitations
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    disturbance in attention
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    dizziness
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    dizziness postural
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    headache
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    2 / 6 (33.33%)
         occurrences all number
    2
    2
    2
    lethargy
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    migraine
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    syncope
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    tension headache
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    iron deficiency anaemia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Ear and labyrinth disorders
    ear pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    2
    Eye disorders
    eye pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    hypermetropia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    swelling of eyelid
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    vision blurred
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    abdominal distension
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    abdominal pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    3
    1
    0
    abdominal pain upper
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    anal fissure
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    constipation
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    diarrhoea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    1
    faeces soft
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    haematochezia
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    nausea
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    toothache
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    vomiting
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    2
    2
    1
    Skin and subcutaneous tissue disorders
    dermatitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    dry skin
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    ecchymosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    0
    hyperkeratosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    petechiae
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    pruritus
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    rash
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    swelling face
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    urticaria
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    musculoskeletal chest pain
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    pain in extremity
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    1
    pain in jaw
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    ear infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    gastroenteritis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    4
    0
    1
    gastrointestinal infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    influenza
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    laryngitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    nasopharyngitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    2 / 6 (33.33%)
         occurrences all number
    5
    1
    7
    otitis media acute
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    pharyngitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    respiratory tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    5
    respiratory tract infection viral
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    sinusitis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    toxoplasmosis
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    upper respiratory tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    2
    urinary tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    viral infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    viral upper respiratory tract infection
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    decreased appetite
    alternative dictionary used: MedDRA 21.1
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    Notes
    [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: Gender specific event
    [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: Gender specific event
    [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: Gender specific event

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Apr 2012
    Amendment b: Substantial due to significant changes to the Inclusion/Exclusion Criteria.
    09 Aug 2015
    Amendment d: Revised tadalafil risk profile with a safety consideration of newly approved guanylate cyclase stimulator under the section of interaction of tadalafil with other drugs. Other changes with Inclusion/Exclusion criteria.

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

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