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    Clinical Trial Results:
    A double blind, randomised, placebo-controlled trial to evaluate the dose-exposure and safety of nintedanib per os on top of standard of care for 24 weeks, followed by open label treatment with nintedanib of variable duration, in children and adolescents (6 to 17 year-old) with clinically significant fibrosing Interstitial Lung Disease

    Summary
    EudraCT number
    		 2018-004530-14
    Trial protocol
    		 ES   PT   FI   NO   DK   FR   CZ   PL   GR   HU   GB   DE   BE   IT  
    Global end of trial date
    24 May 2022

    Results information
    Results version number
    		 v3(current)
    This version publication date
    16 Apr 2023
    First version publication date
    15 Dec 2022
    Other versions
    		 v1 , v2
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1199-0337
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001006-PIP05-18
    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
    15 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study is to evaluate dose-exposure and safety of nintedanib in children and adolescents with fibrosing Interstitial Lung Disease (ILD).
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Treatment interruption and dose reduction were allowed as medically indicated.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Feb 2020
    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: 1
    Country: Number of subjects enrolled
    United States: 12
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Ukraine: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Mexico: 2
    Worldwide total number of subjects
    39
    EEA total number of subjects
    16
    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)
    12
    Adolescents (12-17 years)
    27
    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
    		 This was a multicenter, multinational clinical trial in children and adolescents (6 to 17 years old) with clinically significant fibrosing Interstitial Lung Disease (ILD) in two parts. A randomised, placebo-controlled, double-blind period (DBP) of 24 weeks was followed by an open-label Nintedanib period (OLNP) of variable duration.

    Pre-assignment
    Screening details
    		 Only subjects that met all inclusion and none exclusion criteria could enter the study. Subjects were free to withdraw at any time for any reason given. Subjects were monitored throughout the trial conduct. Treatment interruption and dose reduction were allowed as medically indicated.

    Period 1
    Period 1 title
    Double-blind period (DBP)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    Subjects, investigators and any other site personnel remained blinded with regard to the randomised treatment assignments until after the final database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DBP+OLNP: Randomised to placebo
    Arm description
    		 This arm shows placebo randomised subjects treated orally with a Nintedanib matching placebo soft capsule twice daily (DBP). Subjects who continued with the open-label Nintedanib period (OLNP) after the DBP switched to active Nintedanib treatment and were treated orally with Nintedanib twice daily (OLNP). Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dosing interval was approximately 12 hours from one dose to the next dose in the DBP and OLNP. In this arm subjects received placebo first (DBP), then Nintedanib (OLNP). DBP: Planned was from 1st randomised trial to last blinded drug intake. OLNP: Planned was from 1st open-label to last open-label Nintedanib intake.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dose interval was approximately 12 hours from one to the next dose.

    Arm title
    		 DBP+OLNP: Randomised to Nintedanib
    Arm description
    		 This arm shows Nintedanib randomised subjects treated orally with Nintedanib in the DBP and OLNP twice daily. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dosing interval was approximately 12 hours from one dose to the next dose in the DBP and OLNP. In this arm subjects received Nintedanib only (DBP+OLNP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dose interval was approximately 12 hours from one to the next dose.

    Number of subjects in period 1
    		DBP+OLNP: Randomised to placebo DBP+OLNP: Randomised to Nintedanib
    Started
    13
    26
    Completed
    11
    21
    Not completed
    2
    5
         Discontinued treatment due to adverse event
    -
    2
         Completed prematurely due to administrative EoT
    2
    2
         Discontinued treatment due to other reason
    -
    1
    Period 2
    Period 2 title
    Open-label Nintedanib period (OLNP)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding in the OLNP

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DBP+OLNP: Randomised to placebo
    Arm description
    		 This arm shows placebo randomised subjects treated orally with a Nintedanib matching placebo soft capsule twice daily (DBP). Subjects who continued with the open-label Nintedanib period (OLNP) after the DBP switched to active Nintedanib treatment and were treated orally with Nintedanib twice daily (OLNP). Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dosing interval was approximately 12 hours from one dose to the next dose in the DBP and OLNP. In this arm subjects received placebo first (DBP), then Nintedanib (OLNP). DBP: Planned was from 1st randomised trial to last blinded drug intake. OLNP: Planned was from 1st open-label to last open-label Nintedanib intake.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Medication dosage was per administration 50 milligram (mg) [2 capsules with strength 25 mg],75 mg [3 capsules with strength 25 mg], 100 mg [1 capsule with strength 100 mg or 4 capsules with strength 25 mg] or 150 mg [1 capsule with strength 150 mg or 6 capsules with strength 25 mg] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dose interval was approximately 12 hours from one to the next dose.

    Arm title
    		 DBP+OLNP: Randomised to Nintedanib
    Arm description
    		 This arm shows Nintedanib randomised subjects treated orally with Nintedanib in the DBP and OLNP twice daily. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dosing interval was approximately 12 hours from one dose to the next dose in the DBP and OLNP. In this arm subjects received Nintedanib only (DBP+OLNP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nintedanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Medication dosage was per administration 50 milligram (mg) [2 capsules with strength 25 mg],75 mg [3 capsules with strength 25 mg], 100 mg [1 capsule with strength 100 mg or 4 capsules with strength 25 mg] or 150 mg [1 capsule with strength 150 mg or 6 capsules with strength 25 mg] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dose interval was approximately 12 hours from one to the next dose.

    Number of subjects in period 2
    		DBP+OLNP: Randomised to placebo DBP+OLNP: Randomised to Nintedanib
    Started
    11
    21
    Completed
    11
    20
    Not completed
    0
    1
         Discontinuation of trial medication - other reason
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DBP+OLNP: Randomised to placebo
    Reporting group description
    		 This arm shows placebo randomised subjects treated orally with a Nintedanib matching placebo soft capsule twice daily (DBP). Subjects who continued with the open-label Nintedanib period (OLNP) after the DBP switched to active Nintedanib treatment and were treated orally with Nintedanib twice daily (OLNP). Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dosing interval was approximately 12 hours from one dose to the next dose in the DBP and OLNP. In this arm subjects received placebo first (DBP), then Nintedanib (OLNP). DBP: Planned was from 1st randomised trial to last blinded drug intake. OLNP: Planned was from 1st open-label to last open-label Nintedanib intake.

    Reporting group title
    DBP+OLNP: Randomised to Nintedanib
    Reporting group description
    		 This arm shows Nintedanib randomised subjects treated orally with Nintedanib in the DBP and OLNP twice daily. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dosing interval was approximately 12 hours from one dose to the next dose in the DBP and OLNP. In this arm subjects received Nintedanib only (DBP+OLNP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.

    Reporting group values
    		 DBP+OLNP: Randomised to placebo DBP+OLNP: Randomised to Nintedanib Total
    Number of subjects
    		 13 26 39
    Age categorical
    Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 4 8 12
        Adolescents (12-17 years)
    		 9 18 27
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    Units: years
        arithmetic mean (standard deviation)
    		 12.9 ( 2.8 ) 12.5 ( 3.6 ) -
    Sex: Female, Male
    Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    Units: Subjects
        Female
    		 5 10 15
        Male
    		 8 16 24
    Race (NIH/OMB)
    Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 0 2 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 3 3
        White
    		 12 19 31
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 1 1
    Ethnicity (NIH/OMB)
    Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    Units: Subjects
        Hispanic or Latino
    		 5 7 12
        Not Hispanic or Latino
    		 8 18 26
        Unknown or Not Reported
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    DBP+OLNP: Randomised to placebo
    Reporting group description
    		 This arm shows placebo randomised subjects treated orally with a Nintedanib matching placebo soft capsule twice daily (DBP). Subjects who continued with the open-label Nintedanib period (OLNP) after the DBP switched to active Nintedanib treatment and were treated orally with Nintedanib twice daily (OLNP). Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dosing interval was approximately 12 hours from one dose to the next dose in the DBP and OLNP. In this arm subjects received placebo first (DBP), then Nintedanib (OLNP). DBP: Planned was from 1st randomised trial to last blinded drug intake. OLNP: Planned was from 1st open-label to last open-label Nintedanib intake.

    Reporting group title
    DBP+OLNP: Randomised to Nintedanib
    Reporting group description
    		 This arm shows Nintedanib randomised subjects treated orally with Nintedanib in the DBP and OLNP twice daily. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dosing interval was approximately 12 hours from one dose to the next dose in the DBP and OLNP. In this arm subjects received Nintedanib only (DBP+OLNP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.
    Reporting group title
    DBP+OLNP: Randomised to placebo
    Reporting group description
    		 This arm shows placebo randomised subjects treated orally with a Nintedanib matching placebo soft capsule twice daily (DBP). Subjects who continued with the open-label Nintedanib period (OLNP) after the DBP switched to active Nintedanib treatment and were treated orally with Nintedanib twice daily (OLNP). Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dosing interval was approximately 12 hours from one dose to the next dose in the DBP and OLNP. In this arm subjects received placebo first (DBP), then Nintedanib (OLNP). DBP: Planned was from 1st randomised trial to last blinded drug intake. OLNP: Planned was from 1st open-label to last open-label Nintedanib intake.

    Reporting group title
    DBP+OLNP: Randomised to Nintedanib
    Reporting group description
    		 This arm shows Nintedanib randomised subjects treated orally with Nintedanib in the DBP and OLNP twice daily. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. The dosing interval was approximately 12 hours from one dose to the next dose in the DBP and OLNP. In this arm subjects received Nintedanib only (DBP+OLNP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.

    Subject analysis set title
    DBP+OLNP: 6 to < 12 years - exposed to Nintedanib
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This arm shows subjects aged 6 to < 12 years old who were exposed to Nintedanib only, either randomised placebo (treated with Nintedanib in the OLNP only) and randomised Nintedanib (treated with Nintedanib in both, DBP and OLNP).The 6 to < 12 years old subjects were treated orally with Nintedanib twice daily with a dose interval of approximately 12 hours from one dose to the next dose. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received Nintedanib only (OLNP or DBP+OLNP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.

    Subject analysis set title
    DBP+OLNP: 12 to < 18 years - exposed to Nintedanib
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This arm shows subjects aged 12 to <18 years old who were exposed to Nintedanib only either randomised placebo (treated with Nintedanib in the OLNP only) and randomised Nintedanib (treated with Nintedanib in both, DBP and OLNP). The 12 to 18 years old subjects were treated orally with Nintedanib twice daily with a dose interval of approximately 12 hours from one dose to the next dose. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received Nintedanib only (OLNP or DBP+OLNP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.

    Subject analysis set title
    DBP: Randomised to placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows placebo randomised subjects treated orally with a Nintedanib matching placebo soft capsule twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received placebo only (DBP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to Nintedanib
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows Nintedanib randomised subjects treated orally with Nintedanib in the DBP twice daily with a dose interval of approximately 12 hours from one dose to the next dose. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received Nintedanib only (DBP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    OLNP: Randomised to placebo and switched to Nintedanib
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows subjects who continued with the open-label Nintedanib period (OLNP) after the DBP, switched to active Nintedanib treatment in the OLNP and were treated orally with Nintedanib twice daily with a dose interval of approximately 12 hours from one dose to the next dose. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received placebo first (DBP) and then Nintedanib (OLNP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.

    Subject analysis set title
    DBP+OLNP: Randomised to placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows subjects who continued with the open-label Nintedanib period (OLNP) after the DBP, switched to active Nintedanib treatment in the OLNP and were treated orally with Nintedanib twice daily with a dose interval of approximately 12 hours from one dose to the next dose. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received placebo first (DBP) and then Nintedanib (OLNP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.

    Subject analysis set title
    DBP + OLNP: Randomised to Nintedanib
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows Nintedanib randomised subjects treated orally with Nintedanib in the DBP and OLNP twice daily with a dose interval of approximately 12 hours from one dose to the next dose. Medication dosage was per administration 50 milligram (mg) [2x25 mg capsules (cap)],75 mg [3x25 mg cap], 100 mg [1x100 mg cap or 4x25 mg cap] or 150 mg [1x150 mg cap or 6x25 mg cap] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received Nintedanib in both periods (DBP + OLNP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.

    Subject analysis set title
    DBP: Randomised to placebo - capsule size of 25 mg capsule
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows placebo randomised subjects treated orally with placebo soft capsules of 25 milligram (mg) with a capsule size of 5 millimeter (mm) diameter and 8 mm length, oval shaped, twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage per administration was 50 milligram (mg) [2 capsules with strength 25 mg], 75 mg [3 capsules with strength 25 mg], 100 mg [4 capsules with strength 25 mg] or 150 mg [6 capsules with strength 25 mg] based on the subject's weight at baseline (= 0 weeks). In this arm subjects received placebo only (DBP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to Nintedanib - capsule size of 25 mg capsule
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows Nintedanib randomised subjects treated orally with Nintedanib soft capsules of 25 milligram (mg) with a capsule size of 5 millimeter (mm) diameter and 8 mm length, oval shaped, twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage per administration was 50 milligram (mg) [2 capsules with strength 25 mg], 75 mg [3 capsules with strength 25 mg], 100 mg [4 capsules with strength 25 mg] or 150 mg [6 capsules with strength 25 mg] based on the subject's weight at baseline (= 0 weeks). In this arm subjects received Nintedanib only (DBP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to placebo - capsule size of 100 mg capsule
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows placebo randomised subjects treated orally with placebo soft capsules of 100 mg with a capsule size of 6 mm diameter and 16 mm length, oblong shaped, twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage per administration was 100 mg [1 capsules with strength 100 mg] based on the subject's weight at baseline (= 0 weeks). In this arm subjects received placebo only (DBP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to Nintedanib - capsule size of 100 mg capsule
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows Nintedanib randomised subjects treated orally with Nintedanib soft capsules of 100 mg with a capsule size of 6 mm diameter and 16 mm length, oblong shaped, twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage per administration was 100 mg [1 capsules with strength 100 mg] based on the subject's weight at baseline (= 0 weeks). In this arm subjects received Nintedanib only (DBP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to placebo - capsule size of 150 mg capsule
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows placebo randomised subject treated orally with placebo soft capsules of 150 mg with a capsule size of 7 mm diameter and 18 mm length, oblong shaped, twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage per administration was 150 mg [1 capsules with strength 150 mg] based on the subject's weight at baseline (= 0 weeks). In this arm subjects received placebo only (DBP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to Nintedanib - capsule size of 150 mg capsule
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows Nintedanib randomised subjects treated orally with Nintedanib soft capsules of 150 mg with a capsule size of 7 mm diameter and 18 mm length, oblong shaped, twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage per administration was 150 mg [1 capsules with strength 150 mg] based on the subject's weight at baseline (= 0 weeks). In this arm subjects received Nintedanib only (DBP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to placebo - 2 capsules
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows placebo randomised subjects treated orally with 1 Nintedanib matching placebo soft capsule twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage was per administration 100 mg [1 capsule with strength 100 mg] or 150 mg [1 capsule with strength 150 mg] based on the subject's weight at baseline (= 0 weeks). In this arm subjects received placebo only (DBP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to Nintedanib - 2 capsules
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows Nintedanib randomised subjects treated orally with 1 Nintedanib soft capsule twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage was per administration 100 mg [1 capsule with strength 100 mg] or 150 mg [1 capsule with strength 150 mg] based on the subject's weight at baseline (= 0 weeks). In this arm subjects received Nintedanib only (DBP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to placebo - 4 capsules
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows placebo randomised subjects treated orally with 2 Nintedanib matching placebo soft capsule twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage was per administration 50 milligram (mg) [2 capsules with strength 25 mg], based on the subject's weight at baseline (= 0 weeks). In this arm subjects received placebo only (DBP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to Nintedanib - 4 capsules
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows Nintedanib randomised subjects treated orally with 2 Nintedanib soft capsule twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage was per administration 50 milligram (mg) [2 capsules with strength 25 mg], based on the subject's weight at baseline (= 0 weeks). In this arm subjects received Nintedanib only (DBP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to placebo - 6 capsules
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows placebo randomised subjects treated orally with 3 Nintedanib matching placebo soft capsule twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage was per administration 75 mg [3 capsules with strength 25 mg] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received placebo only (DBP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to Nintedanib - 6 capsules
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows Nintedanib randomised subjects treated orally with 3 Nintedanib soft capsule twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage was per administration 75 mg [3 capsules with strength 25 mg] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received Nintedanib only (DBP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arm. DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Subject analysis set title
    DBP: Randomised to placebo - >6 capsules
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This arm shows placebo randomised subjects treated orally with >3 Nintedanib matching placebo soft capsule twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage was per administration 100 mg [4 capsules with strength 25 mg] or 150 mg [6 capsules with strength 25 mg] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received placebo only (DBP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Primary: Area under the plasma concentration-time curve at steady state (AUCτ,ss) based on sampling at steady state (at Week 2 and Week 26)

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    End point title
    		 Area under the plasma concentration-time curve at steady state (AUCτ,ss) based on sampling at steady state (at Week 2 and Week 26) [1]
    End point description
    Area under the plasma concentration-time curve at steady state (AUCt,ss) based on sampling at steady state (at Week 2 and Week 26) after multiple oraladministration of Nintedanib by age group over all treatments. Values of samples taken at Week 2 (for randomised Nintedanib subjects) and at Week 26 (for randomised placebo subjects) were used. Missing values at Week 2 of randomised Nintedanib subjects were replaced with values taken at Week 26. Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the treated set (TS) who provide at least one pharmacokinetic (PK) endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
    End point type
    Primary
    End point timeframe
    At Week 2 and at Week 26: at 5 minutes before and at 0, 1, 2, 3, 4, 6, and 8 hours post administration of the morning dose
    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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    		 DBP+OLNP: 6 to < 12 years - exposed to Nintedanib DBP+OLNP: 12 to < 18 years - exposed to Nintedanib
    Number of subjects analysed
    10
    23
    Units: Hours timesnanogram per mililiter
        geometric mean (geometric coefficient of variation)
    175 ( 85.1 )
    167 ( 83.6 )
    No statistical analyses for this end point

    Primary: Number of subjects with treatment-emergent adverse events during the double-blind period

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    End point title
    		 Number of subjects with treatment-emergent adverse events during the double-blind period [2]
    End point description
    Treatment-emergent was defined as: Adverse events with onset or worsening on or after date of treatment start until end of double-blind period (defined as the day before first intake of open-label nintedanib or last double-blind drug intake + residual effect period, whichever is earlier) were considered as treatment-emergent and were included in the analysis. Adverse events were counted under the treatment as randomized for the double-blind period. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    From first drug administration until the earlier of (i) first intake of open−label nintedanib (exclusive) and (ii) last drug intake, up to 28 weeks
    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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Subjects
    11
    22
    No statistical analyses for this end point

    Secondary: Number of subjects with at least one treatment-emergent pathological finding of epiphyseal growth plate on imaging up to week 24, and week 52

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    End point title
    		 Number of subjects with at least one treatment-emergent pathological finding of epiphyseal growth plate on imaging up to week 24, and week 52
    End point description
    Number of subjects with at least one treatment-emergent pathological finding of the epiphyseal growth plate imaging (Magnetic Resonance Imaging (MRI)s/x-rays) were analyzed cumulatively and based on central review. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Up to Week 24 (included values at Week 12 and Week 24); Up to Week 52 (included values at Week 12, 24, 36 and 52)
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Subjects
        At Week 24
    1
    2
        At Week 52
    2
    3
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent pathological findings on dental examination or imaging up to week 24

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    End point title
    		 Number of subjects with treatment-emergent pathological findings on dental examination or imaging up to week 24
    End point description
    Number of subjects with treatment-emergent pathological findings on dental examination (clinical examination) based on dentist assessment or imaging (panoramic x-ray) based on central review were analyzed. Number of subjects with treatment-emergent pathological findings on dental imaging were analyzed cumulatively. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Dental examination: at Week 12 and Week 24; Dental imaging: at Week 24
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Subjects
        Dental examination: Pathological findings
    1
    5
        Dental imaging: Stunted growth of dental root
    0
    6
        Dental imaging: Accelerated growth of dental root
    0
    0
        Dental imaging: extra / supernumerary teeth
    0
    0
        Dental imaging: Impacted permanent teeth
    2
    4
        Dental imaging: Additional findings
    1
    5
        Dental imaging: Other findings
    2
    1
    No statistical analyses for this end point

    Secondary: Number of subjects with at least one treatment-emergent pathological findings on dental examination or imaging up to week 52

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    End point title
    		 Number of subjects with at least one treatment-emergent pathological findings on dental examination or imaging up to week 52
    End point description
    Number of subjects with treatment-emergent pathological findings on dental examination (clinical examination) based on dentist assessment or imaging (panoramic x-ray) based on central review were analyzed. Number of subjects with treatment-emergent pathological findings on dental imaging were analyzed cumulatively. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Dental examination: at Week 12, 24, 36, and Week 52; Dental imaging: at Week 24 and at Week 52.
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Subjects
        Dental examination: Pathological findings
    3
    7
        Dental imaging: Stunted growth of dental root
    0
    6
        Dental imaging: Accelerated growth of dental root
    0
    0
        Dental imaging: extra / supernumerary teeth
    0
    0
        Dental imaging: Impacted permanent teeth
    2
    5
        Dental imaging: Additional findings
    1
    6
        Dental imaging: Other findings
    3
    2
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment-emergent adverse events over the whole trial

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    End point title
    		 Number of subjects with treatment-emergent adverse events over the whole trial
    End point description
    Treatment-emergent was defined as: Adverse events with onset or worsening on or after date of treatment start until last drug intake + residual effect period was considered as treatment-emergent and was included in the analysis. Adverse events were counted under the treatment as randomized for the double-blind period. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    From first drug administration until the last drug intake, up to 92 weeks
    End point values
    		 DBP: Randomised to placebo OLNP: Randomised to placebo and switched to Nintedanib DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    11
    26
    Units: Subjects
    11
    11
    26
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in height at Week 24

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    End point title
    		 Absolute change from baseline in height at Week 24
    End point description
    Absolute change from baseline in height at Week 24 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was taken per time point. Absolute change from baseline in height at Week 24 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements pre-administration at -4 weeks and at 0, 12, 24, 36, 52, 64, 76, and 88 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    13
    25
    Units: Centimeter
        least squares mean (confidence interval 95%)
    1.3 (0.6 to 1.9)
    1.3 (0.8 to 1.8)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    No formal hypotheses were tested
    Comparison groups
    DBP: Randomised to placebo v DBP: Randomised to Nintedanib
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9858
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Secondary: Absolute change from baseline in height at Week 52

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    End point title
    		 Absolute change from baseline in height at Week 52
    End point description
    Absolute change from baseline in height at Week 52 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was taken per time point. Absolute change from baseline in height at Week 52 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subjects. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements pre-administration at -4 weeks and at 0, 12, 24, 36, 52, 64, 76, and 88 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    25
    Units: Centimeter
        least squares mean (confidence interval 95%)
    2.8 (1.5 to 4.2)
    2.8 (1.8 to 3.8)
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    No formal hypotheses were tested
    Comparison groups
    DBP+OLNP: Randomised to placebo v DBP + OLNP: Randomised to Nintedanib
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9769
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8

    Secondary: Absolute change from baseline in height at Week 76

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    End point title
    		 Absolute change from baseline in height at Week 76
    End point description
    Absolute change from baseline in height at Week 76 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was taken per time point. MMRM has been calculated but did not provide estimates for this time point due to low sample size. Thus, change in height from baseline to Week 76 was analyzed descriptively only. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Measurements were assessed at Week 0 and at Week 76
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    3
    4
    Units: Centimeter
    arithmetic mean (standard deviation)
        At Baseline
    143.7 ( 11.2 )
    162.5 ( 15.8 )
        At Week 76
    150.0 ( 15.7 )
    165.5 ( 13.0 )
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in sitting height at Week 24

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    End point title
    		 Absolute change from baseline in sitting height at Week 24
    End point description
    Absolute change from baseline in sitting height at Week 24 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was taken per time point. Absolute change from baseline in sitting height at Week 24 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements pre-administration at -4 weeks and at 0, 12, 24, 36, 52, 64, 76, and 88 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    6
    15
    Units: Centimeters
        least squares mean (confidence interval 95%)
    1.0 (-1.3 to 3.4)
    2.1 (0.6 to 3.6)
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    DBP: Randomised to placebo v DBP: Randomised to Nintedanib
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.4442
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 4
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4
    Notes
    [3] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in sitting height at Week 52

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    End point title
    		 Absolute change from baseline in sitting height at Week 52
    End point description
    Absolute change from baseline in sitting height at Week 52 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was taken per time point. MMRM has been calculated but did not provide estimates for this time point due to low sample size. Thus, change in sitting height from baseline to Week 52 was analyzed descriptively only. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication. Only subjects with non-missing results were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Measurements were assessed at Week 0 and at Week 52
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    3
    7
    Units: Centimeters
    arithmetic mean (standard deviation)
        At Baseline
    78.7 ( 11.8 )
    77.6 ( 9.4 )
        At Week 52
    79.0 ( 12.2 )
    79.3 ( 8.6 )
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in sitting height at Week 76

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    End point title
    		 Absolute change from baseline in sitting height at Week 76
    End point description
    Absolute change from baseline in sitting height at Week 76 was measured with a stadiometer 3 times at each time point. The average of these 3 measurements was take per time point. MMRM has been calculated but did not provide estimates for this time point due to low sample size. Thus, change in sitting height from baseline to Week 76 was analyzed descriptively only. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication. Only subjects with non-missing results were included in the analysis. 99999= Not calculable
    End point type
    Secondary
    End point timeframe
    Measurements were assessed at Week 0 and at Week 76
    End point values
    		 DBP+OLNP: Randomised to placebo DBP+OLNP: Randomised to Nintedanib
    Number of subjects analysed
    1
    2
    Units: Centimeters
    arithmetic mean (standard deviation)
        At Baseline
    65.0 ( 99999 )
    83.0 ( 4.2 )
        At Week 76
    65.0 ( 99999 )
    84.5 ( 3.5 )
    No statistical analyses for this end point

    Secondary: Absolute change from baseline in leg length at Week 24 - left

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    End point title
    		 Absolute change from baseline in leg length at Week 24 - left
    End point description
    Absolute change from baseline in left leg length at Week 24 was assessed by measuring distance between anterior iliac spine and medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point. Absolute change from baseline in left leg length at Week 24 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    13
    23
    Units: Centimeters
        least squares mean (confidence interval 95%)
    1.6 (0.3 to 2.9)
    1.7 (0.8 to 2.7)
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    DBP: Randomised to placebo v DBP: Randomised to Nintedanib
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.882
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8
    Notes
    [4] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in leg length at Week 52 - left

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    End point title
    		 Absolute change from baseline in leg length at Week 52 - left
    End point description
    Absolute change from baseline in left leg length at Week 52 was assessed by measuring distance between anterior iliac spine and medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point. Absolute change from baseline in left leg length at Week 52 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    23
    Units: Centimeter
        least squares mean (confidence interval 95%)
    2.8 (0.3 to 5.4)
    2.9 (0.9 to 4.9)
    Statistical analysis title
    		 Statistical analysis 5
    Statistical analysis description
    No formal hypotheses were tested
    Comparison groups
    DBP+OLNP: Randomised to placebo v DBP + OLNP: Randomised to Nintedanib
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.9652
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 3.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.6

    Secondary: Absolute change from baseline in leg length at Week 76 - left

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    End point title
    		 Absolute change from baseline in leg length at Week 76 - left
    End point description
    Absolute change from baseline in left leg length at Week 76 was assessed by measuring distance between anterior iliac spine and medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point. Absolute change from baseline in left leg length at Week 76 was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 76 are reported in the table below
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    23
    Units: Centimeter
        least squares mean (confidence interval 95%)
    5.2 (-0.0 to 10.5)
    2.6 (-1.5 to 6.7)
    Statistical analysis title
    		 Statistical analysis 6
    Statistical analysis description
    No formal hypotheses were tested
    Comparison groups
    DBP+OLNP: Randomised to placebo v DBP + OLNP: Randomised to Nintedanib
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4084
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    -2.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.3
         upper limit
    		 4
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.1

    Secondary: Absolute change from baseline in leg length at Week 24 - right

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    End point title
    		 Absolute change from baseline in leg length at Week 24 - right
    End point description
    Absolute change from baseline in right leg length at Week 24 was assessed by measuring distance between anterior iliac spine and medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point. Absolute change from baseline in right leg length at Week 24 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    13
    23
    Units: Centimeters
        least squares mean (confidence interval 95%)
    1.6 (0.3 to 2.9)
    1.6 (0.6 to 2.6)
    Statistical analysis title
    		 Statistical analysis 7
    Comparison groups
    DBP: Randomised to placebo v DBP: Randomised to Nintedanib
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 = 0.9928
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.6
         upper limit
    		 1.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8
    Notes
    [5] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in leg length at Week 52 - right

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    End point title
    		 Absolute change from baseline in leg length at Week 52 - right
    End point description
    Absolute change from baseline in right leg length at Week 52 was assessed by measuring distance between anterior iliac spine and medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point. Absolute change from baseline in right leg length at Week 52 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    23
    Units: Centimeter
        least squares mean (confidence interval 95%)
    2.8 (0.4 to 5.1)
    3.4 (1.6 to 5.2)
    Statistical analysis title
    		 Statistical analysis 8
    Statistical analysis description
    No formal hypotheses were tested
    Comparison groups
    DBP+OLNP: Randomised to placebo v DBP + OLNP: Randomised to Nintedanib
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.6366
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.3
         upper limit
    		 3.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4

    Secondary: Absolute change from baseline in leg length at Week 76 - right

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    End point title
    		 Absolute change from baseline in leg length at Week 76 - right
    End point description
    Absolute change from baseline in right leg length at Week 76 was assessed by measuring distance between anterior iliac spine and medial malleolus 3 times at each leg and each time point. The average of these 3 measurements was taken per time point. Absolute change from baseline in right leg length was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 12, 24, 36, 52, 64, and 76 weeks after first drug administration. MMRM values at Week 76 are reported in the table below
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    23
    Units: Centimeter
        least squares mean (confidence interval 95%)
    3.9 (-0.5 to 8.3)
    4.3 (0.8 to 7.7)
    Statistical analysis title
    		 Statistical analysis 9
    Statistical analysis description
    No formal hypotheses were tested
    Comparison groups
    DBP+OLNP: Randomised to placebo v DBP + OLNP: Randomised to Nintedanib
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8823
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted mean difference
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.2
         upper limit
    		 5.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.3

    Secondary: Absolute change from baseline in Forced Vital Capacity (FVC) % predicted at Week 24

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    End point title
    		 Absolute change from baseline in Forced Vital Capacity (FVC) % predicted at Week 24
    End point description
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. The predicted values were calculated according to the Global Lungs Initiative (GLI) 2012 equations. Absolute change from baseline in FVC % predicted was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements pre-administration at -4 weeks and at 0, 2, 6, 12, 24, 26, 36, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Percentage of predicted FVC
        least squares mean (confidence interval 95%)
    -0.8939 (-4.6090 to 2.8211)
    0.3112 (-2.3595 to 2.9820)
    Statistical analysis title
    		 Statistical analysis 10
    Comparison groups
    DBP: Randomised to placebo v DBP: Randomised to Nintedanib
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.5962
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    1.2052
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.3966
         upper limit
    		 5.807
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.2491
    Notes
    [6] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in Forced Vital Capacity (FVC) % predicted at Week 52

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    End point title
    		 Absolute change from baseline in Forced Vital Capacity (FVC) % predicted at Week 52
    End point description
    Forced Vital Capacity (FVC) is the volume of air (measured in milliliter) which can be forcibly exhaled from the lungs after taking the deepest breath possible. The predicted values were calculated according to the Global Lungs Initiative (GLI) 2012 equations. Absolute change from baseline in FVC % predicted was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements pre-administration at -4 weeks and at 0, 2, 6, 12, 24, 26, 36, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Percentage of predicted FVC
        least squares mean (confidence interval 95%)
    -0.9827 (-6.2611 to 4.2958)
    0.7906 (-2.9464 to 4.5277)
    Statistical analysis title
    		 Statistical analysis 11
    Comparison groups
    DBP+OLNP: Randomised to placebo v DBP + OLNP: Randomised to Nintedanib
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.5776
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    1.7733
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.7015
         upper limit
    		 8.2481
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.1424
    Notes
    [7] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - parent report

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    End point title
    		 Absolute change from baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - parent report
    End point description
    The PedsQL™ questionnaires is based on 23 items, 5-point Likert scale (0 = never (worst outcome) to 4=almost always (best outcome)). Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100 to 4 = 0). Higher scores indicated better health-related quality of life. To create total scores, the mean was computed. Absolute change from baseline was based on a MMRM, with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    11
    21
    Units: Unit on scale
        least squares mean (confidence interval 95%)
    5.615 (-1.506 to 12.736)
    5.481 (0.384 to 10.578)
    Statistical analysis title
    		 Statistical analysis 12
    Comparison groups
    DBP: Randomised to placebo v DBP: Randomised to Nintedanib
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.9755
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -0.134
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.975
         upper limit
    		 8.707
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.316
    Notes
    [8] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - parent report

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    End point title
    		 Absolute change from baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - parent report
    End point description
    The PedsQL™ questionnaires is based on 23 items, 5-point Likert scale (0 = never (worst outcome) to 4=almost always (best outcome)). Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100 to 4 = 0). Higher scores indicated better health-related quality of life. To create total scores, the mean was computed. Absolute change from baseline was based on a MMRM, with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    11
    21
    Units: Unit on scale
        least squares mean (confidence interval 95%)
    4.377 (-4.403 to 13.157)
    7.830 (1.799 to 13.862)
    Statistical analysis title
    		 Statistical analysis 13
    Comparison groups
    DBP+OLNP: Randomised to placebo v DBP + OLNP: Randomised to Nintedanib
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.514
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    3.453
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.25
         upper limit
    		 14.157
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.225
    Notes
    [9] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - subject report

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    End point title
    		 Absolute change from baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 24 - subject report
    End point description
    The PedsQL™ questionnaires is based on 23 items, 5-point Likert scale (0 = never (worst outcome) to 4=almost always (best outcome)). Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100 to 4 = 0). Higher scores indicated better health-related quality of life. To create total scores, the mean was computed. Absolute change from baseline was based on a MMRM, with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    11
    21
    Units: Unit on scale
        least squares mean (confidence interval 95%)
    5.484 (-0.051 to 11.018)
    6.514 (2.531 to 10.497)
    Statistical analysis title
    		 Statistical analysis 14
    Comparison groups
    DBP: Randomised to placebo v DBP: Randomised to Nintedanib
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    P-value
    		 = 0.7613
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    1.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.848
         upper limit
    		 7.908
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.358
    Notes
    [10] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - subject report

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    End point title
    		 Absolute change from baseline in Pediatric Quality of Life Questionnaire™(PedsQL™) at Week 52 - subject report
    End point description
    The PedsQL™ questionnaires is based on 23 items, 5-point Likert scale (0 = never (worst outcome) to 4=almost always (best outcome)). Items were reverse-scored and linearly transformed to a 0-100 scale (0 = 100 to 4 = 0). Higher scores indicated better health-related quality of life. To create total scores, the mean was computed. Absolute change from baseline was based on a MMRM, with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    11
    21
    Units: Unit on scale
        least squares mean (confidence interval 95%)
    0.902 (-7.616 to 9.420)
    1.243 (-4.598 to 7.083)
    Statistical analysis title
    		 Statistical analysis 15
    Comparison groups
    DBP+OLNP: Randomised to placebo v DBP + OLNP: Randomised to Nintedanib
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    P-value
    		 = 0.9468
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    0.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.026
         upper limit
    		 10.707
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.049
    Notes
    [11] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in oxygen saturation (SpO₂) on room air at rest at Week 24

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    End point title
    		 Absolute change from baseline in oxygen saturation (SpO₂) on room air at rest at Week 24
    End point description
    Oxygen saturation (SpO₂) was measured after minimum 5 minutes on room air by standard pulse oximetry at rest. Absolute change from baseline in SpO₂ at Week 24 in the treated set (TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements pre-administration at -4 weeks and at 0, 2, 6, 12, 24, 26, 36, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Percentage of SpO₂
        least squares mean (confidence interval 95%)
    -2.25 (-4.45 to -0.04)
    0.07 (-1.49 to 1.63)
    Statistical analysis title
    		 Statistical analysis 16
    Comparison groups
    DBP: Randomised to placebo v DBP: Randomised to Nintedanib
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 = 0.0908
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    2.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.39
         upper limit
    		 5.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.33
    Notes
    [12] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in oxygen saturation (SpO₂) on room air at rest at Week 52

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    End point title
    		 Absolute change from baseline in oxygen saturation (SpO₂) on room air at rest at Week 52
    End point description
    Oxygen saturation (SpO₂) was measured after minimum 5 minutes on room air by standard pulse oximetry at rest. Absolute change from baseline in SpO₂ at Week 52 in the treated set(TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements pre-administration at -4 weeks and at 0, 2, 6, 12, 24, 26, 36, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
    End point values
    		 DBP+OLNP: Randomised to placebo DBP+OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Percentage of SpO₂
        least squares mean (confidence interval 95%)
    -2.60 (-5.02 to -0.18)
    -0.32 (-2.03 to 1.40)
    Statistical analysis title
    		 Statistical analysis 17
    Comparison groups
    DBP+OLNP: Randomised to Nintedanib v DBP+OLNP: Randomised to placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.1222
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    2.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.69
         upper limit
    		 5.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.39
    Notes
    [13] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in 6 minutes (min) walk distance at Week 24

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    End point title
    		 Absolute change from baseline in 6 minutes (min) walk distance at Week 24
    End point description
    Absolute change from baseline in 6 minutes (min) walk distance at Week 24 in the treated set(TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 24 are reported in the table below
    End point values
    		 DBP: Randomised to placebo DBP: Randomised to Nintedanib
    Number of subjects analysed
    11
    21
    Units: Meter
        least squares mean (confidence interval 95%)
    10.5 (-36.4 to 57.3)
    17.6 (-16.2 to 51.5)
    Statistical analysis title
    		 Statistical analysis 18
    Comparison groups
    DBP: Randomised to placebo v DBP: Randomised to Nintedanib
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    P-value
    		 = 0.8012
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    7.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -50.7
         upper limit
    		 65
    Variability estimate
    Standard error of the mean
    Dispersion value
    28.2
    Notes
    [14] - No formal hypotheses were tested

    Secondary: Absolute change from baseline in 6 minutes (min) walk distance at Week 52

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    End point title
    		 Absolute change from baseline in 6 minutes (min) walk distance at Week 52
    End point description
    Absolute change from baseline in 6 minutes (min) walk distance at Week 52 in the treated set(TS) was based on a Mixed Model Repeated Measures (MMRM), with fixed categorical effects of (randomised) treatment at each visit, age−group and the fixed continuous effects of baseline at each visit, and random effect for subject. Visit was treated as the repeated measure with an unstructured covariance structure used to model the within−subject measurements. Treated set (TS): The TS consisted of participants who were randomised to a treatment group and received at least one dose of study medication. Only participants with correctly measured baseline and at least one post-baseline measurement were included in the analysis.
    End point type
    Secondary
    End point timeframe
    MMRM included measurements at 0, 24, and 52 weeks after first drug administration. MMRM values at Week 52 are reported in the table below
    End point values
    		 DBP+OLNP: Randomised to placebo DBP + OLNP: Randomised to Nintedanib
    Number of subjects analysed
    11
    21
    Units: Meter (m)
        least squares mean (confidence interval 95%)
    28.1 (-29.4 to 85.5)
    -4.9 (-44.5 to 34.7)
    Statistical analysis title
    		 Statistical analysis 19
    Comparison groups
    DBP+OLNP: Randomised to placebo v DBP + OLNP: Randomised to Nintedanib
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    P-value
    		 = 0.3401
    Method
    		 Mixed Model Repeated Measures (MMRM)
    Parameter type
    		 Adjusted Mean Difference
    Point estimate
    -32.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -103.1
         upper limit
    		 37.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    33.8
    Notes
    [15] - No formal hypotheses were tested

    Secondary: Subjects acceptability based on the size of capsules at Week 24 - patient question

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    End point title
    		 Subjects acceptability based on the size of capsules at Week 24 - patient question
    End point description
    Acceptability is the overall ability and willingness of subjects to use medicinal products as intended. Acceptability based on capsule size was assessed by an acceptability questionnaire (1 item and 3 categories) for subjects. In case the subject was considered not old enough as per investigator judgment the caregiver could assist with completion. Additionally to the commercially available 100 milligram (mg) soft capsules (oblong shape, 6 millimeter (mm) diameter, 16 mm length) and 150 mg soft capsules (oblong shape, 7 mm diameter, 18 mm length), 25 mg Nintedanib soft capsules of smaller size (oval shape, 5 mm diameter, 8 mm length) were provided for subjects who were assigned to a dose smaller than 100 mg or were unable to swallow the larger 100 mg or 150 mg capsules. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication. Only subjects with non-missing results were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Acceptability was assessed at Week 24
    End point values
    		 DBP: Randomised to placebo - capsule size of 25 mg capsule DBP: Randomised to Nintedanib - capsule size of 25 mg capsule DBP: Randomised to placebo - capsule size of 100 mg capsule DBP: Randomised to Nintedanib - capsule size of 100 mg capsule DBP: Randomised to placebo - capsule size of 150 mg capsule DBP: Randomised to Nintedanib - capsule size of 150 mg capsule
    Number of subjects analysed
    4
    6
    4
    14
    3
    2
    Units: Subjects
        OK
    4
    6
    4
    14
    3
    2
        Large
    0
    0
    0
    0
    0
    0
        Very Large
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Subjects acceptability based on the size of capsules at Week 24 - investigator question

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    End point title
    		 Subjects acceptability based on the size of capsules at Week 24 - investigator question
    End point description
    Acceptability the overall ability and willingness of subjects to use medicinal products as intended. Acceptability based on the capsule size was assessed by an acceptability questionnaire (1 item with 3 categories) for investigators. In addition to the commercially available 100 milligram (mg) soft capsules (oblong shape, 6 millimeter (mm) diameter, 16 mm length) and 150 mg soft capsules (oblong shape, 7 mm diameter, 18 mm length), 25 mg Nintedanib soft capsules of smaller size (oval shape, 5 mm diameter, 8 mm length) were provided in this trial for subjects who were assigned to a dose smaller than 100 mg or were unable to swallow the larger 100 mg or 150 mg capsules. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Acceptability was assessed at Week 24
    End point values
    		 DBP: Randomised to placebo - capsule size of 25 mg capsule DBP: Randomised to Nintedanib - capsule size of 25 mg capsule DBP: Randomised to placebo - capsule size of 100 mg capsule DBP: Randomised to Nintedanib - capsule size of 100 mg capsule DBP: Randomised to placebo - capsule size of 150 mg capsule DBP: Randomised to Nintedanib - capsule size of 150 mg capsule
    Number of subjects analysed
    4
    6
    4
    14
    3
    2
    Units: Subjects
        No
    1
    2
    1
    2
    0
    1
        Yes
    0
    0
    0
    0
    0
    0
        Missing
    3
    4
    3
    12
    3
    1
    No statistical analyses for this end point

    Secondary: Subjects acceptability based on the number of capsules at Week 24 - patient question

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    End point title
    		 Subjects acceptability based on the number of capsules at Week 24 - patient question
    End point description
    Acceptability is the overall ability and willingness of subjects to use medicinal products as intended. Acceptability based on capsule number was assessed by an acceptability questionnaire (1 item with 3 categories). If subjects were not old enough the caregiver could assist. Additionally to the commercially available 100 milligram (mg) soft capsules ((SCa) oblong shape, 6 millimeter (mm) diameter, 16 mm length) and 150 mg SCa (oblong shape, 7 mm diameter, 18 mm length), 25 mg Nintedanib smaller sized SCa (oval shape, 5 mm diameter, 8 mm length) were provided for subjects who were assigned to doses smaller than 100 mg or were unable to swallow the larger 100 mg or 150 mg capsules. Dosage was based on subject's weight. Capsule number per administration ranged from 2 to >6 . Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication. Only subjects with non-missing results were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Acceptability was assessed at Week 24
    End point values
    		 DBP: Randomised to placebo - 2 capsules DBP: Randomised to Nintedanib - 2 capsules DBP: Randomised to placebo - 4 capsules DBP: Randomised to Nintedanib - 4 capsules DBP: Randomised to placebo - 6 capsules DBP: Randomised to Nintedanib - 6 capsules DBP: Randomised to placebo - >6 capsules
    Number of subjects analysed
    7
    16
    2
    3
    1
    3
    1
    Units: Subjects
        I had no problem swallowing them
    7
    16
    2
    3
    1
    3
    1
        I swallowed them but it was difficult
    0
    0
    0
    0
    0
    0
    0
        I could not swallow them sometimes
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with occurrence of first respiratory-related hospitalization over the whole trial

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    End point title
    		 Number of subjects with occurrence of first respiratory-related hospitalization over the whole trial
    End point description
    Number of subjects with occurrence of first respiratory-related hospitalization over the whole trial. The number of subjects with first respiratory-related hospitalization is reported instead of a metric summarizing the time-to-event data with unit of time, as the numbers resulting from the Kaplan-Meier-analysis were even below the first quartile. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    From first drug administration until the last drug intake + 28 days Residual Effect Period (REP), up to 92.6 weeks
    End point values
    		 DBP+OLNP: Randomised to placebo DBP+OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Subjects
    0
    3
    No statistical analyses for this end point

    Secondary: Number of subjects with occurrence of first acute Interstitial Lung Disease (ILD) exacerbation or death over the whole trial

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    End point title
    		 Number of subjects with occurrence of first acute Interstitial Lung Disease (ILD) exacerbation or death over the whole trial
    End point description
    Number of subjects with occurrence of first acute Interstitial Lung Disease (ILD) exacerbation or death over the whole trial. The number of subjects with first acute ILD exacerbation is reported instead of a metric summarizing the time-to-event data with unit of time, as the numbers resulting from the Kaplan-Meier-analysis were even below the first quartile. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    From first drug administration until the last drug intake + 28 days REP, up to 92.6 weeks
    End point values
    		 DBP+OLNP: Randomised to placebo DBP+OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Subjects
    0
    2
    No statistical analyses for this end point

    Secondary: Number of subjects with occurrence of death over the whole trial

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    End point title
    		 Number of subjects with occurrence of death over the whole trial
    End point description
    Number of subjects with occurrence of death over the whole trial over the whole trial was computed. The number of subjects with occurrence of death is reported instead of a metric summarizing the time-to-event data with unit of time, as the numbers resulting from the Kaplan-Meier-analysis were even below the first quartile. Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    From first drug administration until the last drug intake + 28 days REP, up to 92.6 weeks
    End point values
    		 DBP+OLNP: Randomised to placebo DBP+OLNP: Randomised to Nintedanib
    Number of subjects analysed
    13
    26
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Placebo DBP+OLNP: 1st till last Placebo intake (DBP), up to 24.4 weeks + 28 days (REP) and 1st till last Nintedanib intake (OLNP), up to 64.6 weeks + 28 days (REP). Nintedanib DBP+OLNP: 1st till last Nintedanib intake, up to 85.1 weeks + 28 days (REP).
    Adverse event reporting additional description
    Treated set (TS): The TS consisted of subjects who were randomised to a treatment group and received at least one dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    DBP: Randomised to placebo‌
    Reporting group description
    		 This arm shows placebo randomised subjects treated orally with a Nintedanib matching placebo soft capsule twice daily with a dose interval of approximately 12 hours from one dose to the next dose in the double-blind period (DBP). Medication dosage was per administration 50 milligram (mg) [2 capsules with strength 25 mg],75 mg [3 capsules with strength 25 mg], 100 mg [1 capsule with strength 100 mg or 4 capsules with strength 25 mg] or 150 mg [1 capsule with strength 150 mg or 6 capsules with strength 25 mg] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received placebo only (DBP). DBP: Planned was from first randomised trial drug intake to last blinded drug intake.

    Reporting group title
    DBP+OLNP: Randomised Nintedanib (Nintedanib exposure period)‌
    Reporting group description
    		 This arm shows Nintedanib randomised subjects treated orally with Nintedanib in the DBP and OLNP twice daily with a dose interval of approximately 12 hours from one dose to the next dose. Medication dosage was per administration 50 milligram (mg) [2 capsules with strength 25 mg],75 mg [3 capsules with strength 25 mg], 100 mg [1 capsule with strength 100 mg or 4 capsules with strength 25 mg] or 150 mg [1 capsule with strength 150 mg or 6 capsules with strength 25 mg] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received Nintedanib in both periods (DBP + OLNP). Subjects in this arm do not entail subjects from the 'randomised to placebo' arms. DBP: Planned was from first randomised trial drug intake to last blinded drug intake. OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.

    Reporting group title
    OLNP: Randomised to placebo and switched to Nintedanib‌
    Reporting group description
    		 This arm shows subjects who continued with the open-label Nintedanib period (OLNP) after the DBP, switched to active Nintedanib treatment in the OLNP and were treated orally with Nintedanib twice daily with a dose interval of approximately 12 hours from one dose to the next dose. Medication dosage was per administration 50 milligram (mg) [2 capsules with strength 25 mg],75 mg [3 capsules with strength 25 mg], 100 mg [1 capsule with strength 100 mg or 4 capsules with strength 25 mg] or 150 mg [1 capsule with strength 150 mg or 6 capsules with strength 25 mg] based on the subject's weight at baseline (= 0 weeks). The dosage was adjusted at subsequent visits if the subject's weight had changed. In this arm subjects received Nintedanib only (OLNP). OLNP: Planned was from first open-label Nintedanib intake to last open-label Nintedanib intake.

    Serious adverse events
    		 DBP: Randomised to placebo‌ DBP+OLNP: Randomised Nintedanib (Nintedanib exposure period)‌ OLNP: Randomised to placebo and switched to Nintedanib‌
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
    5 / 26 (19.23%)
    2 / 11 (18.18%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Carbon dioxide increased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 26 (3.85%)
    0 / 11 (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
    Vascular disorders
    Neurogenic shock
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Frontal lobe epilepsy
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (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
    Gastrointestinal disorders
    Tooth development disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 26 (3.85%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 26 (3.85%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 26 (3.85%)
    0 / 11 (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
    Respiratory distress
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 26 (3.85%)
    0 / 11 (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
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DBP: Randomised to placebo‌ DBP+OLNP: Randomised Nintedanib (Nintedanib exposure period)‌ OLNP: Randomised to placebo and switched to Nintedanib‌
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 13 (84.62%)
    26 / 26 (100.00%)
    11 / 11 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 26 (7.69%)
    2 / 11 (18.18%)
         occurrences all number
    0
    2
    3
    Fatigue
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    3
    2
    0
    Pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 13 (7.69%)
    4 / 26 (15.38%)
    1 / 11 (9.09%)
         occurrences all number
    1
    6
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Multiple allergies
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Reproductive system and breast disorders
    Menstruation delayed
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    1
    0
    3
    Dyspnoea exertional
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 26 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    3
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 26 (3.85%)
    2 / 11 (18.18%)
         occurrences all number
    2
    2
    2
    Nasal congestion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Bruxism
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    SARS-CoV-2 test positive
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 26 (3.85%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    3
    Weight decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    X-ray limb abnormal
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    4
    0
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    2
    Burns second degree
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Congenital, familial and genetic disorders
    Supernumerary teeth
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Right atrial hypertrophy
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 26 (11.54%)
    2 / 11 (18.18%)
         occurrences all number
    2
    5
    2
    Eye disorders
    Eye pruritus
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Lacrimation increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 13 (23.08%)
    6 / 26 (23.08%)
    4 / 11 (36.36%)
         occurrences all number
    4
    9
    5
    Abdominal pain upper
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 26 (11.54%)
    0 / 11 (0.00%)
         occurrences all number
    4
    3
    0
    Constipation
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    2
    0
    Dental caries
         subjects affected / exposed
    3 / 13 (23.08%)
    7 / 26 (26.92%)
    1 / 11 (9.09%)
         occurrences all number
    3
    27
    2
    Dental cyst
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    Diarrhoea
         subjects affected / exposed
    2 / 13 (15.38%)
    12 / 26 (46.15%)
    6 / 11 (54.55%)
         occurrences all number
    2
    26
    7
    Dyspepsia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    6
    0
    1
    Faeces soft
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 26 (3.85%)
    0 / 11 (0.00%)
         occurrences all number
    2
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Malpositioned teeth
         subjects affected / exposed
    1 / 13 (7.69%)
    3 / 26 (11.54%)
    0 / 11 (0.00%)
         occurrences all number
    1
    4
    0
    Nausea
         subjects affected / exposed
    3 / 13 (23.08%)
    6 / 26 (23.08%)
    6 / 11 (54.55%)
         occurrences all number
    3
    7
    12
    Paraesthesia oral
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Tooth development disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    6 / 26 (23.08%)
    0 / 11 (0.00%)
         occurrences all number
    1
    6
    0
    Tooth deposit
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth disorder
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth impacted
         subjects affected / exposed
    2 / 13 (15.38%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    4
    7
    0
    Vomiting
         subjects affected / exposed
    3 / 13 (23.08%)
    7 / 26 (26.92%)
    4 / 11 (36.36%)
         occurrences all number
    3
    21
    17
    Skin and subcutaneous tissue disorders
    Melanosis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 26 (3.85%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    1
    Arthralgia
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    1
    3
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 13 (7.69%)
    7 / 26 (26.92%)
    1 / 11 (9.09%)
         occurrences all number
    1
    7
    1
    Gastrointestinal bacterial overgrowth
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 26 (3.85%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 26 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    0 / 13 (0.00%)
    4 / 26 (15.38%)
    0 / 11 (0.00%)
         occurrences all number
    0
    4
    0
    Respiratory tract infection viral
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 26 (3.85%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    2
    Respiratory tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 26 (3.85%)
    2 / 11 (18.18%)
         occurrences all number
    2
    2
    2
    Tooth abscess
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 26 (7.69%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 26 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    Decreased appetite
         subjects affected / exposed
    0 / 13 (0.00%)
    2 / 26 (7.69%)
    1 / 11 (9.09%)
         occurrences all number
    0
    2
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jun 2020
    This amendment was implemented after the first patient was enrolled into the trial. The following main changes were introduced: •The unblinding of selected non-trial personnel from the sponsor involved in the PK analysis was further specified based on the Food and Drug Administration (FDA) recommendation to conduct an interim PK evaluation at Week 2 post-dose to ensure that the systemic exposure of nintedanib with the proposed weight-based dosing regimen in patients of 6 to 17 years of age is comparable with adults. •It was clarified that SMC members were independent from the trial team and that the SMC reviewed PK data in addition to safety data. Furthermore, the actions expected from the SMC to mitigate the risk in the trial were specified in more detail. •Based on an FDA recommendation, restrictions regarding concomitant use of potent Pgp and CYP3A4 inhibitors and inducers were added to minimise potential impact of these co-medications on the primary PK endpoint. •Exclusion criterion No. 13 was modified to exclude patients with documented allergy to soya to align with the contraindications reported in the Investigator’s Brochure. •Results from the trial in adults with PF-ILD were added, as they had become available. It was clarified that if PK data for the primary analysis were not sufficient at the time of DBL1, further PK data were to be collected. •It was specified that conduct of MRI/x-ray, dental examination, and dental imaging was to only be done in patients who qualified for randomisation in order to avoid unnecessary procedures.
    14 Jun 2021
    Following main changes were introduced by this amendment: •First dose of open-label trial medication of Part B (Visit 6) was administered at trial site to ensure monitoring of immediate adverse reactions to those patients who had received placebo during Part A and received their first dose of active medication at Visit 6. •Clarified laboratory tests with clinically relevant changes at EoT were repeated. •Follow-up Visit time window was reduced from 7 to 3 days. •PK sampling was repeated if blood samples were not taken at required time point, wrong medication was taken, a sample was destroyed/lost during shipment to obtain all required samples for PK analyses, if possible. •Information about reported adverse reactions and risks specific for paediatric population was added.•Mitigation measures to address additional risks due to COVID-19 pandemic were added. If site access was restricted, some activities on site such as on-site source data review and source data verification was performed remotely or replaced by centralised monitoring. No restrictions for trial participants to receive COVID-19 vaccination. •PK sampling in 10 children aged 6 to 11 years was completed at DBL1, if feasible. •If further PK data were needed at DBL1 snapshot was taken once further PK data had been collected and data based on DBL1 snapshot was updated and trial team was informed about number of patients with evaluable PK missing to reach target. •Specified procedures if patient’s weight decrease below 13.5 kg. •Pathological findings in bone imaging and stunted growth in dental imaging were added to list of AESIs •Instructions on treatment interruption and resumption of treatment. •Primary PK analysis was calculated by non-compartmental and compartmental analysis. Clarified Investigational Medicinal Product (IMP) interruption was at most 4 weeks, while re-escalation to dose assigned could occur any time per investigator judgement. •SMC was to have no contact with central readers.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Mar 2020
    Subject recruitment and trial site initiation were paused due to the Covid-19 pandemic.
    04 Jun 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The end of trial (EoT) was planned in the protocol once 30 subjects had completed pharmacokinetic sampling at Week 26 or prematurely discontinued the trial. At EoT no subject had reached Week 100 yet. The trial was completed as per protocol.
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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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