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    Clinical Trial Results:
    A Four-Year Open-Label Multi-Center Randomized Two-Arm Study Of Genotropin In Idiopathic Short Stature Patients: Comparing An Individualized, Target-Driven Treatment Regimen To Standard Dosing Of Genotropin

    Summary
    EudraCT number
    		 2014-004172-32
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    30 Aug 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Apr 2016
    First version publication date
    01 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A6281280
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00396097
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Feb 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that an individualized, formula-based Genotropin regimen for children with Idiopathic Short Stature (ISS) will lead to a targeted height gain (to reach the target of 10th percentile (%), or -1.3 Standard Deviation Score (SDS)) during 24 months of treatment.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and incompliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    08 Dec 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 316
    Worldwide total number of subjects
    316
    EEA total number of subjects
    0
    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)
    292
    Adolescents (12-17 years)
    24
    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 4-year, open-label, randomized study conducted at 40 centers across United States of America (USA). The first 2-years of the study constituted core phase and the last 2 years constituted the maintenance phase.

    Pre-assignment
    Screening details
    		 The subjects were randomized in 2:1 manner to formula-based dosing arm and standard dosing arm for initial 2 years of treatment, following which the subjects in formula-based dosing arm were re-randomized in a 1:1 manner to one of two physiological doses, for next 2 years, to identify the minimum genotropin dosage to maintain the growth.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Standard Dose Arm
    Arm description
    		 The subjects received subcutaneous genotropin throughout the four years.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Genotropin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection in cartridge
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The subjects received subcutaneous genotropin daily, at maintained standard dose of 0.37 milligram per kilogram per week (mg/kg/week), throughout the four years.

    Arm title
    		 Individualized Dose Arm
    Arm description
    		 The subjects received subcutaneous genotropin daily, at formula-calculated dose for the initial 2 years and then lowered to physiological doses for the remaining 2 years.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Genotropin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    The subjects received subcutaneous genotropin daily, at formula-calculated dose (up to maximum dose of 0.7 mg/kg/week) for the initial 2 years and then lowered to one of two approximately physiological doses (0.18 mg/kg/week or 0.24 mg/kg/week) for the remaining 2 years.

    Number of subjects in period 1
    		Standard Dose Arm Individualized Dose Arm
    Started
    114
    202
    Completed
    88
    156
    Not completed
    26
    46
         Consent withdrawn by subject
    17
    17
         Adverse event, non-fatal
    1
    5
         Not specified
    3
    5
         Insufficient Clinical Response
    1
    4
         Lost to follow-up
    4
    9
         Protocol deviation
    -
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Standard Dose Arm
    Reporting group description
    		 The subjects received subcutaneous genotropin throughout the four years.

    Reporting group title
    Individualized Dose Arm
    Reporting group description
    		 The subjects received subcutaneous genotropin daily, at formula-calculated dose for the initial 2 years and then lowered to physiological doses for the remaining 2 years.

    Reporting group values
    		 Standard Dose Arm Individualized Dose Arm Total
    Number of subjects
    		 114 202 316
    Age, Customized
    Units: Participants
        <= 7 years
    		 37 70 107
        >=7 years
    		 77 132 209
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.3 ( 2.1 ) 8.4 ( 2.3 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 31 58 89
        Male
    		 83 144 227

    End points

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    End points reporting groups
    Reporting group title
    Standard Dose Arm
    Reporting group description
    		 The subjects received subcutaneous genotropin throughout the four years.

    Reporting group title
    Individualized Dose Arm
    Reporting group description
    		 The subjects received subcutaneous genotropin daily, at formula-calculated dose for the initial 2 years and then lowered to physiological doses for the remaining 2 years.

    Subject analysis set title
    Individualized Dose Arm Overall
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects received subcutaneous genotropin daily, at formula-calculated dose (up to maximum dose of 0.7 mg/kg/week) for the initial 2 years and then lowered to one of two approximately physiological doses (0.18 mg/kg/week or 0.24 mg/kg/week) for the remaining 2 years.

    Subject analysis set title
    Individualized Dose Arm 0.18 mg/kg/Week
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects received subcutaneous genotropin daily, at formula-calculated dose (up to maximum dose of 0.7 mg/kg/week) for the initial 2 years and then lowered to one of two approximately physiological doses 0.18 mg/kg/week for the remaining 2 years.

    Subject analysis set title
    Individualized Dose Arm 0.24 mg/kg/Week
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The subjects received subcutaneous genotropin daily, at formula-calculated dose (up to maximum dose of 0.7 mg/kg/week) for the initial 2 years and then lowered to one of two approximately physiological doses 0.24 mg/kg/week for the remaining 2 years.

    Primary: Absolute on-target Difference (AOTD) at 24 Months

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    End point title
    		 Absolute on-target Difference (AOTD) at 24 Months
    End point description
    This was defined as an absolute difference between the 24-month height standard deviation score (SDS) and targeted 24-month height SDS (10th percentile (%),or –1.3 SDS). SDS indicates how similar the subjects was to the reference population. These were calculated using 2000 Center for the Disease Control (CDC) growth reference tables (by age and gender). The Full Analysis Set (FAS) included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available. Last observation carried forward (LOCF) rule was applied to impute Month 24 missing height SDS data.
    End point type
    Primary
    End point timeframe
    2 years
    End point values
    		 Standard Dose Arm Individualized Dose Arm
    Number of subjects analysed
    114
    202
    Units: Standard Deviation Score (SDS)
        arithmetic mean (standard deviation)
    0.603 ( 0.2948 )
    0.625 ( 0.3003 )
    Statistical analysis title
    		 Absolute On-target Difference (AOTD) at 24 Months
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5762
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.006
    Confidence interval
         level
    		 97.5%
         sides
    1-sided
         lower limit
    		 -0.071
         upper limit
    		 -
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.033

    Secondary: Variability of Height SDS at 24 Months

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    End point title
    		 Variability of Height SDS at 24 Months
    End point description
    The continuous endpoint of variability of height SDS at 24 months was defined as the SD of the 24 month height SDS. FAS included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available. LOCF rule was applied to impute Month 24 missing height SDS data.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    		 Standard Dose Arm Individualized Dose Arm
    Number of subjects analysed
    114
    202
    Units: Standard Deviation Score (SDS)
    arithmetic mean (standard deviation)
        Change from baseline at 24 months (n=101,184)
    1.12 ( 0.408 )
    1.11 ( 0.518 )
        Change from baseline at 24 months LOCF (n=114,202)
    1.03 ( 0.475 )
    1.04 ( 0.544 )
    Statistical analysis title
    		 Variability of Height SDS at 24 Months
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.627
    Method
    		 ANOVA (Levene's Test)
    Confidence interval

    Secondary: Time Cost (Months Until greater than or equal to (>=) -2 SDS)

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    End point title
    		 Time Cost (Months Until greater than or equal to (>=) -2 SDS)
    End point description
    Time cost was defined as the number of months needed until height SDS was within the normal limit (ie, greater than or equal to (>=) -2 SDS). FAS included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available.
    End point type
    Secondary
    End point timeframe
    2 years
    End point values
    		 Standard Dose Arm Individualized Dose Arm
    Number of subjects analysed
    114
    202
    Units: Months
        median (confidence interval 95%)
    12 (8 to 12)
    12 (8 to 12)
    Statistical analysis title
    		 Time Cost (Months Until >= -2 SDS)
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8016
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.802
         upper limit
    		 1.33

    Secondary: Computed Cost of Height Gain at 48 Months

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    End point title
    		 Computed Cost of Height Gain at 48 Months [1]
    End point description
    The computed cost of height gain was defined as the amount of drug used relative to the observed height-gain, in terms of milligram per centimeter (mg/cm) , this was calculated at Month 48.
    End point type
    Secondary
    End point timeframe
    4 years
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was not collected at the end of study visit for Individual Dose Arm as comparison between the groups was not planned.
    End point values
    		 Standard Dose Arm Individualized Dose Arm Overall Individualized Dose Arm 0.18 mg/kg/Week Individualized Dose Arm 0.24 mg/kg/Week
    Number of subjects analysed
    114
    202
    91
    88
    Units: mg/cm
        arithmetic mean (standard deviation)
    72.77 ( 17.914 )
    67.3 ( 24.382 )
    63.07 ( 21.656 )
    69.62 ( 21.903 )
    Statistical analysis title
    		 Height Gain at 48 Months
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm Overall
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0101
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.822
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.395
         upper limit
    		 10.249
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.25
    Statistical analysis title
    		 Height Gain at 48 Months: 0.18 mg/kg/week
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm 0.18 mg/kg/Week
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    9.281
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.417
         upper limit
    		 14.145
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.471
    Statistical analysis title
    		 Height Gain at 48 Months: 0.24 mg/kg/week
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm 0.24 mg/kg/Week
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.204
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.707
         upper limit
    		 8.114
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.495

    Secondary: Estimated Cost of Height Gain Estimated Until Full Adult Height (FAH) at 48 Months

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    End point title
    		 Estimated Cost of Height Gain Estimated Until Full Adult Height (FAH) at 48 Months [2]
    End point description
    The estimated cost of long-term height gain until FAH was calculated. FAS included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available. LOCF rule was applied to impute Month 24 missing height SDS data.
    End point type
    Secondary
    End point timeframe
    4 years
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was not collected at the end of study visit for Individual Dose Arm as comparison between the groups was not planned.
    End point values
    		 Standard Dose Arm Individualized Dose Arm Overall Individualized Dose Arm 0.18 mg/kg/Week Individualized Dose Arm 0.24 mg/kg/Week
    Number of subjects analysed
    112
    192
    90
    88
    Units: mg/cm
        arithmetic mean (standard deviation)
    127.99 ( 29.708 )
    91.34 ( 31.854 )
    80.06 ( 21 )
    92.24 ( 25.213 )
    Statistical analysis title
    		 Full Adult Height
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm Overall
    Number of subjects included in analysis
    304
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    36.899
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 30.181
         upper limit
    		 43.618
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.414
    Statistical analysis title
    		 Full Adult Height: 0.18mg/kg/Week
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm 0.18 mg/kg/Week
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    48.517
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 42.054
         upper limit
    		 54.98
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.284
    Statistical analysis title
    		 Full Adult Height: 0.24 mg/kg/Week
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm 0.24 mg/kg/Week
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    34.443
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 27.936
         upper limit
    		 40.951
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.306

    Secondary: Change From Baseline in Height SDS at 48 Months.

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    End point title
    		 Change From Baseline in Height SDS at 48 Months. [3]
    End point description
    Change in height SDS was measured at 48 months. FAS included all randomized subjects who received at least 1 dose of study treatment and had at least 1 post-baseline height SDS value available. LOCF rule was applied to impute Month 24 missing height SDS data.
    End point type
    Secondary
    End point timeframe
    4 years
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was not collected at the end of study visit for Individual Dose Arm as comparison between the groups was not planned.
    End point values
    		 Standard Dose Arm Individualized Dose Arm Overall Individualized Dose Arm 0.18 mg/kg/Week Individualized Dose Arm 0.24 mg/kg/Week
    Number of subjects analysed
    114
    202
    91
    88
    Units: Standard Deviation Score (SDS)
        arithmetic mean (standard deviation)
    1.33 ( 0.717 )
    1.24 ( 0.668 )
    1.33 ( 0.637 )
    1.34 ( 0.633 )
    Statistical analysis title
    		 Change From Baseline in Height SDS
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm Overall
    Number of subjects included in analysis
    316
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2618
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.091
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.068
         upper limit
    		 0.249
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.081
    Statistical analysis title
    		 Change From Baseline in Height SDS: 0.18mg/kg/Week
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm 0.18 mg/kg/Week
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8926
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.013
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.172
         upper limit
    		 0.198
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.094
    Statistical analysis title
    		 Change From Baseline in Height SDS: 0.24mg/kg/Week
    Comparison groups
    Standard Dose Arm v Individualized Dose Arm 0.24 mg/kg/Week
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9566
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.005
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.192
         upper limit
    		 0.181
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.095

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    4 years
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as nonserious in another subject, or one subject may have experienced both a serious and nonserious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.0
    Reporting groups
    Reporting group title
    Standard Dose Arm
    Reporting group description
    		 The subjects received subcutaneous genotropin daily, at a maintained standard dose of 0.37 mg/kg/week, throughout the four years.

    Reporting group title
    Individualized Dose Arm
    Reporting group description
    		 The subjects received subcutaneous genotropin daily, at formula-calculated dose (up to maximum dose of 0.7 mg/kg/week) for the initial 2 years and then lowered to one of two approximately physiological doses (0.18 mg/kg/week or 0.24 mg/kg/week) for the remaining 2 years.

    Serious adverse events
    		 Standard Dose Arm Individualized Dose Arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 118 (11.02%)
    7 / 198 (3.54%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign Body
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Arnold-chiari malformation
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    1 / 118 (0.85%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocephalus
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device breakage
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 118 (1.69%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Affective disorder
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Scoliosis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 118 (0.85%)
    1 / 198 (0.51%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 118 (1.69%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 198 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Standard Dose Arm Individualized Dose Arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    103 / 118 (87.29%)
    165 / 198 (83.33%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    33 / 118 (27.97%)
    59 / 198 (29.80%)
         occurrences all number
    71
    147
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    5 / 118 (4.24%)
    13 / 198 (6.57%)
         occurrences all number
    8
    19
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    13 / 118 (11.02%)
    22 / 198 (11.11%)
         occurrences all number
    14
    35
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    6 / 118 (5.08%)
    6 / 198 (3.03%)
         occurrences all number
    12
    9
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 118 (1.69%)
    10 / 198 (5.05%)
         occurrences all number
    2
    15
    Abdominal pain
         subjects affected / exposed
    6 / 118 (5.08%)
    6 / 198 (3.03%)
         occurrences all number
    7
    9
    Abdominal pain upper
         subjects affected / exposed
    9 / 118 (7.63%)
    17 / 198 (8.59%)
         occurrences all number
    11
    19
    Diarrhoea
         subjects affected / exposed
    7 / 118 (5.93%)
    12 / 198 (6.06%)
         occurrences all number
    7
    12
    Nausea
         subjects affected / exposed
    5 / 118 (4.24%)
    11 / 198 (5.56%)
         occurrences all number
    5
    13
    Vomiting
         subjects affected / exposed
    15 / 118 (12.71%)
    21 / 198 (10.61%)
         occurrences all number
    20
    30
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 118 (6.78%)
    26 / 198 (13.13%)
         occurrences all number
    10
    36
    Nasal congestion
         subjects affected / exposed
    10 / 118 (8.47%)
    17 / 198 (8.59%)
         occurrences all number
    14
    26
    Oropharyngeal pain
         subjects affected / exposed
    6 / 118 (5.08%)
    19 / 198 (9.60%)
         occurrences all number
    11
    26
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    15 / 118 (12.71%)
    24 / 198 (12.12%)
         occurrences all number
    24
    33
    Pain in extremity
         subjects affected / exposed
    14 / 118 (11.86%)
    17 / 198 (8.59%)
         occurrences all number
    19
    42
    Scoliosis
         subjects affected / exposed
    11 / 118 (9.32%)
    19 / 198 (9.60%)
         occurrences all number
    11
    20
    Infections and infestations
    Ear infection
         subjects affected / exposed
    1 / 118 (0.85%)
    11 / 198 (5.56%)
         occurrences all number
    1
    17
    Gastroenteritis
         subjects affected / exposed
    10 / 118 (8.47%)
    11 / 198 (5.56%)
         occurrences all number
    13
    18
    Gastroenteritis viral
         subjects affected / exposed
    7 / 118 (5.93%)
    15 / 198 (7.58%)
         occurrences all number
    7
    17
    Influenza
         subjects affected / exposed
    16 / 118 (13.56%)
    22 / 198 (11.11%)
         occurrences all number
    18
    30
    Nasopharyngitis
         subjects affected / exposed
    8 / 118 (6.78%)
    25 / 198 (12.63%)
         occurrences all number
    25
    54
    Otitis externa
         subjects affected / exposed
    2 / 118 (1.69%)
    10 / 198 (5.05%)
         occurrences all number
    2
    13
    Otitis media
         subjects affected / exposed
    11 / 118 (9.32%)
    23 / 198 (11.62%)
         occurrences all number
    12
    29
    Pharyngitis streptococcal
         subjects affected / exposed
    15 / 118 (12.71%)
    30 / 198 (15.15%)
         occurrences all number
    23
    47
    Sinusitis
         subjects affected / exposed
    9 / 118 (7.63%)
    23 / 198 (11.62%)
         occurrences all number
    20
    47
    Upper respiratory tract infection
         subjects affected / exposed
    28 / 118 (23.73%)
    45 / 198 (22.73%)
         occurrences all number
    52
    73
    Viral infection
         subjects affected / exposed
    9 / 118 (7.63%)
    11 / 198 (5.56%)
         occurrences all number
    11
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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