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    Clinical Trial Results:
    Effect of Early Growth Hormone Treatment on Long-term Growth and Skeletal Maturation in Girls with Turner Syndrome (“Turner Tweens and Teens” Study)

    Summary
    EudraCT number
    		 2016-001502-42
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    09 Sep 2015

    Results information
    Results version number
    		 v1
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    10088
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00266656
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Trial Number : 10088, Trial Alias: B9R-US-GDGH
    Sponsors
    Sponsor organisation name
    Eli Lilly and Company
    Sponsor organisation address
    Lilly Corporate Center, Indianapolis, IN, United States, 46285
    Public contact
    Available Mon - Fri 9 AM - 5 PM EST , Eli Lilly and Company, 1 877-CTLilly,
    Scientific contact
    Available Mon - Fri 9 AM - 5 PM EST , Eli Lilly and Company, 1 877-285-4559,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    09 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is an extension study that will gather long-term data on the effect of early growth hormone (GH) treatment on adult height and other aspects of health and development in girls with Turner syndrome. The main purpose is to determine whether girls who received 2 years of GH treatment before 6 years of age achieve taller adult height than girls who were untreated during this time. The study will also look at middle ear and hearing function, and cognitive and behavioral development. Protocol completion is defined as attainment of height velocity less than or equal to 1.0 cm/year, or bone age greater than or equal to 15 years.
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice, and the principles of the Declaration of Helsinki, in addition to following the laws and regulations of the country or countries in which a study is conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Dec 2005
    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: 69
    Worldwide total number of subjects
    69
    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)
    69
    Adolescents (12-17 years)
    0
    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
    		 To be included in this study, participants had to be females with karyotype-proven Turner syndrome who were previously randomized in Study B9R-US-GDFG (NCT00406926).

    Pre-assignment
    Screening details
    		 No Text Entered

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Early Treated
    Arm description
    		 Humatrope administered according to investigator’s clinical practice and guided by the approved package insert. Humatrope administered in B9R-US-GDFG (NCT00406926).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Humatrope
    Investigational medicinal product code
    Other name
    LY137998, Somatropin, Growth hormone
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    According to investigator's clinical practice and guided by the approved package insert.

    Arm title
    		 Early Untreated
    Arm description
    		 Humatrope administered according to investigator’s clinical practice and guided by the approved package insert. Control: Humatrope was not administered in B9R-US-GDFG (NCT00406926).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Humatrope
    Investigational medicinal product code
    Other name
    LY137998, Somatropin, Growth hormone
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    No drug administration in B9R-US-GDFG (NCT00406926). According to investigator's clinical practice and guided by the approved package insert.

    Number of subjects in period 1
    		Early Treated Early Untreated
    Started
    36
    33
    Completed
    22
    20
    Not completed
    14
    13
         Adverse event, serious fatal
    1
    -
         Parent/Caregiver Decision
    1
    2
         Consent withdrawn by subject
    4
    2
         Did Not Reach Final Height
    4
    8
         Lost to follow-up
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Early Treated
    Reporting group description
    		 Humatrope administered according to investigator’s clinical practice and guided by the approved package insert. Humatrope administered in B9R-US-GDFG (NCT00406926).

    Reporting group title
    Early Untreated
    Reporting group description
    		 Humatrope administered according to investigator’s clinical practice and guided by the approved package insert. Control: Humatrope was not administered in B9R-US-GDFG (NCT00406926).

    Reporting group values
    		 Early Treated Early Untreated Total
    Number of subjects
    		 36 33 69
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 36 33 69
        Adolescents (12-17 years)
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 8.29 ± 1.22 8.41 ± 1.3 -
    Gender, Male/Female
    Units: participants
        Female
    		 36 33 69
        Male
    		 0 0 0
    Height
    Units: centimeter (CM)
        arithmetic mean (standard deviation)
    		 124.34 ± 10.08 121.06 ± 9.76 -
    Height Standard Deviation Score (SDS)
    Units: Standard Deviation Score
        arithmetic mean (standard deviation)
    		 -0.84 ± 1.22 -1.48 ± 1.23 -
    Bone Age
    Units: years
        arithmetic mean (standard deviation)
    		 8.73 ± 1.55 8.34 ± 1.57 -

    End points

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    End points reporting groups
    Reporting group title
    Early Treated
    Reporting group description
    		 Humatrope administered according to investigator’s clinical practice and guided by the approved package insert. Humatrope administered in B9R-US-GDFG (NCT00406926).

    Reporting group title
    Early Untreated
    Reporting group description
    		 Humatrope administered according to investigator’s clinical practice and guided by the approved package insert. Control: Humatrope was not administered in B9R-US-GDFG (NCT00406926).

    Primary: Most Mature Height Standard Deviation Score (SDS)

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    End point title
    		 Most Mature Height Standard Deviation Score (SDS)
    End point description
    SDS reports the number of standard deviations from the mean for age and sex for an individual measurement (normal range is -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height. Population Description: All participants who achieved Near Adult Height (NAH). NAH is defined as first height measured when height velocity is less than or equal to 2.0 centimeter per year over the preceding year (in the absence of growth-impairing process such as hypothyroidism or inflammatory bowel disease), or bone age greater than or equal to14.5 years.
    End point type
    Primary
    End point timeframe
    Baseline through End of Study (10 years)
    End point values
    		 Early Treated Early Untreated
    Number of subjects analysed
    25
    26
    Units: standard deviation score
        arithmetic mean (standard deviation)
    -1.37 ± 1.09
    -1.6 ± 1.21
    Statistical analysis title
    		 Statistical Analysis for Primary Outcome
    Comparison groups
    Early Treated v Early Untreated
    Number of subjects included in analysis
    51
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Height SDS at various ages

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    End point title
    		 Height SDS at various ages
    End point description
    SDS reports the number of standard deviations from the mean for age and sex for an individual measurement (normal range is -2 to +2 SDS). Height SDS is derived by subtracting the population mean from individual's height value and then dividing that difference by the population standard deviation. Greater height SDS values indicate greater height. Population Description: All participants who had a baseline visit and at least one post-baseline visit.
    End point type
    Secondary
    End point timeframe
    Age 10, Age 13, Age 16
    End point values
    		 Early Treated Early Untreated
    Number of subjects analysed
    35
    32
    Units: Standard deviation score
    arithmetic mean (standard deviation)
        Age 10 (n=32, 30)
    -0.66 ± 1.16
    -1.28 ± 1.17
        Age 13 (n=29, 29)
    -1.29 ± 1.24
    -1.87 ± 1.16
        Age 16 (n=18, 18)
    -1.66 ± 1.11
    -1.69 ± 1.3
    No statistical analyses for this end point

    Secondary: Age at attainment of Tanner 2 breast development

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    End point title
    		 Age at attainment of Tanner 2 breast development
    End point description
    The Tanner 2 breast development is the age at first evidence of breast development. Population Description: All participants who had a baseline visit and at least one post-baseline visit.
    End point type
    Secondary
    End point timeframe
    Baseline through End of Study (10 years)
    End point values
    		 Early Treated Early Untreated
    Number of subjects analysed
    35
    32
    Units: years
        arithmetic mean (standard error)
    11.8 ± 0.26
    12.14 ± 0.31
    No statistical analyses for this end point

    Secondary: Chronological age at first visit participant attained bone age of 14.5 years

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    End point title
    		 Chronological age at first visit participant attained bone age of 14.5 years
    End point description
    Bone age was measured by standard radiograph, x-ray at baseline and annually for 10 years or until attainment of height velocity less than or equal to 1.0 centimeter per year (cm/year) and bone age greater or equal to 15 years. Population Description: All participants who achieved Near Adult Height (NAH). NAH is defined as first height measured when height velocity is less than or equal to 2.0 centimeter per year over the preceding year (in the absence of growth-impairing process such as hypothyroidism or inflammatory bowel disease), or bone age greater than or equal to14.5 years.
    End point type
    Secondary
    End point timeframe
    Baseline through End of Study (10 years)
    End point values
    		 Early Treated Early Untreated
    Number of subjects analysed
    25
    26
    Units: years
        arithmetic mean (standard error)
    14.64 ± 0.25
    15.26 ± 0.23
    No statistical analyses for this end point

    Secondary: Reports of serious adverse events

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    End point title
    		 Reports of serious adverse events
    End point description
    Number of serious adverse events (SAEs) reported. Any adverse event (AE) from this study that results in one of the following outcomes, or is significant for any other reason were reported as an SAE: death, initial or prolonged inpatient hospitalization, a life-threatening experience (that is, immediate risk of dying), persistent or significant disability/incapacity, congenital anomaly/birth defect in the offspring of a study subject, significant for any other reason (includes cancer, other than superficial, and basal cell or squamous cell carcinomas of the skin, that did not meet other serious adverse event criteria). A summary of other nonserious AEs, and all SAE's, regardless of causality, is located in the Reported Adverse Events section. Population Description: All participants who had a baseline visit, regardless of whether or not they received Humatrope at any time.
    End point type
    Secondary
    End point timeframe
    Baseline through End of Study (10 years)
    End point values
    		 Early Treated Early Untreated
    Number of subjects analysed
    36
    33
    Units: events
        number (not applicable)
    6
    5
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Occurrence of pre-specified clinically relevant events

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    End point title
    		 Percentage of Participants with Occurrence of pre-specified clinically relevant events
    End point description
    Percentage of participants for whom certain non-serious, pre-specified adverse events (AEs; those that are commonly observed in Turner syndrome or are known to be related to GH treatment: impaired glucose tolerance, diabetes mellitus, hypothyroidism, benign intracranial hypertension, scoliosis, slipped capital femoral epiphysis, solid tumor/leukemia, pancreatitis, ear infections, and high blood pressure) are reported. Population Description: All participants who had a baseline visit, regardless of whether or not they received Humatrope at any time.
    End point type
    Secondary
    End point timeframe
    Baseline through End of Study (10 years)
    End point values
    		 Early Treated Early Untreated
    Number of subjects analysed
    36
    33
    Units: percentage of participants
    number (not applicable)
        Baseline Ear infections
    13.9
    18.2
        Baseline High Blood Pressure
    0
    3
        Baseline Hypothyroidism
    13.9
    6.1
        Baseline Scoliosis
    22.2
    9.1
        Year 1 Ear infections
    38.9
    39.4
        Year 1 High Blood Pressure
    0
    3
        Year 1 Hypothyroidism
    11.1
    12.1
        Year 1 Scoliosis
    16.7
    21.2
        Year 2 Diabetes
    2.8
    0
        Year 2 Dilatation of the Aorta
    0
    3
        Year 2 Ear infections
    33.3
    27.3
        Year 2 High Blood Pressure
    0
    3
        Year 2 Hypothyroidism
    11.1
    12.1
        Year 2 Scoliosis
    22.2
    24.2
        Year 3 Diabetes
    2.8
    0
        Year 3 Dilatation of the Aorta
    0
    6.1
        Year 3 Ear infections
    30.6
    36.4
        Year 3 High Blood Pressure
    0
    3
        Year 3 Hypothyroidism
    11.1
    12.1
        Year 3 Scoliosis
    25
    27.3
        Year 4 Diabetes
    2.8
    0
        Year 4 Dilatation of the Aorta
    0
    6.1
        Year 4 Ear infections
    16.7
    30.3
        Year 4 High Blood Pressure
    0
    3
        Year 4 Hypothyroidism
    11.1
    12.1
        Year 4 Scoliosis
    25
    27.3
        Year 5 Diabetes
    2.8
    0
        Year 5 Dilatation of the Aorta
    0
    6.1
        Year 5 Ear infections
    22.2
    27.3
        Year 5 High Blood Pressure
    0
    3
        Year 5 Hypothyroidism
    13.9
    18.2
        Year 5 Scoliosis
    25
    27.3
        Year 6 Diabetes
    2.8
    0
        Year 6 Dilatation of the Aorta
    0
    9.1
        Year 6 Ear infections
    19.4
    24.2
        Year 6 High Blood Pressure
    0
    3
        Year 6 Hypothyroidism
    13.9
    18.2
        Year 6 Scoliosis
    16.7
    30.3
        Year 7 Diabetes
    2.8
    0
        Year 7 Dilatation of the Aorta
    0
    9.1
        Year 7 Ear infections
    19.4
    18.2
        Year 7 High Blood Pressure
    0
    3
        Year 7 Hypothyroidism
    13.9
    15.2
        Year 7 Scoliosis
    13.9
    30.3
        Year 8 Diabetes
    2.8
    0
        Year 8 Dilatation of the Aorta
    2.8
    9.1
        Year 8 Ear infections
    13.9
    18.2
        Year 8 High Blood Pressure
    0
    3
        Year 8 Hypothyroidism
    5.6
    12.1
        Year 8 Scoliosis
    13.9
    33.3
        Year 9 Dilatation of the Aorta
    0
    3
        Year 9 Ear infections
    2.8
    3
        Year 9 High Blood Pressure
    0
    3
        Year 9 Hypothyroidism
    2.8
    6.1
        Year 9 Scoliosis
    5.6
    9.1
        Year 10 Scoliosis
    2.8
    0
    No statistical analyses for this end point

    Secondary: Percentage of participants with abnormal tympanometry results

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    End point title
    		 Percentage of participants with abnormal tympanometry results
    End point description
    Percentage of participants with abnormal tympanometry [defined as middle ear dysfunction / middle ear effusion / patent pressure equalizer tube or possible tympanic membrane perforation] results at baseline, age 10 years, and age 16 years or endpoint. Population Description: All participants who had a baseline visit, regardless of whether or not they received Humatrope at any time.
    End point type
    Secondary
    End point timeframe
    Baseline, Age 10, Age 16, End of Study (10 years)
    End point values
    		 Early Treated Early Untreated
    Number of subjects analysed
    36
    33
    Units: percentage of participants
    number (not applicable)
        Baseline Right Ear
    44.4
    54.5
        Baseline Left Ear
    47.2
    45.5
        Age 10 Right Ear
    27.8
    15.2
        Age 10 Left Ear
    27.8
    15.2
        Age 16 Right Ear
    2.8
    9.1
        Age 16 Left Ear
    2.8
    3
        Endpoint Right Ear
    8.3
    12.1
        Endpoint Left Ear
    11.1
    9.1
    No statistical analyses for this end point

    Secondary: Percentage of participants with prevalence of abnormal Audiometry results

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    End point title
    		 Percentage of participants with prevalence of abnormal Audiometry results
    End point description
    Percentage of participants with abnormal Audiometry results at baseline, age 10 years, and age 16 years or endpoint. Prevalence was calculated as number of participants with abnormal hearing divided by number of participants with measurable pure tone audiometry results at that visit. Population Description: All participants who had a baseline visit, regardless of whether or not they received Humatrope at any time.
    End point type
    Secondary
    End point timeframe
    Baseline, Age 10, Age 16, End of Study (10 years)
    End point values
    		 Early Treated Early Untreated
    Number of subjects analysed
    36
    33
    Units: percentage of participants
    number (not applicable)
        Baseline Visit (n=36, 33)
    52.8
    48.5
        Age 10 (n=27, 24)
    44.4
    29.2
        Age 16 (n=7, 9)
    85.7
    66.7
        Endpoint (n=24, 22)
    37.5
    40.9
    No statistical analyses for this end point

    Secondary: Percentage of participants with abnormal Audiometry results Based on Pure Tone Average (PTA)

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    End point title
    		 Percentage of participants with abnormal Audiometry results Based on Pure Tone Average (PTA)
    End point description
    Percentage of participants with abnormal Audiometry results at baseline, age 10 years, and age 16 years or endpoint. PTA is defined as the average of pure tone hearing thresholds at 500, 1000 and 2000 Hz (Hertz), calculated separately for each ear and for each testing method (air or bone); normal PTA is defined as pure tone hearing threshold less than or equal to 20 dB HL (decibels Hearing Level), and abnormal PTA is defined as pure tone hearing threshold greater than 20 DB HL. Population Description: All participants who had a baseline visit, regardless of whether or not they received Humatrope at any time.
    End point type
    Secondary
    End point timeframe
    Baseline, Age 10, Age 16, End of Study (10 years)
    End point values
    		 Early Treated Early Untreated
    Number of subjects analysed
    36
    33
    Units: percentage of participants
    number (not applicable)
        Baseline Left Ear Air (n=36, 32)
    30.6
    31.3
        Baseline Left Ear Bone (n=36, 32)
    2.8
    0
        Baseline Right Ear Air (n=36, 32)
    22.2
    37.5
        Baseline Right Ear Bone (n=36, 32)
    22.2
    2.8
        Age 10 Left Ear Air (n=27, 21)
    29.6
    14.3
        Age 10 Left Ear Bone (n=27, 21)
    0
    0
        Age 10 Right Ear Air (n=27, 22)
    14.8
    18.2
        Age 10 Right Ear Bone (n=27, 22)
    0
    9.1
        Age 16 Left Ear Air (n=7, 9)
    57.1
    66.7
        Age 16 Left Ear Bone (n=7, 9)
    0
    0
        Age 16 Right Ear Air (n=7, 9)
    28.6
    33.3
        Age 16 Right Ear Bone (n=7, 9)
    0
    22.2
        Endpoint Left Ear Air (n=20, 20)
    30
    35
        Endpoint Left Ear Bone (n=20, 20)
    5
    20
        Endpoint Right Ear Air (n=20, 20)
    20
    35
        Endpoint Right Ear Bone (n=20, 20)
    10
    25
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire Study
    Adverse event reporting additional description
    B9R-US-GDGH
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Early Untreated
    Reporting group description
    		 -

    Reporting group title
    Early Treated
    Reporting group description
    		 -

    Serious adverse events
    		 Early Untreated Early Treated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 33 (15.15%)
    6 / 36 (16.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    medulloblastoma
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         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
    anomalous pulmonary venous connection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    atrial septal defect
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pterygium colli
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (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
    headache
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastrointestinal haemorrhage
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    mediastinal mass
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    scoliosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    cellulitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    gastroenteritis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lobar pneumonia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    pneumonia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    0 / 36 (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
    		 Early Untreated Early Treated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 33 (96.97%)
    34 / 36 (94.44%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    haemangioma
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    melanocytic naevus
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    9 / 33 (27.27%)
    11 / 36 (30.56%)
         occurrences all number
    9
    11
    skin papilloma
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 33 (12.12%)
    6 / 36 (16.67%)
         occurrences all number
    4
    7
    Vascular disorders
    aortic dilatation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    0 / 36 (0.00%)
         occurrences all number
    3
    0
    hypertension
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    lymphoedema
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    Surgical and medical procedures
    adenoidectomy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    ear tube insertion
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 33 (15.15%)
    4 / 36 (11.11%)
         occurrences all number
    7
    5
    mole excision
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    6 / 36 (16.67%)
         occurrences all number
    2
    6
    oral surgery
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    orthodontic procedure
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    7 / 33 (21.21%)
    4 / 36 (11.11%)
         occurrences all number
    7
    4
    palatal operation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    tooth extraction
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    tympanoplasty
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 36 (13.89%)
         occurrences all number
    3
    5
    wisdom teeth removal
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    General disorders and administration site conditions
    pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    peripheral swelling
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    pyrexia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    8 / 33 (24.24%)
    11 / 36 (30.56%)
         occurrences all number
    8
    11
    Immune system disorders
    drug hypersensitivity
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    multiple allergies
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    seasonal allergy
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    5 / 36 (13.89%)
         occurrences all number
    2
    5
    Social circumstances
    corrective lens user
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    8 / 33 (24.24%)
    3 / 36 (8.33%)
         occurrences all number
    8
    3
    orthodontic appliance user
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    7 / 33 (21.21%)
    9 / 36 (25.00%)
         occurrences all number
    7
    9
    Reproductive system and breast disorders
    dysmenorrhoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    Respiratory, thoracic and mediastinal disorders
    cough
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    6 / 33 (18.18%)
    8 / 36 (22.22%)
         occurrences all number
    6
    8
    nasal congestion
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    oropharyngeal pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 33 (12.12%)
    5 / 36 (13.89%)
         occurrences all number
    4
    5
    respiratory disorder
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    rhinorrhoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    sinus congestion
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Psychiatric disorders
    anxiety
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    6 / 33 (18.18%)
    7 / 36 (19.44%)
         occurrences all number
    6
    7
    depression
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    insomnia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    obsessive-compulsive disorder
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Investigations
    echocardiogram normal
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    6 / 33 (18.18%)
    2 / 36 (5.56%)
         occurrences all number
    6
    2
    electrocardiogram normal
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    ultrasound kidney normal
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    ultrasound scan normal
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    joint dislocation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    ligament sprain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    radius fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    wrist fracture
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Cardiac disorders
    palpitations
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    Nervous system disorders
    headache
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    9 / 33 (27.27%)
    11 / 36 (30.56%)
         occurrences all number
    10
    13
    Ear and labyrinth disorders
    conductive deafness
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    4 / 36 (11.11%)
         occurrences all number
    1
    4
    ear pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    6 / 36 (16.67%)
         occurrences all number
    4
    8
    hearing impaired
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    tympanic membrane perforation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    7 / 36 (19.44%)
         occurrences all number
    2
    8
    Eye disorders
    myopia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    abdominal pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    4 / 36 (11.11%)
         occurrences all number
    2
    4
    abdominal pain upper
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    coeliac disease
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    constipation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    3 / 36 (8.33%)
         occurrences all number
    2
    3
    diarrhoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 33 (15.15%)
    5 / 36 (13.89%)
         occurrences all number
    5
    5
    gastrooesophageal reflux disease
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    tooth malformation
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    toothache
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    vomiting
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    12 / 36 (33.33%)
         occurrences all number
    3
    12
    Skin and subcutaneous tissue disorders
    acne
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    3
    eczema
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    keloid scar
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    rash
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 33 (15.15%)
    0 / 36 (0.00%)
         occurrences all number
    5
    0
    seborrhoea
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    seborrhoeic dermatitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    1 / 36 (2.78%)
         occurrences all number
    3
    1
    Renal and urinary disorders
    dysuria
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    enuresis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    1 / 36 (2.78%)
         occurrences all number
    2
    1
    Endocrine disorders
    autoimmune thyroiditis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    goitre
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    hypothyroidism
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 33 (15.15%)
    4 / 36 (11.11%)
         occurrences all number
    5
    4
    Musculoskeletal and connective tissue disorders
    kyphosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    5 / 36 (13.89%)
         occurrences all number
    3
    5
    neck pain
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    scoliosis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    10 / 33 (30.30%)
    7 / 36 (19.44%)
         occurrences all number
    10
    7
    Infections and infestations
    bronchitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 33 (12.12%)
    5 / 36 (13.89%)
         occurrences all number
    4
    5
    conjunctivitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    4 / 36 (11.11%)
         occurrences all number
    3
    4
    croup infectious
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    ear infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    7 / 36 (19.44%)
         occurrences all number
    2
    7
    eye infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    gastroenteritis viral
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 33 (12.12%)
    7 / 36 (19.44%)
         occurrences all number
    5
    7
    impetigo
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    influenza
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    3 / 33 (9.09%)
    6 / 36 (16.67%)
         occurrences all number
    3
    6
    kidney infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    mononucleosis syndrome
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    nasopharyngitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    4 / 33 (12.12%)
    8 / 36 (22.22%)
         occurrences all number
    5
    9
    otitis externa
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    5 / 33 (15.15%)
    3 / 36 (8.33%)
         occurrences all number
    6
    4
    otitis media
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    12 / 33 (36.36%)
    9 / 36 (25.00%)
         occurrences all number
    14
    11
    pharyngitis streptococcal
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    9 / 33 (27.27%)
    4 / 36 (11.11%)
         occurrences all number
    9
    4
    pneumonia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    2 / 33 (6.06%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    sinusitis
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    7 / 33 (21.21%)
    7 / 36 (19.44%)
         occurrences all number
    7
    7
    upper respiratory tract infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    6 / 33 (18.18%)
    1 / 36 (2.78%)
         occurrences all number
    7
    1
    urinary tract infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    8 / 36 (22.22%)
         occurrences all number
    0
    9
    vaginal infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    viral infection
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    0 / 33 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    0
    5
    Metabolism and nutrition disorders
    hyperlipidaemia
    alternative dictionary used: MedDRA 18.0
         subjects affected / exposed
    1 / 33 (3.03%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3

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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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