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    Clinical Trial Results:
    In search for an innovative neural marker and intervention for socio-communicative difficulties in children with and without autism spectrum disorders

    Summary
    EudraCT number
    		 2018-000769-35
    Trial protocol
    		 BE  
    Global end of trial date
    30 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Mar 2022
    First version publication date
    18 Mar 2022
    Other versions
    Summary report(s)
    		 MOX study

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    S61358
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Leuven / KU Leuven
    Sponsor organisation address
    Oude Markt 13, Leuven, Belgium, 3000
    Public contact
    Prof. Dr. K. Alaerts, University Hospital, KU Leuven, 0032 16376446, kaat.alaerts@kuleuven.be
    Scientific contact
    Prof. Dr. K. Alaerts, University Hospital, KU Leuven, 0032 16376446, kaat.alaerts@kuleuven.be
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Aug 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Exploring the effects and mechanism of multiple-dose oxytocin treatment (OT) in children with Autism Spectrum Disorders (ASD) (age 8-12 years). The principal aim of the current clinical trial is to explore the effects and mechanism of multiple-dose OT treatment in children with ASD, by assessing the effects of treatment both at the neural and the behavioral level.
    Protection of trial subjects
    Regular screenings of potential side-effects
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2019
    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
    Belgium: 80
    Worldwide total number of subjects
    80
    EEA total number of subjects
    80
    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)
    11
    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
    		 Children with ASD were recruited mainly via the Expertise Centrum Autisme (ECA) of the UZ Leuven between July 2019 and January 2021.

    Pre-assignment
    Screening details
    		 Screening details: Assessed for eligibility (n= 101) Included: 80 Excluded: 21 not meeting inclusion criteria n = 5 declined to participate n = 16 other reasons n = 0

    Period 1
    Period 1 title
    Phase 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    In phase I, half of the patients will receive oxytocin nasal sprays while the other half will receive placebo nasal sprays. All patients, their parents, and investigators involved in the data collection and analysis will be blind with respect to the allocated treatment condition.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Oxytocin
    Arm description
    		 OT (Syntocinon®) was administered using a twice daily intranasal dose of 12 IU resulting a daily dose of 24IU. They had to administer the spray in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril; 2 IU/ puff).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Syntocinon® nasal spray (40 IU/ml)
    Investigational medicinal product code
    RVG 03716
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    A twice daily intranasal dose of 12 IU resulting a daily dose of 24IU. The participants will be asked to administer the spray in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril; 2 IU/ puff).

    Arm title
    		 Placebo
    Arm description
    		 Physiological water, sodium chloride (NaCl .9%) solution, with added preservatives (aqua conservans, chlorbutanol, glycerin) was used for the placebo (PL) nasal spray. Participants had to administer the spray daily in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (Physiological water, sodium chloride (NaCl .9%) solution, with added preservatives (aqua conservans, chlorbutanol, glycerin)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    Physiological water, sodium chloride (NaCl .9%) solution, with added preservatives (aqua conservans, chlorbutanol, glycerin) was used for the placebo (PL) nasal spray. They had to administer the spray daily in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril; 2 IU/ puff) during four weeks.

    Number of subjects in period 1
    		Oxytocin Placebo
    Started
    40
    40
    Completed
    40
    40
    Period 2
    Period 2 title
    Phase II
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    Both groups of phase I (OT and placebo) received the real multiple-dose OT intervention. Hence, the investigators conducting the trial were no longer blind with respect to the received treatment (all OT). The parents of the participating children were informed that all children will receive the real OT treatment during at least one of the two administration months. All patients and their parents were blind to the treatment assignment, since the order of the treatment phases was concealed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OT - first
    Arm description
    		 Administration via nasal spray Syntocinon® (Oxytocin): Syntocinon nasal spray. A twice daily intranasal dose of 12 IU resulting a daily dose of 24IU during four weeks. They had to administer the spray in the morning and in the afternoon by administering six puffs (three puffs in each nosetril; 2 IU/ puff).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Syntocinon® nasal spray (40 IU/ml)
    Investigational medicinal product code
    RVG 03716
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    A twice daily intranasal dose of 12 IU resulting a daily dose of 24IU. The participants will be asked to administer the spray in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril; 2 IU/ puff).

    Arm title
    		 PL - first
    Arm description
    		 Administration via nasal spray Syntocinon® (Oxytocin): Syntocinon nasal spray. A twice daily intranasal dose of 12 IU resulting a daily dose of 24IU during four weeks. They had to administer the spray in the morning and in the afternoon by administering six puffs (three puffs in each nosetril; 2 IU/ puff).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Syntocinon® nasal spray (40 IU/ml)
    Investigational medicinal product code
    RVG 03716
    Other name
    Pharmaceutical forms
    Nasal spray
    Routes of administration
    Intranasal use
    Dosage and administration details
    A twice daily intranasal dose of 12 IU resulting a daily dose of 24IU. The participants will be asked to administer the spray in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril; 2 IU/ puff).

    Number of subjects in period 2 [1]
    		OT - first PL - first
    Started
    38
    39
    Completed
    38
    39
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The number of subjects starting the period Phase II is not consistent with the number completing the preceding period because 3 subjects (Oxytocin n = 2, Placebo n = 1) withdrew their consent to participate due to time constraints.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Oxytocin
    Reporting group description
    		 OT (Syntocinon®) was administered using a twice daily intranasal dose of 12 IU resulting a daily dose of 24IU. They had to administer the spray in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril; 2 IU/ puff).

    Reporting group title
    Placebo
    Reporting group description
    		 Physiological water, sodium chloride (NaCl .9%) solution, with added preservatives (aqua conservans, chlorbutanol, glycerin) was used for the placebo (PL) nasal spray. Participants had to administer the spray daily in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril).

    Reporting group values
    		 Oxytocin Placebo Total
    Number of subjects
    		 40 40 80
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 34 35 69
        Adolescents (12-17 years)
    		 6 5 11
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.53 ( 1.35 ) 10.45 ( 1.27 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8 16
        Male
    		 32 32 64
    Total IQ
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 104.03 ( 13.10 ) 105.60 ( 11.38 ) -

    End points

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    End points reporting groups
    Reporting group title
    Oxytocin
    Reporting group description
    		 OT (Syntocinon®) was administered using a twice daily intranasal dose of 12 IU resulting a daily dose of 24IU. They had to administer the spray in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril; 2 IU/ puff).

    Reporting group title
    Placebo
    Reporting group description
    		 Physiological water, sodium chloride (NaCl .9%) solution, with added preservatives (aqua conservans, chlorbutanol, glycerin) was used for the placebo (PL) nasal spray. Participants had to administer the spray daily in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril).
    Reporting group title
    OT - first
    Reporting group description
    		 Administration via nasal spray Syntocinon® (Oxytocin): Syntocinon nasal spray. A twice daily intranasal dose of 12 IU resulting a daily dose of 24IU during four weeks. They had to administer the spray in the morning and in the afternoon by administering six puffs (three puffs in each nosetril; 2 IU/ puff).

    Reporting group title
    PL - first
    Reporting group description
    		 Administration via nasal spray Syntocinon® (Oxytocin): Syntocinon nasal spray. A twice daily intranasal dose of 12 IU resulting a daily dose of 24IU during four weeks. They had to administer the spray in the morning and in the afternoon by administering six puffs (three puffs in each nosetril; 2 IU/ puff).

    Subject analysis set title
    Phase 1 Post OT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Phase 1 T1 - OT

    Subject analysis set title
    Phase 1 Follow-up OT
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Phase 1 T2 OT

    Subject analysis set title
    Phase 1 Post PL
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Phase 1 T1 PL

    Subject analysis set title
    Phase 1 Follow-up PL
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Phase 1 T2 PL

    Subject analysis set title
    Phase 2 Post OT First
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Phase 2 Post T3 OT

    Subject analysis set title
    Phase 2 Follow-up OT First
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Phase 2 T4 OT

    Subject analysis set title
    Phase 2 Post PL First
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Phase 2 T3 (PL First)

    Subject analysis set title
    Phase 2 Follow-up PL First
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Phase 2 T4 (PL First)

    Primary: Change from baseline in caregiver-rated scores on questionnaire assessing social functioning after 4 weeks of nasal spray

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    End point title
    		 Change from baseline in caregiver-rated scores on questionnaire assessing social functioning after 4 weeks of nasal spray
    End point description
    Social responsiveness Scale-Children (SRS) - caregiver-rated - four-point Likert-scale - higher scores indicate lower social responsiveness
    End point type
    Primary
    End point timeframe
    Value at 4 weeks minus value at baseline
    End point values
    		 Phase 1 Post OT Phase 1 Post PL
    Number of subjects analysed
    38
    38
    Units: Change from base (units on a scale)
        arithmetic mean (standard deviation)
    -4.08 ( 10.05 )
    -4.55 ( 10.23 )
    Statistical analysis title
    		 SRS after 4 weeks of nasal spray
    Statistical analysis description
    Between-group differences in treatment responses of phase I (double-blind) were assessed, by subjecting change from baseline scores of the post session to independent sample t-tests.
    Comparison groups
    Phase 1 Post OT v Phase 1 Post PL
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.839
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Change from baseline in caregiver-rated scores on questionnaire assessing social functioning after 8 weeks, including 4 weeks without nasal spray

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    End point title
    		 Change from baseline in caregiver-rated scores on questionnaire assessing social functioning after 8 weeks, including 4 weeks without nasal spray
    End point description
    Social responsiveness Scale-Children (SRS) - caregiver-rated - four-point Likert-scale - higher scores indicate lower social responsiveness
    End point type
    Primary
    End point timeframe
    Value at 8 weeks minus value at baseline
    End point values
    		 Phase 1 Follow-up OT Phase 1 Follow-up PL
    Number of subjects analysed
    38
    39
    Units: Change from base (units on a scale)
        arithmetic mean (standard deviation)
    -6.76 ( 11.19 )
    -5.38 ( 13.42 )
    Statistical analysis title
    		 SRS after 8 weeks, including 4 weeks without nasal
    Statistical analysis description
    Between-group differences in treatment responses of phase I (double-blind) were assessed, by subjecting change from baseline scores of the follow-up session to independent sample t-tests.
    Comparison groups
    Phase 1 Follow-up OT v Phase 1 Follow-up PL
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.626
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Change from baseline in caregiver-rated scores on questionnaire assessing repetitive behaviors and anxiety after 4 weeks of nasal spray

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    End point title
    		 Change from baseline in caregiver-rated scores on questionnaire assessing repetitive behaviors and anxiety after 4 weeks of nasal spray
    End point description
    Repetitive Behavior Scale-Revised (RBS-R) – caregiver-rated – four-point Likert-scale – higher scores indicate more severe repetitive behavior Screen for Child Anxiety Related Emotional Disorders (SCARED-NL) – caregiver-rated – three-point Likert scale – higher scores indicate greater risk for an anxiety disorder
    End point type
    Secondary
    End point timeframe
    Value at 4 weeks minus value at baseline
    End point values
    		 Phase 1 Post OT Phase 1 Post PL
    Number of subjects analysed
    38
    38
    Units: Change from base (units on a scale)
    arithmetic mean (standard deviation)
        RBS
    -6.53 ( 11.26 )
    -6.76 ( 9.92 )
        SCARED caregiver report
    -0.47 ( 11.61 )
    -4.95 ( 11.93 )
    No statistical analyses for this end point

    Secondary: Change from baseline in self-report scores on questionnaire assessing attachment and anxiety after 4 weeks of nasal spray

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    End point title
    		 Change from baseline in self-report scores on questionnaire assessing attachment and anxiety after 4 weeks of nasal spray
    End point description
    Screen for Child Anxiety Related Emotional Disorders (SCARED-NL) – self-rated – three-point Likert scale – higher scores indicate greater risk for an anxiety disorder Attachment Style Classification Questionnaire (ASQ), three scales: secure, anxious or avoidant – self-report – five-point Likert-scale – higher scores indicate a more secure, anxious or avoidant attachment toward their peers Attachment questionnaire, three scales: trust, anxiety and avoidance – self-report – seven-point Likert-scale – higher scores indicate more trust, anxiety or avoidance towards their mother
    End point type
    Secondary
    End point timeframe
    Value at 4 weeks minus value at baseline
    End point values
    		 Phase 1 Post OT Phase 1 Post PL
    Number of subjects analysed
    38
    39
    Units: Change from base (units on a scale)
    arithmetic mean (standard deviation)
        SCARED self report
    -4.74 ( 11.47 )
    -3.38 ( 11.32 )
        ASQ - secure
    -0.89 ( 2.42 )
    -0.92 ( 2.93 )
        ASQ - anxious
    -0.92 ( 3.24 )
    -1.00 ( 2.50 )
        ASQ - avoidant
    -0.29 ( 3.73 )
    -1.08 ( 3.30 )
        Attachment peers - anxiety
    0.76 ( 2.95 )
    -0.33 ( 2.57 )
        Attachment peers - avoidance
    -0.21 ( 3.18 )
    -0.82 ( 3.94 )
        Attachment peers - trust
    0.24 ( 4.18 )
    -0.18 ( 2.55 )
    No statistical analyses for this end point

    Secondary: Change from baseline in caregiver-rated scores on questionnaire assessing repetitive behaviors and anxiety after 8 weeks, including 4 weeks without nasal spray

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    End point title
    		 Change from baseline in caregiver-rated scores on questionnaire assessing repetitive behaviors and anxiety after 8 weeks, including 4 weeks without nasal spray
    End point description
    Repetitive Behavior Scale-Revised (RBS-R) – caregiver-rated – four-point Likert-scale – higher scores indicate more severe repetitive behavior Screen for Child Anxiety Related Emotional Disorders (SCARED-NL) – caregiver-rated – three-point Likert scale – higher scores indicate greater risk for an anxiety disorder
    End point type
    Secondary
    End point timeframe
    Value at 8 weeks minus value at baseline
    End point values
    		 Phase 1 Follow-up OT Phase 1 Follow-up PL
    Number of subjects analysed
    38
    39
    Units: Change from base (units on a scale)
    arithmetic mean (standard deviation)
        RBS
    -4.55 ( 10.76 )
    -4.41 ( 8.28 )
        SCARED caregiver rated
    -2.92 ( 11.53 )
    -5.38 ( 9.52 )
    No statistical analyses for this end point

    Secondary: Change from baseline in self-report scores on questionnaire assessing attachment and anxiety after 8 weeks, including 4 weeks without nasal spray

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    End point title
    		 Change from baseline in self-report scores on questionnaire assessing attachment and anxiety after 8 weeks, including 4 weeks without nasal spray
    End point description
    Screen for Child Anxiety Related Emotional Disorders (SCARED-NL) – self-rated – three-point Likert scale – higher scores indicate greater risk for an anxiety disorder Attachment Style Classification Questionnaire (ASQ), three scales: secure, anxious or avoidant – self-report – five-point Likert-scale – higher scores indicate a more secure, anxious or avoidant attachment toward their peers. Attachment questionnaire, three scales: trust, anxiety and avoidance – self-report – seven-point Likert-scale – higher scores indicate more trust, anxiety or avoidance towards their mother.
    End point type
    Secondary
    End point timeframe
    Value at 8 weeks minus value at baseline
    End point values
    		 Phase 1 Follow-up OT Phase 1 Follow-up PL
    Number of subjects analysed
    38
    39
    Units: Change from base (units on a scale)
    arithmetic mean (standard deviation)
        SCARED self report
    -5.97 ( 9.84 )
    -6.36 ( 13.38 )
        ASQ - secure
    -1.37 ( 3.34 )
    -0.82 ( 3.78 )
        ASQ - anxious
    -1.00 ( 3.92 )
    -2.38 ( 3.75 )
        ASQ - avoidant
    -0.84 ( 4.04 )
    -1.46 ( 3.09 )
        Attachment peers - anxiety
    0.84 ( 3.11 )
    0.08 ( 3.07 )
        Attachment peers - avoidance
    -0.61 ( 3.89 )
    -0.67 ( 3.50 )
        Attachment peers - trust
    0.66 ( 3.93 )
    0.13 ( 2.83 )
    No statistical analyses for this end point

    Secondary: Change from baseline in caregiver-rated scores on questionnaires assessing social functioning, repetitive behaviors and anxiety after 12 weeks, including 8 weeks of intermittent nasal spray

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    End point title
    		 Change from baseline in caregiver-rated scores on questionnaires assessing social functioning, repetitive behaviors and anxiety after 12 weeks, including 8 weeks of intermittent nasal spray
    End point description
    Social responsiveness Scale-Children (SRS) - caregiver-rated - four-point Likert-scale - higher scores indicate lower social responsiveness Repetitive Behavior Scale-Revised (RBS-R) – caregiver-rated – four-point Likert-scale – higher scores indicate more severe repetitive behavior Screen for Child Anxiety Related Emotional Disorders (SCARED-NL) – caregiver-rated – three-point Likert scale – higher scores indicate greater risk for an anxiety disorder
    End point type
    Secondary
    End point timeframe
    Value at 12 weeks minus value at baseline
    End point values
    		 Phase 2 Post OT First Phase 2 Post PL First
    Number of subjects analysed
    37
    38
    Units: Change from base (units on a scale)
    arithmetic mean (standard deviation)
        SRS
    -5.57 ( 13.24 )
    -10.84 ( 14.77 )
        RBS
    -6.46 ( 11.96 )
    -7.13 ( 8.54 )
        SCARED caregiver report
    -2.95 ( 9.80 )
    -7.18 ( 10.30 )
    No statistical analyses for this end point

    Secondary: Change from baseline in self-report scores on questionnaires assessing attachment and anxiety after 12 weeks, including 8 weeks of intermittent nasal spray

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    End point title
    		 Change from baseline in self-report scores on questionnaires assessing attachment and anxiety after 12 weeks, including 8 weeks of intermittent nasal spray
    End point description
    Screen for Child Anxiety Related Emotional Disorders (SCARED-NL) – self-rated – three-point Likert scale – higher scores indicate greater risk for an anxiety disorder Attachment questionnaire, three scales: trust, anxiety and avoidance – self-report – seven-point Likert-scale – higher scores indicate more trust, anxiety or avoidance towards their mother Attachment Style Classification Questionnaire (ASQ), three scales: secure, anxious or avoidant – self-report – five-point Likert-scale – higher scores indicate a more secure, anxious or avoidant attachment toward their peers
    End point type
    Secondary
    End point timeframe
    Value at 12 weeks minus value at baseline
    End point values
    		 Phase 2 Post OT First Phase 2 Post PL First
    Number of subjects analysed
    37
    39
    Units: Change from base (units on a scale)
    arithmetic mean (standard deviation)
        SCARED self report
    -8.65 ( 14.26 )
    -7.23 ( 16.85 )
        ASQ - secure
    -1.51 ( 3.68 )
    -0.82 ( 3.60 )
        ASQ - anxious
    -1.32 ( 5.03 )
    -2.44 ( 3.78 )
        ASQ - avoidant
    -1.51 ( 4.27 )
    -1.31 ( 3.33 )
        Attachment peers - anxiety
    0.92 ( 3.77 )
    0.31 ( 3.46 )
        Attachment peers - avoidance
    -0.84 ( 4.17 )
    -1.13 ( 3.47 )
        Attachment peers - trust
    0.32 ( 4.77 )
    -0.85 ( 3.54 )
    No statistical analyses for this end point

    Secondary: Change from baseline in caregiver-rated scores on questionnaires assessing social functioning, repetitive behaviors and anxiety after 16 weeks, including 8 weeks of intermittent nasal spray

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    End point title
    		 Change from baseline in caregiver-rated scores on questionnaires assessing social functioning, repetitive behaviors and anxiety after 16 weeks, including 8 weeks of intermittent nasal spray
    End point description
    Social responsiveness Scale-Children (SRS) – caregiver-rated – four-point Likert-scale – higher scores indicate lower social responsiveness Repetitive Behavior Scale-Revised (RBS-R) – caregiver-rated – four-point Likert-scale – higher scores indicate more severe repetitive behavior Screen for Child Anxiety Related Emotional Disorders (SCARED-NL) – caregiver-rated – three-point Likert scale – higher scores indicate greater risk for an anxiety disorder
    End point type
    Secondary
    End point timeframe
    Value at 16 weeks minus value at baseline
    End point values
    		 Phase 2 Follow-up OT First Phase 2 Follow-up PL First
    Number of subjects analysed
    36
    36
    Units: Change from base (units on a scale)
    arithmetic mean (standard deviation)
        SRS
    -9.61 ( 12.18 )
    -9.81 ( 14.83 )
        RBS
    -7.53 ( 12.88 )
    -7.83 ( 9.35 )
        SCARED caregiver report
    -5.72 ( 13.04 )
    -8.17 ( 10.45 )
    No statistical analyses for this end point

    Secondary: Change from baseline in self-report scores on questionnaires assessing attachment and anxiety after 16 weeks, including 8 weeks of intermittent nasal spray

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    End point title
    		 Change from baseline in self-report scores on questionnaires assessing attachment and anxiety after 16 weeks, including 8 weeks of intermittent nasal spray
    End point description
    Screen for Child Anxiety Related Emotional Disorders (SCARED-NL) – self-rated – three-point Likert scale – higher scores indicate greater risk for an anxiety disorder Attachment questionnaire, three scales: trust, anxiety and avoidance – self-report – seven-point Likert-scale – higher scores indicate more trust, anxiety or avoidance towards their mother Attachment Style Classification Questionnaire (ASQ), three scales: secure, anxious or avoidant – self-report – five-point Likert-scale – higher scores indicate a more secure, anxious or avoidant attachment toward their peers
    End point type
    Secondary
    End point timeframe
    Value at 16 weeks minus value at baseline
    End point values
    		 Phase 2 Follow-up OT First Phase 2 Follow-up PL First
    Number of subjects analysed
    36
    37
    Units: Change from base (units on a scale)
    arithmetic mean (standard deviation)
        SCARED self report
    -9.86 ( 17.39 )
    -10.73 ( 18.14 )
        ASQ - secure
    -1.72 ( 3.50 )
    -1.05 ( 3.47 )
        ASQ - anxious
    -1.44 ( 3.77 )
    -2.14 ( 4.18 )
        ASQ - avoidant
    -1.17 ( 3.79 )
    -0.84 ( 3.85 )
        Attachment peers - anxiety
    1.00 ( 4.53 )
    0.11 ( 3.07 )
        Attachment peers - avoidance
    -0.86 ( 4.00 )
    -0.73 ( 3.30 )
        Attachment peers - trust
    0.11 ( 4.37 )
    -0.38 ( 3.27 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event data were collected over a period of (approximately) 4.3 months (131 days). Reporting of AE took place from baseline until end of trial.
    Adverse event reporting additional description
    At the end of each week during the course of the daily treatment, parents of the patients were asked to indicate whether or not their child experienced any potential adverse events. A medical person, who is not involved in data analysis or data collection, reviewed all potential adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Informant-report
    Dictionary version
    2018
    Reporting groups
    Reporting group title
    Phase 1 - Syntocinon (Oxytocin)
    Reporting group description
    		 Reporting of AE during the first 8 weeks of the trial, administering an OT nasal spray during the first 4 weeks of this reporting time frame OT (Syntocinon®) was administered using a twice daily intranasal dose of 12 IU resulting a daily dose of 24IU. They had to administer the spray in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril; 2 IU/ puff).

    Reporting group title
    Phase 1 - Placebo (Physiological water(sodium chloride (NaCl)
    Reporting group description
    		 Reporting of AE during the first 8 weeks of the trial, administering an PL nasal spray during the first 4 weeks of this reporting time frame. Physiological water, sodium chloride (NaCl .9%) solution, with added preservatives (aqua conservans, chlorbutanol, glycerin) was used for the placebo (PL) nasal spray. They had to administer the spray daily in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril) during four weeks.

    Reporting group title
    Phase 2 - OT first
    Reporting group description
    		 Reporting of AE during the second phase (duration of 8 weeks) of the trial after administering an OT spray in the first phase and administering an OT nasal spray in the first 4 weeks of this second reporting time frame. OT (Syntocinon®) was administered using a twice daily intranasal dose of 12 IU resulting a daily dose of 24IU. They had to administer the spray in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril; 2 IU/ puff).

    Reporting group title
    Phase 2 - PL first
    Reporting group description
    		 Reporting of AE during the second phase (duration of 8 weeks) of the trial after administering a PL spray in the first phase and administering an OT nasal spray in the first 4 weeks of this second reporting time frame. OT (Syntocinon®) was administered using a twice daily intranasal dose of 12 IU resulting a daily dose of 24IU. They had to administer the spray in the morning and in the afternoon (right after school) by administering six puffs (three puffs in each nosetril; 2 IU/ puff).

    Serious adverse events
    		 Phase 1 - Syntocinon (Oxytocin) Phase 1 - Placebo (Physiological water(sodium chloride (NaCl) Phase 2 - OT first Phase 2 - PL first
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
    4 / 40 (10.00%)
    0 / 38 (0.00%)
    4 / 39 (10.26%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 40 (0.00%)
    0 / 38 (0.00%)
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Anger
    Additional description: Severe episode of anger, aggression and irritability
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 40 (2.50%)
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Viral infection
    Additional description: Fever and flu-like symptoms
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
    0 / 38 (0.00%)
    3 / 39 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1 - Syntocinon (Oxytocin) Phase 1 - Placebo (Physiological water(sodium chloride (NaCl) Phase 2 - OT first Phase 2 - PL first
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 40 (67.50%)
    31 / 40 (77.50%)
    23 / 38 (60.53%)
    24 / 39 (61.54%)
    Cardiac disorders
    Changes in heart rate or palpitation
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    2
    0
    General disorders and administration site conditions
    Headache
         subjects affected / exposed
    7 / 40 (17.50%)
    7 / 40 (17.50%)
    6 / 38 (15.79%)
    7 / 39 (17.95%)
         occurrences all number
    14
    9
    9
    10
    Drowsiness
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 40 (5.00%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    8
    3
    2
    1
    Sore throat
         subjects affected / exposed
    3 / 40 (7.50%)
    5 / 40 (12.50%)
    2 / 38 (5.26%)
    5 / 39 (12.82%)
         occurrences all number
    4
    8
    6
    7
    Dry throat/ dry mouth
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 40 (5.00%)
    3 / 38 (7.89%)
    2 / 39 (5.13%)
         occurrences all number
    3
    2
    7
    4
    Hoarseness
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 40 (5.00%)
    3 / 38 (7.89%)
    1 / 39 (2.56%)
         occurrences all number
    1
    3
    3
    1
    Congested nose
         subjects affected / exposed
    9 / 40 (22.50%)
    7 / 40 (17.50%)
    3 / 38 (7.89%)
    4 / 39 (10.26%)
         occurrences all number
    12
    11
    8
    7
    Sneezing
         subjects affected / exposed
    6 / 40 (15.00%)
    3 / 40 (7.50%)
    1 / 38 (2.63%)
    2 / 39 (5.13%)
         occurrences all number
    7
    4
    1
    2
    Nasal irritation
         subjects affected / exposed
    5 / 40 (12.50%)
    3 / 40 (7.50%)
    3 / 38 (7.89%)
    3 / 39 (7.69%)
         occurrences all number
    8
    3
    6
    3
    Runny nose
         subjects affected / exposed
    5 / 40 (12.50%)
    1 / 40 (2.50%)
    2 / 38 (5.26%)
    3 / 39 (7.69%)
         occurrences all number
    6
    2
    2
    5
    Burning sensation in nose and/ or ears
         subjects affected / exposed
    4 / 40 (10.00%)
    0 / 40 (0.00%)
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    7
    0
    1
    1
    Insomnia/ sleep difficulties
         subjects affected / exposed
    4 / 40 (10.00%)
    4 / 40 (10.00%)
    3 / 38 (7.89%)
    3 / 39 (7.69%)
         occurrences all number
    5
    4
    3
    3
    Staring/ daydreams
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 40 (0.00%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    2
    0
    2
    1
    Sensitive for fragrances
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    1
    0
    3
    1
    Ear and labyrinth disorders
    Dizziness
         subjects affected / exposed
    6 / 40 (15.00%)
    1 / 40 (2.50%)
    0 / 38 (0.00%)
    2 / 39 (5.13%)
         occurrences all number
    8
    2
    0
    2
    Eye disorders
    Watery eyes
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 40 (0.00%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Social circumstances
    Less talk to others
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 40 (5.00%)
    1 / 38 (2.63%)
    4 / 39 (10.26%)
         occurrences all number
    2
    2
    1
    5
    Persistent thoughts and/or feelings
         subjects affected / exposed
    2 / 40 (5.00%)
    5 / 40 (12.50%)
    2 / 38 (5.26%)
    3 / 39 (7.69%)
         occurrences all number
    2
    7
    4
    3
    Irritability / anger
         subjects affected / exposed
    6 / 40 (15.00%)
    7 / 40 (17.50%)
    7 / 38 (18.42%)
    6 / 39 (15.38%)
         occurrences all number
    8
    11
    8
    7
    Sad
         subjects affected / exposed
    4 / 40 (10.00%)
    5 / 40 (12.50%)
    4 / 38 (10.53%)
    2 / 39 (5.13%)
         occurrences all number
    4
    7
    5
    2
    Prone to crying or more emotional
         subjects affected / exposed
    5 / 40 (12.50%)
    9 / 40 (22.50%)
    6 / 38 (15.79%)
    4 / 39 (10.26%)
         occurrences all number
    6
    15
    10
    4
    Anxious, worried or discomfort
         subjects affected / exposed
    3 / 40 (7.50%)
    1 / 40 (2.50%)
    4 / 38 (10.53%)
    1 / 39 (2.56%)
         occurrences all number
    5
    2
    6
    1
    Happy or satisfied
         subjects affected / exposed
    8 / 40 (20.00%)
    14 / 40 (35.00%)
    12 / 38 (31.58%)
    10 / 39 (25.64%)
         occurrences all number
    15
    27
    19
    16
    Euphoric or unusually happy
         subjects affected / exposed
    5 / 40 (12.50%)
    6 / 40 (15.00%)
    4 / 38 (10.53%)
    2 / 39 (5.13%)
         occurrences all number
    9
    10
    6
    2
    Calm, relaxed or comfortable
         subjects affected / exposed
    11 / 40 (27.50%)
    17 / 40 (42.50%)
    12 / 38 (31.58%)
    11 / 39 (28.21%)
         occurrences all number
    18
    30
    19
    20
    More focused
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 40 (7.50%)
    3 / 38 (7.89%)
    3 / 39 (7.69%)
         occurrences all number
    1
    5
    4
    4
    More confidence
         subjects affected / exposed
    4 / 40 (10.00%)
    8 / 40 (20.00%)
    5 / 38 (13.16%)
    6 / 39 (15.38%)
         occurrences all number
    5
    13
    6
    10
    Uninterested in others
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 40 (2.50%)
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    4
    1
    2
    1
    Nail biting
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    1
    0
    2
    1
    Gastrointestinal disorders
    Nausea and/ or vomiting
         subjects affected / exposed
    3 / 40 (7.50%)
    3 / 40 (7.50%)
    3 / 38 (7.89%)
    1 / 39 (2.56%)
         occurrences all number
    4
    4
    5
    1
    Abdominal or stomach pain
         subjects affected / exposed
    9 / 40 (22.50%)
    8 / 40 (20.00%)
    6 / 38 (15.79%)
    5 / 39 (12.82%)
         occurrences all number
    19
    10
    10
    6
    Decreased appetite
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 40 (5.00%)
    4 / 38 (10.53%)
    5 / 39 (12.82%)
         occurrences all number
    5
    3
    6
    6
    Hungry or increased appetite
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 40 (5.00%)
    1 / 38 (2.63%)
    1 / 39 (2.56%)
         occurrences all number
    1
    2
    1
    1
    Constipation
         subjects affected / exposed
    5 / 40 (12.50%)
    2 / 40 (5.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    11
    2
    1
    0
    Diarrhea
         subjects affected / exposed
    2 / 40 (5.00%)
    1 / 40 (2.50%)
    3 / 38 (7.89%)
    0 / 39 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Increased fluid intake
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 40 (0.00%)
    2 / 38 (5.26%)
    1 / 39 (2.56%)
         occurrences all number
    1
    0
    4
    2
    Respiratory, thoracic and mediastinal disorders
    Coughing
         subjects affected / exposed
    4 / 40 (10.00%)
    2 / 40 (5.00%)
    3 / 38 (7.89%)
    2 / 39 (5.13%)
         occurrences all number
    6
    3
    5
    2
    Coughing up mucus
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 40 (0.00%)
    2 / 38 (5.26%)
    0 / 39 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Skin rash
         subjects affected / exposed
    2 / 40 (5.00%)
    0 / 40 (0.00%)
    3 / 38 (7.89%)
    1 / 39 (2.56%)
         occurrences all number
    4
    0
    4
    1
    Renal and urinary disorders
    Bed wetting
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 40 (5.00%)
    1 / 38 (2.63%)
    0 / 39 (0.00%)
         occurrences all number
    0
    3
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle pain/ cramps
         subjects affected / exposed
    5 / 40 (12.50%)
    1 / 40 (2.50%)
    5 / 38 (13.16%)
    2 / 39 (5.13%)
         occurrences all number
    8
    1
    7
    2
    Infections and infestations
    Fever
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 40 (2.50%)
    0 / 38 (0.00%)
    3 / 39 (7.69%)
         occurrences all number
    1
    1
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Sep 2020
    Reference to the EU Regulation 2016/679 (General Data Protection Regulation) or GDPR (General Data Protection Regulation) and the Belgian Legislation on the protection of natural persons with regard to the processing of personal data on the free movement of such data was added to the protocol.
    31 Mar 2021
    Inclusion of more participants in the study: increased from 60 to 80 patients with ASD

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The covid pandemic caused some delay (and sometimes loss) of the follow up data.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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