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Trial registered on ANZCTR


Registration number
ACTRN12618001029280
Ethics application status
Approved
Date submitted
25/05/2018
Date registered
19/06/2018
Date last updated
30/01/2019
Date data sharing statement initially provided
30/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
Oxytocin in Preschoolers with Autism receiving Social Learning Therapy
Scientific title
Intranasal Oxytocin in Preschoolers with Autism receiving Social Learning Therapy: A Randomised, Double-blind, Repeated Dose Study Analysing Caregiver-rated Social Responsiveness as a Primary Outcome.
Secondary ID [1] 294922 0
None.
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autism Spectrum Disorders 307885 0
Condition category
Condition code
Mental Health 306934 306934 0 0
Autistic spectrum disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will be randomly allocated to receive either active oxytocin or placebo nasal spray twice daily over a period of 12 weeks. Participants randomly allocated to receive active oxytocin will administer 16 IU of nasal spay twice a day (1 x 8 IU spray per nostril), receiving a total of 32IU per day of oxytocin. Caregivers will assist participants in administering the nasal spray.

Caregivers will be requested to complete a Compliance/Side Effects Monitoring Form to verify that the nasal spray was administered each morning and evening. This form will be given to parents at Study Visit 1 (prior to the nasal spray administration) and will be returned for site review at Study Visit 2 (Mid-treatment Assessment visit) and Study Visit 3 (Post-treatment Assessment Visit). Compliance will also be assessed by the trial coordinator through discussion with parents at Study Visits 1 and 2. Finally, parents will be requested to return the nasal spray bottles at each study visit so that compliance can be monitored via weighing each bottle at Study Visits 2 and 3.

All participants will receive a Social Learning Therapy known as the Parent-delivered Early Start Denver Model (P-ESDM) over the course of the 12-week Placebo/Oxytocin treatment period. The P-ESDM involves 16 parent/caregiver training session delivered by a certified P-ESDM therapist. Parents will receive 2 parent/caregiver training sessions which will be delivered onsite each week for a period of 4 weeks. Parents/caregivers will then receive 1 training session per week for the remaining 8 weeks. Each session will last 1 hour in duration.

Each P-ESDM session will focus on improving caregiver intervention skills through the use of fun and interactive social games. Parents will be trained on the delivery of P-ESDM techniques by an P-ESDM certified coach. The content of each session will focus on learning activities and techniques that will: increase the child's attention and motivation, improve the use of sensory social routines, promote dyadic engagement and joint activity routines; enhance nonverbal communication, build imitation skills; facilitate joint attention; promote speech development; increase the use of antecedent-behaviour-consequence relationships.

P-ESDM compliance will be assessed through the use of a Fidelity tool. Here, parents will have the first 10-minutes of their onsite P-ESDM session recorded. Trained assessors will then use this video to code parent behaviours and compliance to P-ESDM principles before completing a fidelity tool. Parents will also be asked to keep a daily log of the number of hours spent with their child during which they utilised the P-ESDM strategies. This will be reviewed by study staff at each study visit.
Intervention code [1] 301239 0
Treatment: Drugs
Intervention code [2] 301240 0
Behaviour
Comparator / control treatment
Participants that are randomly allocated to the placebo group will receive a placebo nasal spray with the following ingredients: Excipient (non-active) ingredients include sorbitol crystalline powder 2%, glycerine 2%, and benzyl alcohol 0.9% preservative, excipients to 8 ml.

All participants in the study will receive the P-ESDM intervention.
Control group
Placebo

Outcomes
Primary outcome [1] 305932 0
Changes in parent rated Social Deficit Scores as assessed by the Pervasive Developmental Disorder Behaviour Inventory - Screening Version (PDDBI-SV).
Timepoint [1] 305932 0
The PDDBI-SV will be administered pre-treatment at Visit 1 (Study week 1), post-treatment at Visit 3 (study week 12 - primary endpoint) and at 3-month follow-up (Post-treatment, study week 26).
Secondary outcome [1] 347065 0
Changes in social responsiveness as measured through the use of the Social Responsiveness Scale - Second Edition (SRS-2).
Timepoint [1] 347065 0
The SRS-2 will be given to parents to complete pre-treatment at Visit 1 (Study week 1), post-treatment at Visit 3 (Study week 12) and at 3-month follow-up (Visit 4, Study week 26),
Secondary outcome [2] 347092 0
Changes in joint attention behaviour - measured through participant performance on social interaction assessments. Each parent-child social interaction assessment will involve the administration of social-interaction tasks selected from the Autism Diagnosis and Observation Scale - 2. All sessions will be video recorded and behaviourally coded for joint attention behaviours such as shared child-parent attentiveness to toys and play based objects.
Timepoint [2] 347092 0
Parent-child social interaction assessments will be conducted pre-treatment at study Visit 1 (Study week 1), post-treatment Visit 3 (Study week 12) and at 3-month follow-up (Visit 4, Study week 26).
Secondary outcome [3] 347093 0
Changes in eye-gaze behaviour including number and duration of fixations to social stimuli measured using eye tracking and behavioural coding of social interactions. This is a composite measure of eye-gaze behaviour and will be assessed through the use of Tobii eye-tracking and recording equipment.
Timepoint [3] 347093 0
Eye tracking and social interaction measures will be conducted pre-treatment at study Visit 1 (Study week 1), post-treatment Visit 3 (Study week 12) and at 3-month follow-up (Visit 4, Study week 26) and coded for further analysis.
Secondary outcome [4] 347094 0
Changes in bio-behavioural synchrony as measured through observational and physiological measures (ECG and Heart Rate Variance) of parent-child synchrony during social interaction tasks. This is a composite measure of bio-behavioural synchrony and will be measured through the use of ECG recording equipment and a Heart Rate Variance software package.
Timepoint [4] 347094 0
Observational and physiological assessment of parent-child bio-behavioural synchrony during social interaction tasks will be conducted pre-treatment at study Visit 1 (Study week 1), post-treatment Visit 3 (Study week 12) and at 3-month follow-up (Visit 4, Study week 26).
Secondary outcome [5] 347097 0
Parental Distress, Parent-Child Dysfunctional Interactions and Difficult Child ratings will be assessed through the use of the Parent Stress Index - Short Form (PSI-4 SF). This is a composite secondary outcome measure.
Timepoint [5] 347097 0
The Parent Stress Index (PSI-4 SF) will be administered pre-treatment at Visit 1 (study week 1), mid-treatment at Visit 2 (Study week 7), post-treatment at Visit 3 (study week 12) and at 3-month follow-up (study week 26).
Secondary outcome [6] 347107 0
Social cognition and performance on joint attention tasks as measured by eye-tracking software. This is a composite secondary outcome measure. A joint attention paradigm will be used as part of this task in which participants will be shown a short video of an experimenter reading an illustrated story. Eye-gaze patterns and number of duration fixations to social versus non-social stimuli will be analysed.
Timepoint [6] 347107 0
Eye-tracking measures will be conducted pre-treatment at Visit 1 (study week 1), post-treatment at Visit 3 (study week 12) and at 3-month follow-up (Visit 4, study week 26).
Secondary outcome [7] 347108 0
OT levels in blood plasma/saliva as measured by DNA methylation assay. This is a composite secondary outcome measure.
Timepoint [7] 347108 0
OT levels in Blood plasma/saliva will be analysed pre-treatment at Visit 1 (Study week 1), post-treatment at Visit 3 (Study week 12) and at 3-month follow-up (Visit 4, Study week 26).
Secondary outcome [8] 347109 0
Cortisol levels in blood plasma/saliva as measured by DNA methylation assay. This is a composite secondary outcome measure.
Timepoint [8] 347109 0
Cortisol levels in blood plasma/saliva will be analysed pre-treatment at Visit 1 (Study week 1), post-treatment at Visit 3 (Study week 12) and at 3-month follow-up (Visit 4, Study week 26).
Secondary outcome [9] 347110 0
Brain-Derived Neurotrophic Factor (BDNF) levels in blood plasma/saliva as measured by DNA multiplex assay. This is a composite secondary outcome measure.
Timepoint [9] 347110 0
BDNF levels in blood plasma/saliva will be analysed pre-treatment at Visit 1 (Study week 1), post-treatment at Visit 3 (Study week 12) and at 3-month follow-up (Visit 4, Study week 26).
Secondary outcome [10] 347111 0
Vasopressin (AVP) levels in blood plasma/saliva and ratio of OT to AVP as measured by DNA methylation assay. This is a composite secondary outcome measure..
Timepoint [10] 347111 0
AVP levels in blood plasma/saliva and ratio of OT to AVP will be analysed at pre-treatment (study week 1), post-treatment (study week 12) and at 3-month follow-up (study week 26).
Secondary outcome [11] 347112 0
Presence of inflammatory markers; interleukin-1beta, interleukin-6, interleukin-8 and interferon-gamma in blood plasma/saliva samples will be analysed through multiplex assay.
This is a composite secondary outcome measure.
Timepoint [11] 347112 0
Presence of inflammatory markers will be analysed at pre-treatment (study week 1), post-treatment (study week 12) and at 3-month follow-up (study week 26)
Secondary outcome [12] 347154 0
Methylation status of the OXTR promotor region CpGs in blood analysis, The method of assessment will be pyrosequencing using two pre-designed assays.
Timepoint [12] 347154 0
Methylation status of the OXTR promotor region CpGs will be analysed pre-treatment at Visit 1 (Study week 1), post-treatment at Visit 3 (Study week 12) and at 3-month follow-up (Visit 4, study week 26).
Secondary outcome [13] 347160 0
Parent/Caregiver Fidelity as measured through a five-point Likert rating tool. Parent/Caregiver Fidelity will be measured through the use of 10-minute video recordings which will be subsequently rated by expert P-ESDM therapists for adherence to P-ESDM principles.
Timepoint [13] 347160 0
Parent/Caregiver Fidelity will be measured through the use of 10-minute video recordings which will be subsequently rated by expert P-ESDM therapists for adherence to P-ESDM principles. Measurements will be taken mid-treatment (Study week 7), post-treatment (Study week 12) and at 3-month follow up (Study week 26).

Eligibility
Key inclusion criteria
Children who:
• Are aged 3 to 5 years old
• Meet the criteria for Autism Spectrum Disorder (ASD) according to the Diagnostic and Statistical Manual for Mental Disorders – Fifth Edition (DSM-5). The diagnostic term incorporates the previously separate diagnoses of Autistic Disorder, Asperger’s Disorder, and Pervasive Developmental Disorder – Not Otherwise Specified or PDD-NOS)
• Meet the ADOS-2 classification of autism spectrum (administered at, or within 6 months of the Screening Visit)

Caregivers who:
• Provide written informed consent
• Are committed to attending the parent/caregiver coaching session throughout the study period in order to utilize the strategies taught to them for 15 – 20 hours a week, with their child at home
• Agree not to start a new intensive behavioural treatment during the course of the study.
Minimum age
3 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Children who:
• Severe nasal obstruction
• Severe hepatic, renal or cardiac dysfunction
• Known genetic disorder (e.g. Fragile X) or neurological syndromes
• Severe co-morbid developmental delay (DQ<35)
• Significant vision, hearing or motor impairment that would interfere with ability to respond to P-ESDM or complete assessments
• Stabilised on psychoactive medications for more than 8 weeks prior to enrolment
• Untreated epilepsy or any non-febrile seizure within 6 months prior to enrolment

Caregivers who:
• Are not fluent in English

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation involves contacting the holder of the allocation schedule who is "off-site" or external to the central administration site. Participants will be enrolled "on-site" at the administration site (Brain and Mind Centre, University of Sydney, Camperdown NSW and La Trobe University, Victoria).
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software (i.e. computerised sequence generation).
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Generalized linear mixed models will be used to analyze both efficacy and safety outcomes as these models have a number of features relevant to this study: (1) tolerance of missing data; (2) allow both normal outcomes (e.g, PDDBI-SV). A multiple logistic regression model is employed to evaluate the relationship between change in putative mechanisms (joint attention, reward responsiveness in social play, physiological and behavioural synchrony) and markers of response of primary outcome (PDDBI-SV). Missing data: The study will employ an intention-to-treat analysis and some imputation for missing data will be required. Analysis will involve imputation assuming that children show no effect and then additional analyses will assess other approaches to imputation, and to test their assumptions. Priority will be to minimize missing data. This study will have a protocol for follow-up that maximizes data in all participants.

All data analyses will be performed using the Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA). Partial eta squared will be used a measure of effect size. We will employ an intention-to-treat analysis with last observations carried forward. All eligible participants who have been randomised to OT or placebo will be included in our analyses, regardless of treatment actually received or withdrawal from the study. For participants with missing baseline data, analysis for that measure will be excluded listwise. Level of significance will be set at p < .05 and Bonferroni adjusted p-values used for multiple comparisons. Any deviations from the original statistical plan will be described and justified in the protocol. Prior to analysis, scatter plots and box plots with outlier and normality statistics will be generated for all variables to identify outliers and issues with variable distribution. Extreme outliers (beyond 3 z scores in either direction) will be checked against source data and testing notes to verify whether they are the result of an error in data entry or a specific issue during testing (e.g., equipment failure), and any errors rectified. If they are not the result of an error in data entry, outliers will be curtailed.

Levels of OT, AVP, cortisol, BDNF and methylation of OXTR:
The average methylation level (%) will be determined for each participant and these values will be used to generate an average percentage methylation for responders and non-responders. The Welch-Satterthwaite t-test will be employed to adjust for unequal variances between groups (responders and non-responders) and to compare the mean methylation level (%) at each site between the ASD groups. A nominal significance of p = 0.05 will indicate a significant change in the methylation state between the two groups. The direction of the change will be determined by comparing the average methylation level at each site between the two groups. The same procedure will be followed for plasma and saliva levels of key biomarkers (OT, AVP, cortisol, BDNF).

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 10994 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment hospital [2] 10995 0
Austin Health - Austin Hospital - Heidelberg
Recruitment postcode(s) [1] 22785 0
2050 - Camperdown
Recruitment postcode(s) [2] 22786 0
3084 - Heidelberg

Funding & Sponsors
Funding source category [1] 299504 0
Government body
Name [1] 299504 0
National Health and Medical Research Council
Address [1] 299504 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 299504 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
The University of Sydney
NSW Australia 2006
Country
Australia
Secondary sponsor category [1] 298848 0
None
Name [1] 298848 0
None
Address [1] 298848 0
None
Country [1] 298848 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300405 0
University of Sydney Human Research Ethics Committee
Ethics committee address [1] 300405 0
University of Sydney Human Research Ethics Committee
Ethics and Research Integrity
Margaret Telfer Building (K07)
University of Sydney
NSW 2006
Ethics committee country [1] 300405 0
Australia
Date submitted for ethics approval [1] 300405 0
16/04/2018
Approval date [1] 300405 0
12/06/2018
Ethics approval number [1] 300405 0

Summary
Brief summary
Children with ASD aged 3 - 5 years old will receive a twice-daily nasally-administered oxytocin or placebo nasal spray for a period of 12-weeks and will also concurrently receive 16 sessions of the Parent-Delivered Early Start Denver Model early learning intervention. Assignment to either the placebo or oxytocin group will be randomised with researchers and participants unaware of treatment group allocation (blinded). Using this double-blinded placebo-controlled between subjects design we hope to identify children with ASD who may benefit from this treatment and the associated cognitive/neurobiological markers that predict these benefits.

It is hypothesised that at post-treatment and at three-month follow up, OT treatment combined with P-ESDM will:
1. Improve caregiver-rated social responsiveness as measured by the Pervasive Developmental Disorder Behavior Inventory – Screening Version (PDDBI-SV)
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83558 0
Prof Adam Guastella
Address 83558 0
Brain and Mind Centre
94 Mallett Street
Camperdown NSW 2050
Country 83558 0
Australia
Phone 83558 0
+61 2 9351 0539
Fax 83558 0
Email 83558 0
adam.gaustella@sydney.edu.au
Contact person for public queries
Name 83559 0
Prof Adam Guastella
Address 83559 0
Brain and Mind Centre
94 Mallett Street
Camperdown NSW 2050
Country 83559 0
Australia
Phone 83559 0
+61 2 9351 0539
Fax 83559 0
Email 83559 0
med.actr@sydney.edu.au
Contact person for scientific queries
Name 83560 0
Prof Adam Guastella
Address 83560 0
Brain and Mind Centre
94 Mallett Street
Camperdown NSW 2050
Country 83560 0
Australia
Phone 83560 0
+61 2 9351 0539
Fax 83560 0
Email 83560 0
adam.gaustella@sydney.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Individual participant data will not be shared due to privacy and confidentiality concerns. Group level data will be published in academic journal articles that may be open source.
What supporting documents are/will be available?
No other documents available
Summary results
No Results