The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12617000441314
Ethics application status
Approved
Date submitted
15/02/2017
Date registered
27/03/2017
Date last updated
22/02/2019
Date data sharing statement initially provided
22/02/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
A Course of Oxytocin to Improve Social Communication in Young Children with Autism
Scientific title
A Course of Oxytocin to Improve Social Communication in Young Children with Autism
Secondary ID [1] 290917 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Autism Spectrum Disorder 301666 0
Condition category
Condition code
Mental Health 301377 301377 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.

Prior to randomisation to either active treatment or placebo, all participants will be requested to administer a placebo spray for 3 weeks in order to establish a baseline to control for expectancy effects. Participants will be unaware (masked) that they are receiving a placebo spray. Study staff will be aware that participants are receiving a placebo spray during this 3-week period.


Caregivers will be requested to complete a twice-daily check of treatment adherence, on a compliance and side effects monitoring sheet which will be provided to them at the outset of the study. Treatment compliance will also be assessed by a study staff member during a follow-up phone call to participants' caregivers which is to be placed 6 weeks after the initiation of either active oxytocin or placebo nasal spray administration.
Intervention code [1] 296877 0
Treatment: Drugs
Comparator / control treatment
Placebo nasal spray: Excipient (non-active) ingredients include saline; E 216, E 218, and chlorobutanol hemihydrate as preservatives, excipients to 1 ml.
Control group
Placebo

Outcomes
Primary outcome [1] 300774 0
1. Social interaction skills assessed by the Social Responsiveness Scale (SRS)
Timepoint [1] 300774 0
Social interaction skills as measured by the SRS at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Primary outcome [2] 301274 0
2. Scores on the Clinical Global Impression - Improvement Scale (CGI-I)
Timepoint [2] 301274 0
Scores on CGI-I at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [1] 330824 0
1. Performance on key experimental social-cognitive tasks and behavioural synchrony, measured by assessment of gaze duration and number of fixations to social stimuli
Timepoint [1] 330824 0
Performance on social-cognitive tasks and behavioural synchrony at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [2] 332175 0
2. Changes in repetitive and restricted behaviours as measured by the Repetitive Behaviour Scale - Revised (RBS-R)
Timepoint [2] 332175 0
Scores on RBS-R at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [3] 332177 0
3. Caregiver strain as measured on the Caregive Strain Questionnare (CSQ)
Timepoint [3] 332177 0
Scores on the CSQ at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [4] 332178 0
4. Adaptive and maladaptive behaviour as measured by the PDD Behaviour Inventory - Screening Version (PDDBI-SV)
Timepoint [4] 332178 0
Scores on the PDDBI-SV at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [5] 332179 0
5. Aberrant behaviour as indicated by scores on the Aberrant Behaviour Checklist (ABC)
Timepoint [5] 332179 0
Scores on the ABC at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [6] 332180 0
6. Methylation status of the OXTR promotor region CpGs in blood analysis, The method of assessment will be pyrosequencing using two pre-designed assays.
Timepoint [6] 332180 0
Methylation status of the OXTR promotor region CpGs at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [7] 332183 0
7. OT levels in blood plasma/saliva. The method of assessment will be DNA methylation assay.
Timepoint [7] 332183 0
OT levels in blood plasma/saliva at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [8] 332185 0
8. Cortisol levels in blood plasma/saliva. The method of assessment will be DNA methylation assay.

Timepoint [8] 332185 0
Cortisol levels in blood plasma/saliva at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [9] 332186 0
9. BDNF levels in blood plasma/saliva. The method of assessment will be a multiplex assay.
Timepoint [9] 332186 0
BDNF levels in blood plasma/saliva at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [10] 332187 0
10. AVP levels in blood plasma/saliva and ratio of OT to AVP. The method of assessment will be DNA methylation assay.

Timepoint [10] 332187 0
AVP levels in blood plasma/saliva and ratio of OT to AVP at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [11] 332188 0
11. Inflammatory markers interleukin-1beta, interleukin-6, interleukin-8 and interferon-gamma will be measured through blood plasma or saliva analysis. The method of assessment will be a multiplex assay.
Timepoint [11] 332188 0
Inflammatory markers in blood plasma/saliva at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [12] 332189 0
12. Neuroimaging measures will include fMRI, Diffusion Tensor Imaging (DTI) and Magnetic Resonance Spectroscopy (MRS). The method of assessment will be MRI scans.
Timepoint [12] 332189 0
Neuroimaging analysis at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)
Secondary outcome [13] 332190 0
13. Psychophysiological measures. The method of assessment will be electrocardiography (ECG) traces analysed for heart rate variability.
Timepoint [13] 332190 0
Psychophysiological analysis at visit 3 (immediately after 12 weeks treatment) and visit 4 (3 month follow-up)

Eligibility
Key inclusion criteria
Participants must meet DSM-5 criteria for Autism Spectrum Disorder (ASD)..
Minimum age
3 Years
Maximum age
12 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Participants will be excluded if they are known to be hypersensitive to the preservatives in the nasal spray (E216, E218, and chlorobutanol hemihydrates). Participants with severe nasal obstruction/blockage will be excluded as this is likely to reduce the efficacy of the nasal spray medication. Further, participants whose caregivers report that they have a serious medical condition from one of the following categories will be excluded (evidenced through medical examination):
1. severely compromised cardiac function
2. severely compromised hepatic function
3. severely compromised renal function

These categories relate to common side-effects reported in previous oxytocin studies and recommended contraindications from product information for the nasal spray and intravenous formulations of oxytocin that have been marketed previously.

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 central administration site (Brain and Mind Centre, University of Sydney, Camperdown NSW)
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
Children with ASD will take a placebo spray for 3 weeks, followed by being randomised to a course of twice-daily nasally-administered oxytocin or placebo for 12 weeks in a double-blind, placebo-controlled between-subject design study.
Phase
Phase 4
Type of endpoint(s)
Efficacy
Statistical methods / analysis
All data analyses will be performed using Statistical Package for the Social Sciences (SPSS, Chicago, IL, USA). Partial eta squared will be used to measure effect size. We will employ an intention-to-treat analysis with last observations carried forward. All eligible participants who have been randomised to oxytocin 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.

Mixed MANOVA will be used to model change in all primary outcome variables (length of eye-gaze, fixation count; ADOS; RBS-R; SRS; DBC; CGI) over time as functions of treatment (OT, Placebo). Power for the detection of drug effect will depend on the outcome measured and numbers retained in the trial. The study will enroll 160 young children with ASD. The present research design incorporates four measurements. For all measures, we will analyse results based on parents’ treatment guess (whether they believed their child was on OT or placebo), because we have found in previous research that parents’ perceptions of which treatment their child received moderate treatment outcome for parent-report questionnaires. We will also look at age-related effects. With a regression based longitudinal analysis there will be power of .99 to detect treatment-related differences in eye-gaze length 50% as large as those previously found in healthy subjects, after allowing for effective sample size reduction to 130 due to dropout. (Power analysis parameters: linear multiple regression model with power of .20, sample size of 160, 10 predictors and an alpha level of .05).

For MRI data: all volume measurements between the two groups; pre-treatment scan against post-treatment scan for amygdala normalisation and increased social brain FA hypothesis; responders compared to non-responders for neurobiological markers hypothesis, will be compared using Student's t-test (independent-samples t-test). An analysis of covariance is used to compare the two groups on brain region measurements while controlling for age and total brain volume (TBV). Two-tailed statistical significance level is set at p < 0.05 for all analyses. Given that the age of the children in both groups span 9 years, during a time of major maturational change and development, age-related effects will be examined with volume-age Pearson correlations for each group.

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,WA
Recruitment hospital [1] 7332 0
Brain and Mind Centre - University of Sydney - Camperdown
Recruitment postcode(s) [1] 15114 0
2050 - Camperdown
Recruitment postcode(s) [2] 15140 0
6872 - West Perth

Funding & Sponsors
Funding source category [1] 295365 0
Government body
Name [1] 295365 0
National Health and Medical Research Council
Address [1] 295365 0
National Health and Medical Research Council
GPO Box 1421
Canberra ACT 2601
Country [1] 295365 0
Australia
Funding source category [2] 295366 0
Charities/Societies/Foundations
Name [2] 295366 0
BUPA Health Foundation
Address [2] 295366 0
Bupa
600 Glenferrie Road
Hawthorn VIC 3122
Country [2] 295366 0
Australia
Primary sponsor type
University
Name
University of Sydney
Address
University of Sydney
Camperdown NSW 2006
Country
Australia
Secondary sponsor category [1] 294189 0
University
Name [1] 294189 0
University of Western Australia
Address [1] 294189 0
University of Western Australia
35 Stirling Hwy, Crawley WA 6009
Country [1] 294189 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296696 0
University of Sydney Human Research Ethics Committee
Ethics committee address [1] 296696 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] 296696 0
Australia
Date submitted for ethics approval [1] 296696 0
06/03/2013
Approval date [1] 296696 0
06/02/2017
Ethics approval number [1] 296696 0
2013/502
Ethics committee name [2] 296698 0
Princess Margaret Hospital (PMH) - Child and Adolescent Health Service (CAHS) Ethics Committee
Ethics committee address [2] 296698 0
Princess Margaret Hospital (PMH) - Child and Adolescent Health Service (CAHS) Ethics Committee
Princess Margaret Hospital
Roberts Road, Subiaco, Perth
Western Australia 6008
Ethics committee country [2] 296698 0
Australia
Date submitted for ethics approval [2] 296698 0
01/05/2013
Approval date [2] 296698 0
22/05/2014
Ethics approval number [2] 296698 0
2013050EP

Summary
Brief summary
Children with ASD aged 3 to 12 years will take a placebo spray for 3 weeks, followed by being randomised to a course of twice-daily nasally-administered oxytocin or placebo for 12 weeks in a double-blind, placebo-controlled between-subject design. We hope to identify children with ASD who benefit from this treatment and the associated cognitive and neurobiological markers that predict such changes.
Trial website
Trial related presentations / publications
Public notes
An independent statistical analysis was requested by the University of Sydney's Data Safety and Monitoring Board. The analysis was requested to determine whether the study should continue recruiting participants. The Data Safety and Monitoring Board at the University of Sydney made formal recommendation to continue recruiting children aged 3 to 6 years of age but to cease recruiting children in the 7 - 12 year range.

Contacts
Principal investigator
Name 71726 0
Prof Adam Guastella
Address 71726 0
Brain and Mind Centre
94 Mallett Street
Camperdown NSW 2050
Country 71726 0
Australia
Phone 71726 0
+61 2 9351 0539
Fax 71726 0
Email 71726 0
adam.gaustella@sydney.edu.au
Contact person for public queries
Name 71727 0
Prof Adam Guastella
Address 71727 0
Brain and Mind Centre
94 Mallett Street
Camperdown NSW 2050
Country 71727 0
Australia
Phone 71727 0
+61 2 9114 4104
Fax 71727 0
Email 71727 0
med.actr@sydney.edu.au
Contact person for scientific queries
Name 71728 0
Prof Adam Guastella
Address 71728 0
Brain and Mind Centre
94 Mallett Street
Camperdown NSW 2050
Country 71728 0
Australia
Phone 71728 0
+61 2 9351 0539
Fax 71728 0
Email 71728 0
adam.guastella@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 patient data will not be made available for privacy and confidentiality reasons.
What supporting documents are/will be available?
No other documents available
Summary results
No Results