Intranasal Oxytocin Treatment for Social Deficits in Children With Autism

Study Overview
=================
Brief Summary
-----------------
Autism is a pervasive developmental disorder characterized by core deficits in social behavior and communication, and the presence of repetitive or stereotyped behaviors. It is one of three recognized disorders in the autism spectrum which affects an estimated 1 in 88 children in the United States. At present, pharmacotherapies target only associated features of autism, with no effective drug treatments for the social impairments. Several lines of evidence now suggest that the neuropeptide oxytocin (OT) may be an effective treatment for the core social deficits in autism. Here we will test the effects of twice daily intranasal OT (24 IU) over a 4-week period for enhancing social deficits in male and female children aged 6-12 years with autism. This research has high potential to lead to the development of more effective treatments and earlier interventions for children with autism.

Detailed Description
-----------------
In recent years, the neuropeptide oxytocin (OT) has been implicated in a wide range of social behaviors including attachment bonds, emotion recognition, eye gaze to social cues, and memory for social information. Social impairments represent one of the most intractable features of autism, and evidence now suggests that OT biology is dysregulated in individuals with this disorder. The central aim of the research outlined here is to test whether OT administration to children with autism increases their quality and quantity of social interactions and enhances their ability to process emotional and social information. Findings from initial single-dose OT administration studies in teenaged and adult males with autism have shown improvement in some aspects of social functioning, but replication and extension to well-controlled treatment trials with younger male and female subjects is necessary to evaluate effectiveness. We therefore aim to investigate the effect of intranasal OT on social cognition and behavior immediately following a single-dose (24IU) and following a 4-week period of OT (24IU BID) administration in a sample of 50 subjects with autism aged 6 to 12 years. The primary outcome for this study is change in social behavior, as determined by parent ratings on the Social Responsiveness Scale (SRS) after the 4-week treatment period. Secondary outcomes are changes in functioning on laboratory-based measures of social behavior and cognition following single-dose and 4-week OT administration. Research in a small study sample (N=13) also identified treatment responders and non-responders to a single-dose of OT. Thus, we also aim to identify biological and cognitive and behavioral variables (i.e., pretreatment levels of social functioning and pretreatment plasma hormone levels) that may influence treatment response efficacy in our larger study sample. On completion of the 4-week treatment period all subjects will have the option of participating in another 4-week double-blind trial in which they will be switched to the alternate nasal spray to that which they previously received. They will then undergo a fourth and final assessment time-point using the same testing procedures as outlined above on completion of the 4-week dosing. By providing subjects with the option of participating in a second 4-week treatment trial, all subjects will have an opportunity to receive the active oxytocin nasal spray. We also will be able to examine any ongoing effects of oxytocin treatment in the group receiving placebo during the second 4-week administration period. Subjects not willing to take part in the second trial will exit the study and will be referred to their treating physician.

Official Title
-----------------
Double-blind, Randomized, Placebo Controlled Trial of Intranasal Oxytocin Treatment for Social Deficits in Children With Autism.

Conditions
-----------------
Autism

Intervention / Treatment
-----------------
* Drug: Oxytocin nasal spray
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Medically healthy outpatients between 6 and 12 years of age (cut off 12 years and 11 months) Intelligence Quotient > 40 Diagnosis of autism spectrum disorder based on the Autism Diagnostic Interview - Revised, Autism Diagnostic Observation Schedule, and DSM-IV criteria Clinical Global Impression severity rating of 4 or higher Care provider who can reliably bring subject to clinic visits, provide trustworthy ratings, and interacts with the subject on a regular basis Stable medications for at least 4 weeks No planned changes in psychosocial interventions during the trial Willingness to provide blood samples. Exclusion Criteria: Diagnostics and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of schizophrenia, schizoaffective disorder, or psychotic disorder Regular nasal obstruction or nosebleeds Active medical problems: unstable seizures, significant physical illness (e.g., serious liver, renal, or cardiac pathology) Sensitivity to preservatives (in particular E 216, E 218, and chlorobutanol hemihydrate) A genetic abnormality (e.g., Fragile X Syndrome) Significant hearing or vision impairments Habitually drinks large volumes of water Pregnancy, breastfeeding, or child birth within the last 6 months Sexually active females not using a reliable method of contraception.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 12 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Oxytocin nasal spray<br>Prior to randomization, all subjects will participate in a 1-week open-label placebo lead-in trial. Each subject will be administered the placebo nasal spray at Stanford University and then their parent will continue administering the nasal spray to the subject for 1 week at home. Each subject will then be randomly assigned either to the active group or to the placebo (stratified by gender) and will be given the appropriate nasal spray bottle and their parents will be responsible for administering 3 puffs per nostril (4 IU/puff) to their child for a total dose of 24 IU oxytocin or placebo twice daily (BID; morning and evening) for 4-weeks. On completion of this 4-week treatment trial subjects will have the option of participating in a second double-blind trial in which they will be assigned to the alternate nasal spray, to that which they received during the first 4-week trial, for an additional 4-week period. | Drug: Oxytocin nasal spray<br>* 24IU BID (3 x 0.1 mL [4IU] sprays per nostril twice daily for 4-weeks.<br>* Other names: Syntocinon® Nasal Spray;|
| Placebo Comparator: Placebo nasal spray<br>The placebo nasal spray bottles will be prepared by adding all of the ingredients used in the Syntocinon nasal sprays with the exception of the concentrated oxytocin solution. | Drug: Placebo<br>* 3 x 0.1 mL sprays per nostril twice daily for 4-weeks.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Parent Rated Social Responsiveness Scale (SRS) Scores During Treatment. | Social Responsiveness Scale (SRS) raw scores measure social abilities with lower raw scores meaning better social abilities. (Raw Score Range: 0 - 195) | Baseline; Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Plasma Oxytocin Levels During Treatment. | This outcome originally specified that oxytocin, vasopressin, and cortisol levels would be assessed; however, data on vasopressin and cortisol levels were not collected during the study. There are no clinical laboratory tests that establish a normative range for oxytocin. Measurements prior to and following treatment were intended to evaluate oxytocin level as a predictor of response. | Up to 4 weeks | 
| Change From Baseline in Parent Rated Repetitive Behavior Scale- Revised (RBS-R) Scores During Treatment. | Higher scores on the Repetitive Behavior Scale- Revised mean higher levels of repetitive and restricted behaviors. (Raw Score Total Range: 0 - 129) | Baseline; Week 4 | 
| Change From Baseline in Weight |  | Baseline; Week 4 | 
| Change From Baseline in Heart Rate |  | Baseline; Week 4 | 
| Change From Baseline in Blood Pressure |  | Baseline; Week 4 | 
| Number of Participants With Side Effects Assessed Using Parent Rated Dosage Record Treatment Emergent Symptom Scale (DOTES) Scores During Treatment | Dosage Record Treatment Emergent Symptom Scale (DOTES) side effects reported by parents during 4-weeks of treatment. Participant Counts are used. | Baseline through Week 4 | 
| Change From Baseline in Height. |  | Baseline; Week 4 | 
| Clinical Global Impression-Improvement (CGI-I) Score at Week 4 | This outcome is reported as the count of participants in each CGI-I rating category at the week 4 visit, assessing change over the 4-week period. CGI-I rating of 1=Very Much Improved, 2=Much Improved, 3=Minimally Improved, 4=No Change, 5=Minimally Worse, 6=Much Worse, and 7=Very Much Worse. | Baseline to Week 4 | 
| Parent Rated Aberrant Behavior Checklist (ABC) Irritability Scores at Baseline and Week 4 | Higher scores indicate more symptoms, lower scores indicate fewer symptoms. Irritability scores can range from 0-45. Lethargy scores can range from 0-48. Stereotypy scores can range from 0-21. Hyperactivity scores can range from 0-48. Inappropriate speech scores can from 0-12. | Baseline; Week 4 | 
| Change From Baseline in Parent Rated Spence Children's Anxiety Scale (SCAS) During Treatment. | Scale measuring severity of anxiety symptoms. Higher scores mean higher levels of anxiety, lower scores mean lower levels of anxiety. (Raw Score Range: 0 - 114) | Baseline; Week 4 | 
| Change From Baseline in Vineland Adaptive Behavior Scales, Second Edition - Social and Communication Subscales During Treatment. | Higher Social Standard Score means better social skills, lower Social Standard Score means worse social skills. Higher Communication Standard Score means better communication skills, lower Communication Standard Score means worse communication skills. Standard Scores can range from 20 to 160. | Baseline; Week 4 | 
| Change From Baseline in Laboratory Based Facial Emotion Recognition Abilities During Treatment. |  | Up to 4 weeks | 
| Change From Baseline in Laboratory Based Eye-gaze to Social Cues During Treatment. |  | Baseline; Week 4 | 
| Change From Baseline in Reading the Mind in the Eyes Test, Child Version (RMET-child) Scores During Treatment. |  | Up to 4 weeks | 
| Change From Baseline in Laboratory Based Social Mimicry Abilities During Treatment. |  | Up to 4 weeks | 
| Change From Baseline in Developmental NEuroPSYchological Assessment (NEPSY-II) Affect Recognition Scores During Treatment. | Higher Affect Recognition scores mean better affect recognition abilities, lower Affect Recognition scores mean worse affect recognition abilities. Scores can range from 1 to 19. | Baseline; Week 4 |