A Study of Oxytocin in Children and Adolescents With Autistic Disorder

Study Overview
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Brief Summary
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The investigators propose to conduct this pilot study to evaluate oxytocin as a supplemental treatment for improving social difficulties in individuals with autism.

Detailed Description
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The proposed pilot study is an essential first step toward rigorously evaluating oxytocin treatment of individuals with autism. The biologic actions of oxytocin on social cognition and prosocial behaviors and the clinical, genetic and epigenetic evidence for involvement of the oxytocin system in the pathophysiology of some cases of autism strongly suggest that supplemental oxytocin therapy could significantly improve the social disabilities involved in autism. Many people feel that these social difficulties are the most characteristic and central feature of autism. Overall, this study aims to determine the tolerability, accessibility, and feasibility of an oxytocin pilot study. This study will consent up to 30 subjects in order to randomize up to 25 subjects into a 2-month (8 weeks) randomized double-blind, placebo-controlled initial treatment period, a subsequent 2-month (8 weeks) period in which all participants receive oxytocin, and up to three post-treatment visits that occur at week 28 (±2 weeks),an interim visit anytime between week 16 and week 76 only for those patients who plan to start oxytocin on their own outside of study treatment and who will experience a lag time between week 16 (end of open label treatment) and when outside oxytocin treatment will begin, and some time before week 76. The investigators hope that this study will help to inform future study designs in determining whether a short term or long term treatment trial is necessary to observe significant effects. This will also help to develop systematic preliminary safety measures.

Official Title
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A Pilot Study of Oxytocin in Children and Adolescents With Autistic Disorder

Conditions
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Autism

Intervention / Treatment
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* Drug: Oxytocin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Between 3 and 17 years old, inclusive. Have a clinical diagnosis of autistic disorder confirmed according to Diagnostic Statistical Manual of Mental Disorders-IV criteria by using the Autism Diagnostic Interview - Revised (ADI-R) and/or the Autism Diagnostic Observation Scale (ADOS, Lord et al., 1989). Exclusion Criteria: Changes in allied health therapies, behavioral or educational interventions within the past 2 months of the baseline visit other than those associated with school holidays. Changes in psychotropic and alternative medication doses in the last 30 days of the baseline visit. Subjects with a medical condition that might interfere with the conduct of the study, confound interpretation of the study results, or endanger their own well-being. This includes, but is not limited to, Rett Syndrome, impairment of renal function, evidence or history of malignancy or any significant hematological, endocrine, cardiovascular (including any rhythm disorder and uncontrolled hypertension), respiratory, hepatic, or gastrointestinal disease. Marked sensory impairment such as deafness or blindness that would interfere with conduct of the study. Pregnancy/Nursing because of the unknown effects of oxytocin to unborn babies and/or nursing infants. All females of child-bearing potential will be administered a urine or serum pregnancy test at screening and at any point during the study at physician discretion. Refusal to undergo a pregnancy test will result in exclusion from the study. The investigators will share results of pregnancy test with the subject's legal guardian. Refusal to practice contraception if sexually active because the effects of exposure to high concentrations of oxytocin on sperm or newly conceived embryos are unknown. Sexually active men and women should not take part in this study if they and their partners are not both using an effective birth control method (for example, women use birth control pills, an intrauterine device (IUD) or a diaphragm and men use condoms). Inability of caretakers to speak English. Absence of a consistent caretaker to report on symptoms. Subjects who, in the Investigator's opinion, might not be suitable for the study.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Intervention: Drug: placebo | Drug: Placebo<br>* Placebo Nasal Spray<br>|
| Active Comparator: Oxytocin<br>Intervention: Drug: Syntocinon® Nasal Spray | Drug: Oxytocin<br>* Subjects will use the Syntocinon® Nasal Spray (oxytocin) twice daily for 8 weeks if they are randomized to that arm in the Randomized Phase. All subjects will use the Syntocinon® Nasal Spray twice daily for 8 weeks in the Open Label Phase. Subjects ages 3-10 years old will be titrated up to a maximum dose of 24 International units (IU). Subjects ages 11-17 years old will be titrated up to a maximum dose of 32IU.<br>* Other names: Syntocinon® Nasal Spray;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Could Tolerate Twice Daily Oxytocin | This study will help to determine tolerability of intranasal oxytocin treatment in children with autism by measuring the ability of at least 80% of the sample to tolerate twice daily intranasal administration of oxytocin. | Week 0 to week 8 | 
| Number of Participants Who Could Tolerate Twice Daily Oxytocin | This study will help to determine tolerability of intranasal oxytocin treatment in children with autism by measuring the ability of at least 80% of the sample to tolerate twice daily intranasal administration of oxytocin. | Week 0 to week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mean Plasma Oxytocin Level During Period 1 - Double Blind Phase | Blood samples will be collected to obtain proof of concept data regarding changes in afternoon plasma oxytocin levels | Week 0 to week 8 | 
| Change in Mean Weight | changes during period 1 | between weeks 0 and 8 | 
| Change in Mean Total Social Social Responsiveness Scale (SRS) T-score | The 65-item SRS is a standardized measure of the core symptoms of autism. Each item is scored on a 4-point Likert scale. The raw score of each individual item is summed to create a total raw score. The total raw score is then translated into a total T-scores (which are the equivalent of standard scores). Total T-scores results are as follows: 59 and below: within normal limits, 60-65: Mild range of impairment 66-75: Moderate range of impairment 76 or higher: Severe range of impairment. | 0-8 weeks, blinded treatment, period 1 | 
| Change in Mean Autism Diagnostic Observation Schedule (ADOS) Total Score | The ADOS is a semi-structured assessment used to assess and diagnose individuals suspected of having autism of varying ages, developmental levels, and language skills (from no speech to verbally fluent). The ADOS includes four modules, each requiring just 35-40 minutes to administer. The individual being evaluated is given just one of 4 modules, depending on his or her expressive language level and chronological age. The rater will observe social and communication behaviors during various activities in the appropriate module. A rater then uses a 0-3 scale to rate each type of behavior. A select number of individual items will be summed for a total score representing communication and reciprocal social interaction. In scoring all 3's are collapsed to a 2. A higher score indicates more severe impairment. Ranges of scores are as follows: Module 1: 0-24, Module 2: 0-24, Module 3: 0-22, Module 4: 0-22. | Baseline to 16 Weeks | 
| Change in Mean Aberrant Behavior Checklist (ABC)-Social Withdrawal Subscale Score Over Both Periods | Efficacy measures included the Aberrant Behavior Checklist -Social Withdrawal subscale scor. The ABC which focuses on problem behaviors in five subdomains, including irritability, attention, repetitive behaviors, unusual speech, and lethargy. A modified version of the lethargy subscale was used. Typically the Lethargy subscale includes 16 items, however, for our purposes 3 items that were specifically related to lethargy (i.e.: listlessness) were removed so that the focus could primarily be on aberrant social behavior. Differences in only the Social Withdrawal domain were assessed.The is the sum of items, each rated among 0 = Not at all; 1 = Slight in degree; 2 = Moderately serious; and 3 = Severe in degree. The ABC- Social Withdrawal total score ranges from 0 to 39. Higher values represent greater severity of illness. | Baseline to 16 Weeks | 
| Change in Mean Pervasive Developmental Disorder Behavior Inventory - Screening Version (PDDBI-SV) Total Score Over Both Periods | The PDDBI-SV examines both adaptive and maladaptive behaviors related to autism. It has normative scores for children between 2-11 years. For children 12 years and older, the norms (11 years, 11 months) will be used. Each item is scored on a scale from 0-3. For the first 9 items, the total of individual items is summed. For items 10-18, the scores are reversed and then summed (i.e.: 0=3, 1 =2, 2=2, 3 = 0). Then the total of 0-9 and then the reversed scored items 10-18 are summed for a final total score. Higher scores indicate more impairment. The range of total scores is 0-54. ASD/Social deficits unlikely: 0-6, More information needed/borderline: 7-10, autism spectrum disorder (ASD)/social deficits likely (mild):11-14, ASD/social deficits likely (moderate): 15-29, ASD/social deficits likely (severe): 30-37, ASD/social deficits likely (extreme): 38 or higher. | Baseline to 16 Weeks | 
| Change in Mean Systolic Blood Pressure During Period 1 | Change in mean systolic blood pressure during double blind phase | Week 0 to 8 | 
| Mean Change in Prolactin Levels Over Period 1 | Serum prolactin levels were collected and analyzed in participants | Week 0 to 8 | 
| Mean Change in Temperature During Period 1 | Temperature was collected on each participant via oral or temporal thermometer. The mean change in each group was assessed. | Week 0 to 8 |