Oxytocin Effects on Bone Metabolism in Children With Autism Spectrum Disorder

Study Overview
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Brief Summary
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This is a randomized, double blind, placebo-controlled study of the effects of intranasal oxytocin on bone health in children with autism spectrum disorder, ages 6-18 years old. Subjects will be randomized to receive intranasal oxytocin or placebo (30 IU, 2 times daily) for 12 months in the double-blind phase, followed by a 6-month open label phase during which all study subjects will receive intranasal oxytocin (30 IU, 2 times daily). Study visits include screening to determine eligibility, followed by study visits at baseline, week 2, and months 6, 12, 18 and phone calls every two weeks for the first two months and monthly thereafter for the duration of the study. Study assessments include history and physical examinations, anthropometric measurements, electrocardiogram (EKG), adverse event monitoring, laboratory tests for chemistries, hormones and biomarkers for bone metabolism, questionnaires regarding diet and exercise, and imaging to assess body composition, bone density and structure.

Detailed Description
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The prevalence of autism spectrum disorder (ASD), a group of behaviorally-defined disorders characterized by impaired social interactions and verbal and non-verbal communication, is increasing among children. Studies have shown that children with ASD are at a higher risk for low bone mineral density and fractures. ASD is also characterized by low levels of oxytocin (OXT), a peptide hormone with prosocial effects. In addition, OXT promotes bone formation over resorption and low levels of OXT are associated with poor bone health. Hence, OXT administration represents a potential strategy for improving bone health in children with ASD, particularly during the childhood and adolescent years when bone accrual peaks. The investigators aim to examine (i) whether intranasal OXT administration vs. placebo increases areal bone mineral density (BMD) and improves overall bone health in children with ASD, and (ii) other pathways whereby OXT may impact bone health favorably. The investigators will enroll 96 participants 6-18 years old with ASD and randomize them into the intranasal oxytocin vs. placebo groups. The study subjects will undergo history and physical examinations, anthropometric measurements, electrocardiogram (EKG), adverse event monitoring, laboratory tests for chemistries, hormones and biomarkers for bone metabolism, questionnaires regarding diet and exercise, and imaging to assess body composition, bone density and structure.

Official Title
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A Randomized, Double-blind, Placebo-controlled Study of Intranasal Oxytocin for Bone Health in Children With Autism Spectrum Disorder

Conditions
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Autism Spectrum Disorder, Bone Health

Intervention / Treatment
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* Drug: 1. Intranasal oxytocin spray
* Drug: 2. Intranasal placebo spray
* Drug: 3. Intranasal Oxytocin spray


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ages 6 to 18 years old at Randomization BMI between the 10th-85th percentiles Expert clinical diagnosis of ASD confirmed using the Diagnostic and Statistical Manual of Mental Disorders (DSM) -5 Checklist and a Social Communication Questionnaire (SCQ)-Lifetime Availability of parent/guardian to provide informed consent If cognitively able, the subject must be able to provide informed assent/consent Exclusion Criteria: Fragile X, tuberous sclerosis, and other single gene defects that are syndromic Other conditions that may contribute to low bone density (e.g., hyperprolactinemia, hypogonadism) Medications that may impact bone such as specific anti-seizure medications, oral glucocorticoids, combined hormonal contraception Hyponatremia Creatinine or liver enzymes more than twice the upper limit of the normal range Changes in doses of antipsychotics that can cause hyperprolactinemia within 2 months of the baseline visit Substance use disorder within the last 6 months History of known coronary artery disease, heart failure, reduced ejection fraction, hypertrophic cardiomyopathy, ventricular arrhythmias, or prolonged QT Active seizures within 6 months preceding the Screening visit or the Baseline visit Subjects who are pregnant, lactating, or who refuse contraception if sexually active Subjects who have had previous treatment with OXT (within 2 months of Randomization) Subjects who are not able to cooperate with medication administration, blood drawing, or imaging procedures despite behavior training Caregivers who are unable to speak English, be consistently present at study visits to report on symptoms or, per the judgement of the data collection team, are unable to comply with the protocol

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 18 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: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1. Intranasal Oxytocin<br>Intranasal oxytocin spray (30 IU twice daily) for 12 months in the double-blinded phase followed by intranasal oxytocin spray (30 IU twice daily) for 6-months in the open-label phase | Drug: 1. Intranasal oxytocin spray<br>* 30 IU, twice daily for 12 months in the experimental arm in double-blinded phase<br>Drug: 3. Intranasal Oxytocin spray<br>* 30 IU, twice daily for 6 months in both experimental and placebo comparator arm in open-label phase<br>|
| Placebo Comparator: 2. Placebo<br>Intranasal placebo spray (30 IU twice daily (total 60 IU per day) for 12 months followed by intranasal oxytocin spray (30 IU twice daily) for 6-months in the open-label phase | Drug: 2. Intranasal placebo spray<br>* 30 IU, twice daily for 12 months in the placebo comparator arm in double-blinded phase<br>Drug: 3. Intranasal Oxytocin spray<br>* 30 IU, twice daily for 6 months in both experimental and placebo comparator arm in open-label phase<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The 12-month change in the whole body less head areal BMD Z-score between IN OXT vs. placebo | A whole body less head areal BMD Z-score between -2 to +2 indicates normal bone mineral density | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The 12-month change in femoral neck areal BMD Z-score between IN OXT vs. placebo | A femoral neck areal BMD Z-score between -2 to +2 indicates normal bone mineral density | 12 months | 
| The 12-month change in the radial cortical area between IN OXT vs. placebo | High-resolution peripheral quantitative computed topography (HR-pQCT) will be used to assess the radial cortical area at the non-dominant wrist (if fracture history, then non-fractured side will be used). Using a scout, the reference line will be set at the bone endplate. Scans will be acquired at a distance from the endplate relative to the individual's limb length (ultradistal sites: 7%; diaphyseal sites: 30%) to adjust for body size. Each scan includes 168 slices with an isotropic voxel size of 61 µm3. | 12 months | 
| The 12-month change in tibial cortical area between IN OXT vs. placebo | High-resolution peripheral quantitative computed topography (HR-pQCT) will be used to assess the tibial cortical area at the non-dominant leg (if fracture history, then non-fractured side will be used). Using a scout, the reference line will be set at the bone endplate. Scans will be acquired at a distance from the endplate relative to the individual's limb length (ultradistal sites: 7%; diaphyseal sites: 30%) to adjust for body size. Each scan includes 168 slices with an isotropic voxel size of 61 µm3. | 12 months | 
| The 12-month change in radial trabecular thickness between IN OXT vs. placebo | High-resolution peripheral quantitative computed topography (HR-pQCT) will be used to assess the radial trabecular thickness at the non-dominant wrist (if fracture history, then non-fractured side will be used). Using a scout, the reference line will be set at the bone endplate. Scans will be acquired at a distance from the endplate relative to the individual's limb length (ultradistal sites: 7%; diaphyseal sites: 30%) to adjust for body size. Each scan includes 168 slices with an isotropic voxel size of 61 µm3. The trabecular thickness will be calculated using the direct 3D distance transformation method. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autism spectrum disorder, Bone density, Oxytocin, Peri-pubertal children