Autism Spectrum Disorder
Conditions
Keywords
Autism Spectrum disorder, Oxytocin, Clinical Trial, Children, Pharmacology
Brief summary
Extensive data has been accumulated to suggest that central release of oxytocin is important for social cognition and function, as well as likely involved in anxiety modulation and repetitive behaviors. The principal investigators of this study have previously documented: 1) an association between Autism Spectrum Disorder and a single nuclear polymorphism of the oxytocin receptor gene, 2) ability to measure oxytocin levels in the blood by enzyme immunoassay and 3) preliminary data to support safety and efficacy of intranasal oxytocin in the treatment of social deficits and repetitive behaviors in adults with autism. A medication treatment targeting the core deficits of Autism Spectrum Disorder in childhood is highly valuable because it could influence the developmental trajectory and make further psychosocial interventions possible. In this context, we propose a small dose finding study to confirm that the dose used in the adult study is not more than the maximum tolerated dose in youth. '
Interventions
DRUGIntranasal Oxytocin
We are selecting morning and afternoon dosing to try to influence most hours where youth are in settings with increased potential for social interaction (school, after school). Medication will be administered by the parents before school and early afternoon. All patients will receive their first dose by the study physician to educate parents and themselves on proper administration and determine safety of first dose.
Sponsors
Holland Bloorview Kids Rehabilitation Hospital
The Hospital for Sick Children
University of Illinois at Chicago
Evdokia Anagnostou
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
1. Male or female outpatients 10-17 years of age inclusive. 2. Meet Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision criteria for Autistic Disorder or Asperger's Disorder as established by a clinician and supported by the Autism Diagnostic Observation Schedule and the Autism Diagnostic Interview - Revised. 3. Have a Clinician's Global Impression-Severity score ≥ 4 (moderately ill) at Baseline. 4. Verbal Intelligent Quotient \>/= 70. 5. If already receiving stable pharmacological and or non-pharmacologic educational, behavioral, and/or dietary interventions, have continuous participation during the preceding 3 months prior to Screening and will not electively initiate new or modify ongoing interventions for the duration of the study. 6. Have normal physical examination and laboratory test results at Screening. If abnormal, the finding(s) must be deemed clinically insignificant by the Investigator. 7. The participant and caregiver must be able to speak and understand English sufficiently to allow for the completion of all study assessments.
Exclusion criteria
1. Patients born prior to 35 weeks gestational age. 2. Patients with any primary psychiatric diagnosis other than autism at Screening. 3. Patients with current neurological disease, including, but not limited to, epilepsy/seizure disorder (except simple febrile seizures), movement disorder, tuberous sclerosis, fragile X, and any other known genetic syndromes, or known abnormal MRI/structural lesion of the brain. 4. Pregnant female patients, sexually active female patients on hormonal birth control and sexually active females who do not use two types of non-hormonal birth control 5. Patients 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. Patients with evidence or history of malignancy or any significant hematological, endocrine, cardiovascular (including any rhythm disorder), respiratory, renal, hepatic, or gastrointestinal disease. 6. Patients who are sensitive to Syntocinon or any components of its formulation 7. Patients with one or more of the following: HIV, Hepatitis B virus, Hepatitis C virus, hemophilia (bleeding problems, recent nose and brain injuries), abnormal blood pressure (hypotension or hypertension), drug abuse, immunity disorder or severe depression. 8. Patients unable to tolerate venipuncture procedures for blood sampling.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | 12 Weeks | The hypothesis is that the maximum tolerated dose in a range of 0.2-0.4 IU/kg / dose will be 0.4 IU/kg / dose, as was the case in the adult study, given that oxytocin is not stored in body fat and does not depend on liver or renal clearance. |
| Number of Participants With Serious Adverse Events | 24 Weeks | This will be reported as the number of participants who experienced a serious advert event throughout the study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Baseline Levels of Oxytocin in Relation to Either Safety or Treatment Response | 12 Weeks | Children and adolescents with lower plasma oxytocin levels at baseline will show treatment related changes in social cognition. Children and adolescents with higher oxytocin plasma levels will show diminished or less dramatic treatment responses and may have more difficulty tolerating the treatment. |
| Blood Levels of Oxytocin During the Trial in Relation to Safety or Treatment Response | 12 Weeks | Children and adolescents with minimal changes in plasma level of oxytocin after treatment will be less responsive to treatment. Children and adolescents with atypical patterns of increase in oxytocin may be more sensitive to dose-related tolerability. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | 12 Weeks | Social Cognition (higher score=positive response) 1. Let's Face It Skills Battery; i. Matchmaker (0-100); ii. Faces (0-100); iii. Houses (0-100) 2. Eyes Test (0-28) 3. Strange Stories (0-16) 4. Irony and Empathy (0-24) Social Function 1. Aberrant Behavior Checklist (0-48) (lower score=positive response) 2. Behavioral Assessment System for Children (higher score=positive response); i. Social: age 8 to 11 & 15 to 18 (18-69); age 12 to 14 (21-70); ii. Functional: age 8 to 14 (10-66); age 15 to 18 (10-64) 3. Social Responsiveness Scale (higher score=positive response); male (34-127); female (35-142) Anxiety (lower score=positive response) a. Child Symptom Inventory; i. Separation: male (44-106); female (44-101); ii. Generalized: male (40-101); female (41-96) Repetitive Behaviors (lower score=positive response) 1. Child Yale-Brown Obsessive-Compulsive Scale (0-20) 2. Repetitive Behavior Scale (0-129) Measures insensitive to change will be omitted from results. |
| Measures of Social Function - The Clinical Global Impressions - Social Scale (Baseline to Week 12) | 12 Weeks | Social Function a) Clinical Global Impressions - Social Scale (1-7) (lower score=positive response). The results will be reported as the number of participants that were classified as a social responder (achieving a score of 1 or 2 on the scale). |
Countries
Canada
Participant flow
Recruitment details
Participants were recruited from the hospital clinical database, as well as presentations at local conferences and media. Diagnosis was established using the Diagnostic and Statistical Manual, Fourth Edition for an Autism Spectrum Disorder supported by the Autism Diagnostic Observations Schedule and the Autism Diagnostic Interview - Revised.
Pre-assignment details
Cohort 1 Dosage: 0.20 IU/kg - 3 participants Cohort 2 Dosage: 0.26 IU/kg - 3 participants Cohort 3 Dosage: 0.33 IU/kg - 3 participants Cohort 4 Dosage: 0.40 IU/kg - 6 participants
Participants by arm
| Arm | Count |
|---|---|
| Intanasal Oxytocin A modified dose finding method was used to determine safety among four dose levels. Half the dose (0.2 IU/kg /dose) was the minimum dose and two intermediate doses were also evaluated (0.26 and 0.33 IU/kg / dose) Dose-finding escalations were done in groups of three patients.
1. Three patients were studied at the first dose level
2. If none of these patients experienced dose limiting toxicity, the dose was escalated.
3. If one patient experienced dose limiting toxicity, up to three more patients were accrued at the same level. (a) If none of these patients experienced dose limiting toxicity, the dose was escalated. (b) If one or more experienced dose-limiting toxicity, entry at that dose level would be stopped, the maximum tolerated dose exceeded, and dose escalation would be stopped. Up to three more patients would be treated at the next lower dose. If zero out of three patients experience dose limiting toxicity, an additional three patients were to be treated at that dose. | 15 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Intanasal Oxytocin |
|---|---|
| Age, Categorical <=18 years | 15 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Region of Enrollment Canada | 15 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 15 / 15 |
| serious Total, serious adverse events | 0 / 15 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
The hypothesis is that the maximum tolerated dose in a range of 0.2-0.4 IU/kg / dose will be 0.4 IU/kg / dose, as was the case in the adult study, given that oxytocin is not stored in body fat and does not depend on liver or renal clearance.
Time frame: 12 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intanasal Oxytocin | Maximum Tolerated Dose (MTD) | 0.40 IU / kg |
Primary
Number of Participants With Serious Adverse Events
This will be reported as the number of participants who experienced a serious advert event throughout the study.
Time frame: 24 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intanasal Oxytocin | Number of Participants With Serious Adverse Events | 0 participants |
Secondary
Baseline Levels of Oxytocin in Relation to Either Safety or Treatment Response
Children and adolescents with lower plasma oxytocin levels at baseline will show treatment related changes in social cognition. Children and adolescents with higher oxytocin plasma levels will show diminished or less dramatic treatment responses and may have more difficulty tolerating the treatment.
Time frame: 12 Weeks
Secondary
Blood Levels of Oxytocin During the Trial in Relation to Safety or Treatment Response
Children and adolescents with minimal changes in plasma level of oxytocin after treatment will be less responsive to treatment. Children and adolescents with atypical patterns of increase in oxytocin may be more sensitive to dose-related tolerability.
Time frame: 12 Weeks
Other Pre-specified
Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12)
Social Cognition (higher score=positive response) 1. Let's Face It Skills Battery; i. Matchmaker (0-100); ii. Faces (0-100); iii. Houses (0-100) 2. Eyes Test (0-28) 3. Strange Stories (0-16) 4. Irony and Empathy (0-24) Social Function 1. Aberrant Behavior Checklist (0-48) (lower score=positive response) 2. Behavioral Assessment System for Children (higher score=positive response); i. Social: age 8 to 11 & 15 to 18 (18-69); age 12 to 14 (21-70); ii. Functional: age 8 to 14 (10-66); age 15 to 18 (10-64) 3. Social Responsiveness Scale (higher score=positive response); male (34-127); female (35-142) Anxiety (lower score=positive response) a. Child Symptom Inventory; i. Separation: male (44-106); female (44-101); ii. Generalized: male (40-101); female (41-96) Repetitive Behaviors (lower score=positive response) 1. Child Yale-Brown Obsessive-Compulsive Scale (0-20) 2. Repetitive Behavior Scale (0-129) Measures insensitive to change will be omitted from results.
Time frame: 12 Weeks
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Let's Face It! Skills Battery-Matchmaker | -10.9 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Let's Face It! Skills Battery-Faces | -9.21 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Let's Face It! Skills Battery-Houses | -10.73 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | The Revised Eyes Test | -0.14 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Strange Stories Task | -1.36 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Irony and Empathy Task | -1.64 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Aberrant Behavior Checklist | 3.00 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Social Responsiveness Scale | 9.8 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Behavioral Assessment System for Children-Social | -2.84 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Behavioral Assessment System for Children-Function | -4.10 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Child Yale-Brown Obsessive-Compulsive Scale | 2.93 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Repetitive Behavior Scale-Revised | 17.3 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Child and Adolescent Symptom Inventory-Separation | 7.5 units on a scale |
| Intanasal Oxytocin | Changes in Measures of Social Cognition, Social Function, Repetitive Behaviors, and Anxiety (Baseline to Week 12) | Child and Adolescent Symptom Inventory-General | 11.0 units on a scale |
Other Pre-specified
Measures of Social Function - The Clinical Global Impressions - Social Scale (Baseline to Week 12)
Social Function a) Clinical Global Impressions - Social Scale (1-7) (lower score=positive response). The results will be reported as the number of participants that were classified as a social responder (achieving a score of 1 or 2 on the scale).
Time frame: 12 Weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Intanasal Oxytocin | Measures of Social Function - The Clinical Global Impressions - Social Scale (Baseline to Week 12) | 7 participants |