Autism
Conditions
Brief summary
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
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.
Interventions
DRUGOxytocin
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.
DRUGPlacebo
Placebo Nasal Spray
Sponsors
Autism Speaks
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
3 Years to 17 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Could Tolerate Twice Daily Oxytocin | Week 0 to week 8 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Mean Weight | between weeks 0 and 8 | changes during period 1 |
| Change in Mean Total Social Social Responsiveness Scale (SRS) T-score | 0-8 weeks, blinded treatment, period 1 | 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. |
| Change in Mean Autism Diagnostic Observation Schedule (ADOS) Total Score | Baseline to 16 Weeks | 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. |
| Change in Mean Aberrant Behavior Checklist (ABC)-Social Withdrawal Subscale Score Over Both Periods | Baseline to 16 Weeks | 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. |
| Change in Mean Plasma Oxytocin Level During Period 1 - Double Blind Phase | Week 0 to week 8 | Blood samples will be collected to obtain proof of concept data regarding changes in afternoon plasma oxytocin levels |
| Change in Mean Systolic Blood Pressure During Period 1 | Week 0 to 8 | Change in mean systolic blood pressure during double blind phase |
| Mean Change in Prolactin Levels Over Period 1 | Week 0 to 8 | Serum prolactin levels were collected and analyzed in participants |
| Mean Change in Temperature During Period 1 | Week 0 to 8 | Temperature was collected on each participant via oral or temporal thermometer. The mean change in each group was assessed. |
| Change in Mean Pervasive Developmental Disorder Behavior Inventory - Screening Version (PDDBI-SV) Total Score Over Both Periods | Baseline to 16 Weeks | 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. |
Countries
United States
Participant flow
Pre-assignment details
This study is a 2 sequence (arm) study with 2 periods - double-blind (0-8 weeks) and open label (8-16 weeks). The sequences are 1: oxytocin-oxytocin and 2: placebo-oxytocin. 1 participant from sequence 1 did not enter period 2 due to withdrawal due to adverse events.
Participants by arm
| Arm | Count |
|---|---|
| Sequence 2:Placebo-oxytocin Intervention: Drug: placebo
Placebo: Placebo Nasal Spray | 13 |
| Sequence 1: Oxytocin-oxytocin Intervention: Drug: Syntocinon® Nasal Spray
Oxytocin: 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. | 12 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Period 1: Double Blind Treatment | Adverse Event | 1 | 0 |
| Period 2: Open Label Treatment | Adverse Event | 0 | 1 |
| Period 2: Open Label Treatment | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Sequence 2:Placebo-oxytocin | Sequence 1: Oxytocin-oxytocin | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 13 Participants | 12 Participants | 25 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 10.0 years STANDARD_DEVIATION 4.4 | 10.6 years STANDARD_DEVIATION 4.4 | 10.3 years STANDARD_DEVIATION 4.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 12 Participants | 25 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Intelligence Quotient (IQ) <70 | 10 Participants | 4 Participants | 14 Participants |
| Non-verbal | 7 Participants | 4 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 11 Participants | 10 Participants | 21 Participants |
| Sex: Female, Male Female | 2 Participants | 0 Participants | 2 Participants |
| Sex: Female, Male Male | 11 Participants | 12 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 13 | 0 / 11 | 0 / 13 |
| other Total, other adverse events | 12 / 12 | 10 / 13 | 8 / 11 | 12 / 13 |
| serious Total, serious adverse events | 1 / 12 | 0 / 13 | 0 / 24 | 0 / 13 |
Outcome results
Primary
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.
Time frame: Week 0 to week 8
Population: This is over period 1, the double blind phase (week 0 to week 8) only
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sequence 2: Placebo:Oxytocin | Number of Participants Who Could Tolerate Twice Daily Oxytocin | 13 Participants |
| Sequence 1: Oxytocin:Oxytocin | Number of Participants Who Could Tolerate Twice Daily Oxytocin | 11 Participants |
Primary
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.
Time frame: Week 0 to week 16
Population: all participants who recieved oxytocin at any time
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Sequence 2: Placebo:Oxytocin | Number of Participants Who Could Tolerate Twice Daily Oxytocin | 11 Participants |
| Sequence 1: Oxytocin:Oxytocin | Number of Participants Who Could Tolerate Twice Daily Oxytocin | 11 Participants |
Secondary
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.
Time frame: Baseline to 16 Weeks
Population: population of participants with all data available for mixed models analysis no data carried forward
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence 2: Placebo:Oxytocin | Change in Mean Aberrant Behavior Checklist (ABC)-Social Withdrawal Subscale Score Over Both Periods | -3.7 scores on a scale | Standard Error 1 |
| Sequence 1: Oxytocin:Oxytocin | Change in Mean Aberrant Behavior Checklist (ABC)-Social Withdrawal Subscale Score Over Both Periods | -2.2 scores on a scale | Standard Error 1.9 |
p-value: 0.23t-test, 2 sided
Secondary
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.
Time frame: Baseline to 16 Weeks
Population: 1 patient without post baseline measures is not included
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence 2: Placebo:Oxytocin | Change in Mean Autism Diagnostic Observation Schedule (ADOS) Total Score | -0.36 scores on a scale | Standard Error 0.39 |
| Sequence 1: Oxytocin:Oxytocin | Change in Mean Autism Diagnostic Observation Schedule (ADOS) Total Score | -0.31 scores on a scale | Standard Error 0.29 |
Secondary
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.
Time frame: Baseline to 16 Weeks
Population: used only subjects with all data points no data carried forward
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence 2: Placebo:Oxytocin | Change in Mean Pervasive Developmental Disorder Behavior Inventory - Screening Version (PDDBI-SV) Total Score Over Both Periods | -3.6 scores on a scale | Standard Error 2.4 |
| Sequence 1: Oxytocin:Oxytocin | Change in Mean Pervasive Developmental Disorder Behavior Inventory - Screening Version (PDDBI-SV) Total Score Over Both Periods | -3.0 scores on a scale | Standard Error 2.2 |
Secondary
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
Time frame: Week 0 to week 8
Population: participants with oxytocin plasma levels at baseline and week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence 2: Placebo:Oxytocin | Change in Mean Plasma Oxytocin Level During Period 1 - Double Blind Phase | -0.69 picograms/mL (pg/mL) | Standard Deviation 1.69 |
| Sequence 1: Oxytocin:Oxytocin | Change in Mean Plasma Oxytocin Level During Period 1 - Double Blind Phase | -0.15 picograms/mL (pg/mL) | Standard Deviation 1.53 |
Secondary
Change in Mean Systolic Blood Pressure During Period 1
Change in mean systolic blood pressure during double blind phase
Time frame: Week 0 to 8
Population: The one subject who discontinued at week 1 did not have follow up data to include in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence 2: Placebo:Oxytocin | Change in Mean Systolic Blood Pressure During Period 1 | -7.6 millimeters of mercury (mmHg) | Standard Error 2.8 |
| Sequence 1: Oxytocin:Oxytocin | Change in Mean Systolic Blood Pressure During Period 1 | 1.5 millimeters of mercury (mmHg) | Standard Error 3.2 |
Secondary
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.
Time frame: 0-8 weeks, blinded treatment, period 1
Population: All participants with at least one post baseline assessment, 1 person from sequence 1 discontinued due to no post baseline measures
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence 2: Placebo:Oxytocin | Change in Mean Total Social Social Responsiveness Scale (SRS) T-score | -5.1 T-scores | Standard Error 2.3 |
| Sequence 1: Oxytocin:Oxytocin | Change in Mean Total Social Social Responsiveness Scale (SRS) T-score | -3.9 T-scores | Standard Error 3.3 |
p-value: 0.023t-test, 2 sided
Secondary
Change in Mean Weight
changes during period 1
Time frame: between weeks 0 and 8
Population: The subject who discontinued after 2 days did not have repeat assessments and is excluded from these analyses
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence 2: Placebo:Oxytocin | Change in Mean Weight | 1.4 pounds | Standard Error 1.3 |
| Sequence 1: Oxytocin:Oxytocin | Change in Mean Weight | 2.4 pounds | Standard Error 0.7 |
Secondary
Mean Change in Prolactin Levels Over Period 1
Serum prolactin levels were collected and analyzed in participants
Time frame: Week 0 to 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence 2: Placebo:Oxytocin | Mean Change in Prolactin Levels Over Period 1 | -3.6 nanograms per milliliter (ng/mL) | Standard Error 2.68 |
| Sequence 1: Oxytocin:Oxytocin | Mean Change in Prolactin Levels Over Period 1 | 1.17 nanograms per milliliter (ng/mL) | Standard Error 1.63 |
Secondary
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.
Time frame: Week 0 to 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Sequence 2: Placebo:Oxytocin | Mean Change in Temperature During Period 1 | -0.7 degrees fahrenheit | Standard Error 0.2 |
| Sequence 1: Oxytocin:Oxytocin | Mean Change in Temperature During Period 1 | -0.1 degrees fahrenheit | Standard Error 0.2 |