Placebo

One of three computerized eye tracking tasks to measure attention. three computer screens are set up side by side. A stimulus initially appears on the central screen, and once the participant orients to that stimulus, another stimulus will appear on one of the lateral screens. In the "gap" condition, the central stimulus will disappear before the peripheral stimulus appears. In the "overlap" condition, the central stimulus will remain on the screen while the peripheral stimulus appears. In both conditions, reaction times of the participant's eye movements (saccadic reaction time) from the central stimulus to the peripheral stimulus will be measured. Gap Effect measures the difference between average Gap and Overlap saccade latencies.

One of three computerized eye tracking tasks to measure attention. The "flicker task," or the four-alternative forced-choice preferential looking paradigm - the time interval over which the visual system is able to parse information. Scores range from -1 to 1 with higher scores indicating better (more typical) performance.

Mean change in scale at week 12 as compared to baseline. Vineland Adaptive Behavior Communication Domain measures adaptive functioning.

Vineland-II subdomains (Communication, Daily Living Skills, Socialization, Motor, Adaptive Behavior Composite, Internalizing, Externalizing and maladaptive) are V-scale scores (M=15, SD=3). Higher scores indicate better developed adaptive social behavior.

Vineland-II domain and composite values are standard scores (M=100, SD=15). Higher scores indicate better developed adaptive social behavior.

Change in Repetitive Behavior Scale at week 12 as compared to baseline. the RBS-R is a 44-item self-report questionnaire consisting of subscales and one additional global rating score from 1-100. Score range for Stereotypic Behavior subscale is 0-27, Self-Injurious Behavior subscale is 0-24, Compulsive Behavior subscale is 0-18, Ritualistic/Sameness Behavior subscale is 0-36, and Restricted Interests subscale 0-9. Total scale for RBS-R is 0-214, with higher score indicating more severe problem.

Mean Change in Clinical Global Impression-Severity Scales at week 12 as compared to baseline. Clinical Global Impressions (CGI) Rating Scales are commonly used to measure symptom severity and global improvement in treatment studies of patients with developmental disorders. There Severity Scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of illness at the time of assessment. Full scale from 1 - 7. Higher scores indicate greater symptom severity.

Mean Change in Short Sensory Profile Scale at week 12 as compared to baseline, measuring sensory sensitivity and sensory seeking behavior. The SSP is a 38-item caregiver questionnaire. Items are based on a 5-point Liker scale ranging from 1=always to 5=never. Tactile Sensitivity ranges from 7-35. Taste/Smell Sensitivity ranges from 4-20. Movement Sensitivity ranges from 3-15. Underresponsive/Seeks Sensation ranges from 7-35. Auditory Filtering ranges from 6-30. Low Energy/Weak ranges from 6-30. Visual/Auditory Sensitivity ranges from 5-25. Total scale range from 38-190. Lower scores indicate a higher probability of sensory processing abnormalities.

Macarthur-Bates Communicative Development Inventory at week 12 as compared to baseline, measuring language. Words and Gestures Forms are for children ages 8-18 months. In the form, the first part prompts parents to document the child's understanding of hundreds of early vocabulary items separated into semantic categories such as animal names, household items, and action words. Parents mark the words understood or used, and the forms yield separate indexes of words understood and words produced. The second part of each form asks parents to record the communicative and symbolic gestures the child has tried or completed. Ranges for each subscale score are as follows: Phrases understood (0-28), Words understood (0-396), Words produced (0-396), Early gestures (0-18), Later gestures (0-45), Total gestures (0-63). Higher scores indicate a great number of words, phrases, or gestures understood or produced.

In the Auditory Habituation EEG task, participants listen to a series of 4 tones and the neural responses to each of these tones (event related potentials, ERPs ) are averaged. The N1 and P2 components are typical responses to auditory stimuli. The N1 response is the initial, quick response to hearing a stimulus, and P2 reflects the later processing of the stimulus. Both of these should be greater in response to the first tone, and then reduce in response to each subsequent tone. This is known as habituation, and is calculated as the change in Tone 1 minus Tone 2 response for both N1 and P2 components.

Number of Adverse Events through week 12

Mean Change Caregiver Strain Index at week 12 as compared to baseline. The Caregiver Strain Questionnaire is a 21-item measure of self-reported strain experienced by caregivers and families of youth with emotional problems, with responses on a 5-point Likert scale (0 = Not at all, 4 = very much). Full scale from 0 to 84, higher score indicates higher caregiver burden

Change in Mullen Scales of Early Learning (MSEL) at week 12 as compared to baseline. The Mullen Scales results are reported using Age Equivalents, which provides an estimate of the chronological age (CA) in years and months at which a typically developing child demonstrates the skills displayed by the child being assessed. The Mullen Scales results are reported using T scores. (M = 100, SD = 15). Each subscale is standardized to calculate an age-equivalent score. Higher scores represent a higher CA, and therefore better outcome.

Total of all reporting groups

Race and Ethnicity were not collected from any participant.

16 items, Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem). Total scores range from 0 to 48, with higher scores indicating poorer health outcomes.

Developmental quotients are calculated by averaging the age equivalent (AE) scores of the components, dividing by chronological age, and multiplying by 100. The verbal DQ (VDQ) includes Expressive Language (EL) and Receptive Language (RL). The average (mean) is 100 with a standard deviation of 15 points. Higher scores indicate greater cognitive ability.

Developmental quotients are calculated by averaging the age equivalent (AE) scores of the components, dividing by chronological age, and multiplying by 100. The nonverbal DQ (NVDQ) includes scales of Visual Reception (VR) and Fine Motor (FM) abilities. The average (mean) is 100 with a standard deviation of 15 points. Higher scores indicate greater cognitive ability.

Developmental quotients are calculated by averaging the age equivalent (AE) scores of the components, dividing by chronological age, and multiplying by 100. The average (mean) is 100 with a standard deviation of 15 points. Higher scores indicate greater cognitive ability. An IQ below 70 is part of the diagnostic criteria for intellectual disability.

The first phase of the study followed a double-blind, placebo-controlled design. Participants randomized to the experimental group received intranasal oxytocin started the trial with a dose of 24 international units (IU) twice daily (BID), which was adjusted to 12 IU BID, subsequently the dose was increased to 24IU BID. Each insufflation delivered 4 IU and three insufflations (12 IU) in each nostril were given twice daily for a total daily dose of 48 IU. The second phase was a 12-week open-label extension phase during which all participants received intranasal oxytocin.

Change in VPC Task has 2 subscores at week 12 as compared to baseline. The subject is initially presented with a target for familiarization and the familiar target is then paired with a novel target. Recognition is indexed by a novelty score derived from the percentage of time looking at the novel stimulus vs. the familiar stimulus. The Social-Novel Preference score refers to the proportion of time spent looking at novel stimuli out of all the time spent looking at both novel and familiar stimuli in the social test. The Nonsocial-Novel Preference score refers to the proportion of time spent looking at novel stimuli out of all the time spent looking at both novel and familiar stimuli in the nonsocial test.The scores are given in proportions with a range from -1 to 1. A score of -1 would mean the participant shows a preference for familiar stimuli and a score of 1 demonstrates a preference for novel stimuli.

Only 3 participants with data from baseline and week 12

One of three computerized eye tracking tasks to measure attention. three computer screens are set up side by side. A stimulus initially appears on the central screen, and once the participant orients to that stimulus, another stimulus will appear on one of the lateral screens. In the "gap" condition, the central stimulus will disappear before the peripheral stimulus appears. In the "overlap" condition, the central stimulus will remain on the screen while the peripheral stimulus appears. In both conditions, reaction times of the participant's eye movements (saccadic reaction time) from the central stimulus to the peripheral stimulus will be measured. Gap Effect measures the difference between average Gap and Overlap saccade latencies.

Only 2 participants with data from both baseline and Week 12

One of three computerized eye tracking tasks to measure attention. The "flicker task," or the four-alternative forced-choice preferential looking paradigm - the time interval over which the visual system is able to parse information. Scores range from -1 to 1 with higher scores indicating better (more typical) performance.

Only 1 participant with data from baseline and Week 12

Mean change in scale at week 12 as compared to baseline. Vineland Adaptive Behavior Communication Domain measures adaptive functioning.

Vineland-II subdomains (Communication, Daily Living Skills, Socialization, Motor, Adaptive Behavior Composite, Internalizing, Externalizing and maladaptive) are V-scale scores (M=15, SD=3). Higher scores indicate better developed adaptive social behavior.

Vineland-II domain and composite values are standard scores (M=100, SD=15). Higher scores indicate better developed adaptive social behavior.

Participants were only included in this analysis if they had Vinelands at BL and Week 12. One incomplete Maladaptive subdomain form for one participant.

Change in Repetitive Behavior Scale at week 12 as compared to baseline. the RBS-R is a 44-item self-report questionnaire consisting of subscales and one additional global rating score from 1-100. Score range for Stereotypic Behavior subscale is 0-27, Self-Injurious Behavior subscale is 0-24, Compulsive Behavior subscale is 0-18, Ritualistic/Sameness Behavior subscale is 0-36, and Restricted Interests subscale 0-9. Total scale for RBS-R is 0-214, with higher score indicating more severe problem.

Patients were only included in this analysis if they had RBS-R at BL and Week 12

Mean Change in Clinical Global Impression-Severity Scales at week 12 as compared to baseline. Clinical Global Impressions (CGI) Rating Scales are commonly used to measure symptom severity and global improvement in treatment studies of patients with developmental disorders. There Severity Scale (CGI-S) is a 7-point scale that requires the clinician to rate the severity of illness at the time of assessment. Full scale from 1 - 7. Higher scores indicate greater symptom severity.

Data from all participants who had data collected at 12 weeks.

Mean Change in Short Sensory Profile Scale at week 12 as compared to baseline, measuring sensory sensitivity and sensory seeking behavior. The SSP is a 38-item caregiver questionnaire. Items are based on a 5-point Liker scale ranging from 1=always to 5=never. Tactile Sensitivity ranges from 7-35. Taste/Smell Sensitivity ranges from 4-20. Movement Sensitivity ranges from 3-15. Underresponsive/Seeks Sensation ranges from 7-35. Auditory Filtering ranges from 6-30. Low Energy/Weak ranges from 6-30. Visual/Auditory Sensitivity ranges from 5-25. Total scale range from 38-190. Lower scores indicate a higher probability of sensory processing abnormalities.

In the case of two participants who dropped out after week 4, difference scores were calculated for each outcome measure using the last observation carried forward (This is why some measures have N's of 9 and 7). Two participants dropped out after BL and were not included in the analysis.

Macarthur-Bates Communicative Development Inventory at week 12 as compared to baseline, measuring language. Words and Gestures Forms are for children ages 8-18 months. In the form, the first part prompts parents to document the child's understanding of hundreds of early vocabulary items separated into semantic categories such as animal names, household items, and action words. Parents mark the words understood or used, and the forms yield separate indexes of words understood and words produced. The second part of each form asks parents to record the communicative and symbolic gestures the child has tried or completed. Ranges for each subscale score are as follows: Phrases understood (0-28), Words understood (0-396), Words produced (0-396), Early gestures (0-18), Later gestures (0-45), Total gestures (0-63). Higher scores indicate a great number of words, phrases, or gestures understood or produced.

In the Auditory Habituation EEG task, participants listen to a series of 4 tones and the neural responses to each of these tones (event related potentials, ERPs ) are averaged. The N1 and P2 components are typical responses to auditory stimuli. The N1 response is the initial, quick response to hearing a stimulus, and P2 reflects the later processing of the stimulus. Both of these should be greater in response to the first tone, and then reduce in response to each subsequent tone. This is known as habituation, and is calculated as the change in Tone 1 minus Tone 2 response for both N1 and P2 components.

Data results available only for those who underwent Auditory Habituation EEG task

Number of Adverse Events through week 12

Mean Change Caregiver Strain Index at week 12 as compared to baseline. The Caregiver Strain Questionnaire is a 21-item measure of self-reported strain experienced by caregivers and families of youth with emotional problems, with responses on a 5-point Likert scale (0 = Not at all, 4 = very much). Full scale from 0 to 84, higher score indicates higher caregiver burden

incomplete form for one participant

Change in Mullen Scales of Early Learning (MSEL) at week 12 as compared to baseline. The Mullen Scales results are reported using Age Equivalents, which provides an estimate of the chronological age (CA) in years and months at which a typically developing child demonstrates the skills displayed by the child being assessed. The Mullen Scales results are reported using T scores. (M = 100, SD = 15). Each subscale is standardized to calculate an age-equivalent score. Higher scores represent a higher CA, and therefore better outcome.

The first phase of the study followed a double-blind, placebo-controlled design. Participants randomized to the experimental group received intranasal oxytocin started the trial with a dose of 24 international units (IU) twice daily (BID), which was adjusted to 12 IU BID, subsequently the dose was increased to 24IU BID. Each insufflation delivered 4 IU and three insufflations (12 IU) in each nostril were given twice daily for a total daily dose of 48 IU. During the second phase of the study, all participants received oxytocin, in identical doses.