Trial Outcomes & Findings for Piloting Treatment With Intranasal Oxytocin in Phelan-McDermid Syndrome (NCT NCT02710084)

Last Updated: 2021-12-06

Results Overview

Change in scale at week 12 as compared to baseline. Aberrant Behavior Checklist - behavior rating subscales for the assessment of treatment effects.16 items, Each item is scored as 0 (never a problem), 1 (slight problem), 2 (moderately serious problem), or 3 (severe problem). Total score range from 0 to 48, with higher score indicating poorer health outcomes.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

18 participants

Primary outcome timeframe

Baseline and Week 12

Results posted on

2021-12-06

Participant Flow

Participant milestones

Participant milestones
Measure	Saline Then Oxytocin During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin 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.
First Phase - 12 Weeks STARTED	10	8
First Phase - 12 Weeks COMPLETED	7	7
First Phase - 12 Weeks NOT COMPLETED	3	1
Open Label Phase: Week 12 to 24 STARTED	7	7
Open Label Phase: Week 12 to 24 COMPLETED	7	7
Open Label Phase: Week 12 to 24 NOT COMPLETED	0	0

Reasons for withdrawal

Reasons for withdrawal
Measure	Saline Then Oxytocin During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin 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.
First Phase - 12 Weeks Withdrawal by Subject	3	1

Baseline Characteristics

Race and Ethnicity were not collected from any participant.

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Saline Then Oxytocin n=10 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=8 Participants 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.	Total n=18 Participants Total of all reporting groups
Age, Continuous	9.8 years STANDARD_DEVIATION 3.6 • n=10 Participants	6.8 years STANDARD_DEVIATION 1.4 • n=8 Participants	8.4 years STANDARD_DEVIATION 3.2 • n=18 Participants
Sex: Female, Male Female	5 Participants n=10 Participants	4 Participants n=8 Participants	9 Participants n=18 Participants
Sex: Female, Male Male	5 Participants n=10 Participants	4 Participants n=8 Participants	9 Participants n=18 Participants
Race and Ethnicity Not Collected	—	—	0 Participants Race and Ethnicity were not collected from any participant.
Aberrant Behavior Checklist Social Withdrawal (ABC-SW) subscale	20.1 units on a scale STANDARD_DEVIATION 6.1 • n=10 Participants	14. units on a scale STANDARD_DEVIATION 3.4 • n=8 Participants	17.4 units on a scale STANDARD_DEVIATION 5.9 • n=18 Participants
Verbal DQ - developmental quotient	14.9 T-score STANDARD_DEVIATION 12.8 • n=10 Participants	26.4 T-score STANDARD_DEVIATION 21.3 • n=8 Participants	20 T-score STANDARD_DEVIATION 17.6 • n=18 Participants
Nonverbal DQ	20.1 T-score STANDARD_DEVIATION 11.7 • n=10 Participants	26.1 T-score STANDARD_DEVIATION 13.1 • n=8 Participants	22.7 T-score STANDARD_DEVIATION 12.3 • n=18 Participants
Full Scale DQ	17.4 T-score STANDARD_DEVIATION 11.8 • n=10 Participants	26.3 T-score STANDARD_DEVIATION 16.7 • n=8 Participants	21.4 T-score STANDARD_DEVIATION 14.5 • n=18 Participants

PRIMARY outcome

Timeframe: Baseline and Week 12

Population: 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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=9 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=7 Participants 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 Aberrant Behavior Checklist Hyperactivity	-8.11 score on a scale Standard Deviation 11.85	-2.71 score on a scale Standard Deviation 7.34
Change in Aberrant Behavior Checklist Inappropriate speech	-1.67 score on a scale Standard Deviation 3.04	-7.14 score on a scale Standard Deviation 2.21
Change in Aberrant Behavior Checklist Social Withdrawal	-7.44 score on a scale Standard Deviation 4.58	-2.42 score on a scale Standard Deviation 3.15
Change in Aberrant Behavior Checklist Irritability	-5 score on a scale Standard Deviation 6.63	-1.71 score on a scale Standard Deviation 7.13
Change in Aberrant Behavior Checklist Stereotypy	-2.22 score on a scale Standard Deviation 4.66	0.57 score on a scale Standard Deviation 2.99

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: Only 3 participants with data from baseline and week 12

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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=1 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=2 Participants 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 Visual Paired Comparison (VPC) Task Social-Novel Preference	0.01 score on a scale Standard Deviation NA Data collected from 1 participant and hence the measure of dispersion (i.e., standard deviation) cannot be calculated.	0.02 score on a scale Standard Deviation 0.12
Change in Visual Paired Comparison (VPC) Task Nonsocial-Novel Preference	-0.38 score on a scale Standard Deviation NA Data collected from 1 participant and hence the measure of dispersion (i.e., standard deviation) cannot be calculated.	0.22 score on a scale Standard Deviation 0.12

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: Only 2 participants with data from both 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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=2 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin 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 Gap-Overlap Task	63.81 milliseconds (ms) Standard Deviation 34.19	—

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: Only 1 participant with data from 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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=1 Participants 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 Flicker Tasks Preference for the Target Box at 0.2 Hz	—	0.10 score on a scale Standard Deviation NA Data collected from 1 participant and hence the measure of dispersion (i.e., standard deviation) cannot be calculated.
Change in Flicker Tasks Preference for the Target Box at 0.5 Hz	—	0.30 score on a scale Standard Deviation NA Data collected from 1 participant and hence the measure of dispersion (i.e., standard deviation) cannot be calculated.
Change in Flicker Tasks Preference for the Target Box at 1 Hz	—	-0.12 score on a scale Standard Deviation NA Data collected from 1 participant and hence the measure of dispersion (i.e., standard deviation) cannot be calculated.
Change in Flicker Tasks Preference for the Target Box at 2 Hz	—	0.03 score on a scale Standard Deviation NA Data collected from 1 participant and hence the measure of dispersion (i.e., standard deviation) cannot be calculated.

SECONDARY outcome

Timeframe: Baseline and Week 12

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

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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=7 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=6 Participants 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 Vineland Adaptive Behavior Scales Communication	4 score on a scale Standard Deviation 7.72	2.83 score on a scale Standard Deviation 4.83
Change in Vineland Adaptive Behavior Scales Daily Living Skills	3.29 score on a scale Standard Deviation 8.39	1.17 score on a scale Standard Deviation 5.13
Change in Vineland Adaptive Behavior Scales Socialization	3 score on a scale Standard Deviation 4.86	-0.5 score on a scale Standard Deviation 4.46
Change in Vineland Adaptive Behavior Scales Motor	1 score on a scale Standard Deviation 3.46	3.17 score on a scale Standard Deviation 6.18
Change in Vineland Adaptive Behavior Scales Adaptive Behavior Composite	3.14 score on a scale Standard Deviation 3.80	2 score on a scale Standard Deviation 3.22
Change in Vineland Adaptive Behavior Scales Internalizing	-1.14 score on a scale Standard Deviation 1.07	6 score on a scale Standard Deviation 0.84
Change in Vineland Adaptive Behavior Scales Externalizing	-1.14 score on a scale Standard Deviation 2.73	6 score on a scale Standard Deviation 1.33
Change in Vineland Adaptive Behavior Scales Maladaptive	-1.33 score on a scale Standard Deviation 2.42	6 score on a scale Standard Deviation 0.55

SECONDARY outcome

Timeframe: Baseline and Week 12

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

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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=9 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=7 Participants 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 Repetitive Behavior Scale-Revised (RBS-R) Stereotypic behaviors	-1.67 score on a scale Standard Deviation 2.78	0.29 score on a scale Standard Deviation 2.87
Change in Repetitive Behavior Scale-Revised (RBS-R) Self-injury	-1.22 score on a scale Standard Deviation 3.11	1 score on a scale Standard Deviation 2.31
Change in Repetitive Behavior Scale-Revised (RBS-R) Compulsive behaviors	-1.56 score on a scale Standard Deviation 3.09	-0.14 score on a scale Standard Deviation 0.69
Change in Repetitive Behavior Scale-Revised (RBS-R) Ritualistic behaviors	-1.33 score on a scale Standard Deviation 2.40	-0.43 score on a scale Standard Deviation 1.62
Change in Repetitive Behavior Scale-Revised (RBS-R) Sameness behaviors	-2 score on a scale Standard Deviation 2.65	-0.29 score on a scale Standard Deviation 1.60
Change in Repetitive Behavior Scale-Revised (RBS-R) Restrictive behaviors	-1.43 score on a scale Standard Deviation 2.39	0.14 score on a scale Standard Deviation 0.90
Change in Repetitive Behavior Scale-Revised (RBS-R) Overall Score	-8.56 score on a scale Standard Deviation 13.29	0 score on a scale Standard Deviation 5.56

SECONDARY outcome

Timeframe: Baseline and Week 12

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

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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=9 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=7 Participants 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 Clinical Global Impression - Severity Scales	-0.11 score on a scale Standard Deviation 0.17	-0.1 score on a scale Standard Deviation 0.24

SECONDARY outcome

Timeframe: Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=9 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=7 Participants 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 Short Sensory Profile (SSP) Tactile	2.56 score on a scale Standard Deviation 5.17	1.57 score on a scale Standard Deviation 3.78
Change in Short Sensory Profile (SSP) Taste/Smell	1.67 score on a scale Standard Deviation 2.88	0.71 score on a scale Standard Deviation 1.89
Change in Short Sensory Profile (SSP) Movement	-0.67 score on a scale Standard Deviation 2.0	0.29 score on a scale Standard Deviation 0.76
Change in Short Sensory Profile (SSP) Under-responsive/seeks attention	4.44 score on a scale Standard Deviation 5.50	0.71 score on a scale Standard Deviation 4.68
Change in Short Sensory Profile (SSP) Auditory filtering	4 score on a scale Standard Deviation 5.68	0.29 score on a scale Standard Deviation 5.21
Change in Short Sensory Profile (SSP) Low energy/weak	1.67 score on a scale Standard Deviation 6.18	-0.71 score on a scale Standard Deviation 4.19
Change in Short Sensory Profile (SSP) Visual/auditory sensitivity	1.89 score on a scale Standard Deviation 2.57	-0.86 score on a scale Standard Deviation 2.67
Change in Short Sensory Profile (SSP) Summary total	14.33 score on a scale Standard Deviation 21.31	1 score on a scale Standard Deviation 17.95

SECONDARY outcome

Timeframe: Baseline and Week 12

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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=7 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=7 Participants 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 Macarthur-Bates Communicative Development Inventory (MCDI) Early gestures	1.83 score on a scale Standard Deviation 2.64	0.29 score on a scale Standard Deviation 1.38
Change in Macarthur-Bates Communicative Development Inventory (MCDI) Phrases understood	0.83 score on a scale Standard Deviation 6.62	1.43 score on a scale Standard Deviation 3.55
Change in Macarthur-Bates Communicative Development Inventory (MCDI) Words understood	-9.17 score on a scale Standard Deviation 52.59	7 score on a scale Standard Deviation 13.41
Change in Macarthur-Bates Communicative Development Inventory (MCDI) Words produced	11.67 score on a scale Standard Deviation 41.90	2.57 score on a scale Standard Deviation 10.23
Change in Macarthur-Bates Communicative Development Inventory (MCDI) Later gestures	3 score on a scale Standard Deviation 7.48	0.86 score on a scale Standard Deviation 1.95
Change in Macarthur-Bates Communicative Development Inventory (MCDI) Total gestures	4.83 score on a scale Standard Deviation 9.97	0.57 score on a scale Standard Deviation 2.07

SECONDARY outcome

Timeframe: Baseline and Week 12

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

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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=2 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=1 Participants 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 EEG Tasks: Auditory Habituation Auditory Habituation: N1 Habituation Change	0.05 microvolts (µV) Standard Deviation 0.37	0.12 microvolts (µV) Standard Deviation NA Data collected from 1 participant and hence the measure of dispersion (i.e., standard deviation) cannot be calculated.
Change in EEG Tasks: Auditory Habituation Auditory Habituation: P2 Habituation Change	1.15 microvolts (µV) Standard Deviation 0.91	-3.48 microvolts (µV) Standard Deviation NA Data collected from 1 participant and hence the measure of dispersion (i.e., standard deviation) cannot be calculated.

SECONDARY outcome

Timeframe: week 12

Number of Adverse Events through week 12

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=10 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=8 Participants 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.
Number of Adverse Events	41 events	35 events

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: incomplete form for one participant

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

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=6 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=7 Participants 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 Caregiver Strain Index	-1.83 score on a scale Standard Deviation 1.47	-0.86 score on a scale Standard Deviation 1.07

SECONDARY outcome

Timeframe: baseline and 12 weeks.

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.

Outcome measures

Outcome measures
Measure	Saline Then Oxytocin n=7 Participants During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU. During the second phase of the study, all participants received intranasal oxytocin, in identical doses.	Intranasal Oxytocin n=7 Participants 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 Mullen Scales of Early Learning (MSEL) Gross motor	-1.57 T-score Standard Deviation 4.69	-0.86 T-score Standard Deviation 1.46
Change in Mullen Scales of Early Learning (MSEL) Visual Reception	0.29 T-score Standard Deviation 7.0	2.86 T-score Standard Deviation 3.30
Change in Mullen Scales of Early Learning (MSEL) Fine Motor	-0.29 T-score Standard Deviation 1.11	0.71 T-score Standard Deviation 1.80
Change in Mullen Scales of Early Learning (MSEL) Receptive Language	-1.86 T-score Standard Deviation 4.86	1.71 T-score Standard Deviation 2.70
Change in Mullen Scales of Early Learning (MSEL) Expressive Language	0.43 T-score Standard Deviation 2.61	0.43 T-score Standard Deviation 1.80

Adverse Events

Saline

Serious events: 0 serious events

Other events: 9 other events

Deaths: 0 deaths

Intranasal Oxytocin

Serious events: 0 serious events

Other events: 15 other events

Deaths: 15 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Alexander Kolevzon, MD

Icahn School of Medicine at Mount Sinai

Phone: 212-659-9134

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	Saline n=10 participants at risk During the first phase, patients randomized to the placebo group received intranasal saline solution in doses of 24 IU two times daily, for a total of 48 IU.	Intranasal Oxytocin n=15 participants at risk 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.
Gastrointestinal disorders Tooth pain	0.00% 0/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
General disorders Sedation	20.0% 2/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Metabolism and nutrition disorders Decreased appetite	20.0% 2/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	0.00% 0/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
General disorders Periorbital / facial swelling	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Gastrointestinal disorders Diarrhea	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	13.3% 2/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Infections and infestations Upper respiratory tract infection	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	13.3% 2/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
General disorders Sleep disturbance	20.0% 2/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	46.7% 7/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Metabolism and nutrition disorders Increased appetite	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Psychiatric disorders Irritability/agitation	30.0% 3/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	20.0% 3/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Respiratory, thoracic and mediastinal disorders Cough	0.00% 0/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	13.3% 2/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Respiratory, thoracic and mediastinal disorders Runny nose/congestion	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
General disorders Fever	40.0% 4/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	60.0% 9/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Psychiatric disorders Aggression/self-injury	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	13.3% 2/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Infections and infestations Infection	30.0% 3/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	40.0% 6/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Psychiatric disorders Elated mood/Silliness	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	33.3% 5/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
General disorders Leg weakness	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Psychiatric disorders Restlessness/hyperactivity	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	53.3% 8/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
General disorders Bloody nose	0.00% 0/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	20.0% 3/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Psychiatric disorders Stereotypies	20.0% 2/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	26.7% 4/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Psychiatric disorders Apathy	0.00% 0/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
General disorders Foot pain	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	0.00% 0/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Endocrine disorders Hirsutism	0.00% 0/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Skin and subcutaneous tissue disorders Eczema	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	20.0% 3/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Respiratory, thoracic and mediastinal disorders Allergies/asthma	20.0% 2/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	20.0% 3/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Renal and urinary disorders Enuresis	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Injury, poisoning and procedural complications Accidental injury	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	0.00% 0/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Nervous system disorders Seizure	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	0.00% 0/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Ear and labyrinth disorders Rubbing ears	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	0.00% 0/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Psychiatric disorders Disinhibited	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Psychiatric disorders Oppositional behavior	30.0% 3/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	13.3% 2/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Psychiatric disorders Low frustration tolerance	10.0% 1/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	20.0% 3/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.
Psychiatric disorders Tantrums	0.00% 0/10 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.	6.7% 1/15 • through week 12 Monitoring of adverse events (AEs) was done using an adapted semi-structured interview, the Safety and Monitoring Uniform Report Form (SMURF). AEs were documented with respect to severity, duration, management, relationship to study drug, and outcome. Severity was graded using a scale of mild, moderate, or severe.