Trial Outcomes & Findings for Trial of Sertraline to Treat Children With Fragile X Syndrome (NCT NCT01474746)

Results Overview

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. Shown here are the baseline and 6-month follow-up raw scores from the expressive language scale. This scale's raw scores range from 0 to 50. The lower the score on this scale, the weaker the ability; the higher the score, the greater the ability. The MSEL was administered at the baseline visit and at the 6-month follow-up visit.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

57 participants

Primary outcome timeframe

From baseline visit to six-month visit.

Results posted on

2017-09-25

Participant Flow

Participant milestones

Participant milestones
Measure	Placebo This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Overall Study STARTED	30	27
Overall Study COMPLETED	27	25
Overall Study NOT COMPLETED	3	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Overall Study Lost to Follow-up	1	1
Overall Study Withdrawal by Subject	2	1

Baseline Characteristics

Trial of Sertraline to Treat Children With Fragile X Syndrome

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=27 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.	Total n=57 Participants Total of all reporting groups
Age, Categorical <=18 years	30 Participants n=5 Participants	27 Participants n=7 Participants	57 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Sex: Female, Male Female	3 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants
Sex: Female, Male Male	27 Participants n=5 Participants	21 Participants n=7 Participants	48 Participants n=5 Participants
Region of Enrollment United States	30 participants n=5 Participants	27 participants n=7 Participants	57 participants n=5 Participants

PRIMARY outcome

Timeframe: From baseline visit to six-month visit.

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. Shown here are the baseline and 6-month follow-up raw scores from the expressive language scale. This scale's raw scores range from 0 to 50. The lower the score on this scale, the weaker the ability; the higher the score, the greater the ability. The MSEL was administered at the baseline visit and at the 6-month follow-up visit.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=25 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Change in Mullen Scales of Early Learning - Expressive Language Raw Score Baseline	19.3 units on a scale Standard Deviation 9.68	21.3 units on a scale Standard Deviation 10.32
Change in Mullen Scales of Early Learning - Expressive Language Raw Score Follow-Up	21.3 units on a scale Standard Deviation 9.59	25.04 units on a scale Standard Deviation 10.78

PRIMARY outcome

Timeframe: 6-month follow-up visit score

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Clinical Global Impression - Improvement (CGI-I) is used to measure the overall behavioral change of an individual and their therapeutic response. The CGI-I is a 3-item observer-rated scale administered by the physician to the caregiver, who assesses improvement using a 7-point scale: 1 = Very much improved; 2 = Much improved; 3 = Minimally improved; 4 = No change; 5 = Minimally worse; 6 = Much worse; and 7 = Very much worse. Therefore, the lower the score, the greater the behavioral improvement as rated by the caregiver. Shown here are the CGI-I mean scores from the 6-month follow-up visit.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=25 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Clinical Global Impression - Improvement	2.59 units on a scale Standard Deviation 0.84	2.28 units on a scale Standard Deviation 1.06

PRIMARY outcome

Timeframe: From baseline visit to six-month visit

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language and expressive language. Based on the raw score obtained by the participant in each scale the scoring software computes T scores, percentile ranks, and age equivalents for each scale separately. Shown here are the baseline and 6-month follow-up T scores from the expressive language scale. T scores have a range of 20 to 80, a mean of 50, and a standard deviation of 10. Any child scoring at or below 1.5 standard deviations below the average is considered presenting significant delays. The lower the T score, the worse the outcome. The MSEL was administered at the baseline visit and at the 6-month follow-up visit.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=25 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Change in Mullen Scales of Early Learning - Expressive Language Standard T Score Baseline	23.3 T scores Standard Deviation 5.8	25.8 T scores Standard Deviation 11.78
Change in Mullen Scales of Early Learning - Expressive Language Standard T Score 6-Month Follow-Up	22.6 T scores Standard Deviation 6.47	25.8 T scores Standard Deviation 10.87

SECONDARY outcome

Timeframe: At baseline visit

Population: The ADOS was not administered to all subjects at baseline due to the PI's decision to remove this assessment from the protocol partway through the study; due to staff oversight, however, this assessment remained listed among the measures in the protocol.

The Autism Diagnostic Observation Schedule (ADOS-2) assesses and diagnoses autism spectrum disorder. This test was administered at baseline and at the six-month follow-up visit. The choice to administer Module 1 or Module 2 depends on the verbal ability of each subject: Module 1 is used for children who are 31 months and older and/or who do not consistently use phrase speech, and Module 2 is used for children of any age who use phrase speech but are not verbally fluent. The scoring algorithm gives an overall total, which ranges from 0 to 28. The higher the score, the higher the level of autism-related symptoms. The overall total ranges from 0 to 28. On Module 1, for children with few to no words, scores at 11 and above indicate autism spectrum; for children with some words, the cutoff is scores 8 and above. On Module 2, the cutoff for autism spectrum is 7 or above for kids under 5 years, and 8 or above for those 5 years and older.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=24 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Autism Diagnostic Observation Schedule	10.73 units on a scale Standard Deviation 6.23	11.00 units on a scale Standard Deviation 6.57

SECONDARY outcome

Timeframe: At baseline visit

The Visual Analog Scale will be used to measure the severity of three specific behavioral symptoms chosen by the caregiver(s). Parents mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm. The parents choose two key behaviors that they want to target for this trial (e.g., aggression, hyperarousal, anxiety, hyperactivity) and the third target measurement is language/communication. For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 6-month visit. The calculated distance in cm between the baseline and 6-month visit marks thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much. Shown here is the mean distance in cm from the "worst behavior" side, at baseline. The smaller the value, the worse the behavior. The range is minimum 0 cm to maximum 10 cm.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=27 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Visual Analog Scale	2.95 centimeters Standard Deviation 1.72	2.62 centimeters Standard Deviation 1.74

SECONDARY outcome

Timeframe: At baseline visit

Population: Data were collected and analyzed on those participants who were compliant with the eye tracking protocol: 13 in the placebo group, and 9 in the active group.

There are several eye tracking measures, each intended to measure different outcomes including social gaze, social reciprocity, and attention. All stimuli are presented on a Tobii T120 binocular eye tracker monitor. The system consists of a high-resolution camera embedded in a 17-inch TFT monitor. Stimuli consist of sixty colored photographs of adult human face (equal numbers of males and females, different races and ethnicities) from the NimStim Face Stimulus Set, each showing a calm, happy, or fearful expression, and sixty scrambled versions of the face images. Shown here are the averaged response times (in seconds) to the presented stimuli, at the baseline visit.

Outcome measures

Outcome measures
Measure	Placebo n=13 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=9 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Eye Tracking	0.510136154 seconds Standard Deviation 0.056	0.451205556 seconds Standard Deviation 0.07

SECONDARY outcome

Timeframe: At baseline visit

The Preschool Language Scale-fifth edition (PLS-5) is designed to measure auditory comprehension (AC) and expressive communication (EC) for children birth to 7 years 11 months. The measure examines the child's attention, play, gestures, social communication, semantics, language structure, integrative language skills and emergent literacy skills. The PLS-5 has expanded coverage of early play behaviors, concepts, Theory of Mind, as well as emergent literacy skills. The PLS-5 yields norm-referenced scores including standard scores, percentile ranks and age equivalents for the AC and EC scales as well as for Total Language (TL). Raw score ranges are 0 to 65 in AC, 0 to 67 in EC, and therefore 0 to 132 in TL (calculated by summing AC+EC raw scores). The higher the scores, the greater the language ability. Shown here are the mean TL raw scores from the baseline visit.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=27 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Preschool Language Scale-fifth Edition (PLS-5): AC+EC Total Raw Score	53.90 units on a scale Standard Deviation 18.84	55.59 units on a scale Standard Deviation 21.13

SECONDARY outcome

Timeframe: At baseline visit

Population: The SPM-P was removed from the protocol after the trial was initiated and was therefore not administered to 1 subject in the active treatment group at baseline.

The Sensory Processing Measure - Preschool (SPM-P) is a questionnaire that was used to measure specific problems, including under- and over-responsiveness, sensory-seeking behavior, and perceptual problems in multiple environments (at home, at school, and in the community) for children aged 2 to 5 years old. The SPM-P provides norm-referenced standard scores for two higher level integrative functions (praxis and social participation) and five sensor sensory systems (visual, auditory, tactile, proprioceptive, and vestibular functioning). Reported here is the Social Participation subscale mean raw score, which ranges from 8 to 32. The lower the raw score, the more limited the child's level of social participation. The higher the score, the greater the child's level of social participation.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=26 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Sensory Processing Measure - Preschool (SPM-P) Social Participation: Raw Score	20.6 units on a scale Standard Deviation 6.85	20.5 units on a scale Standard Deviation 5.49

SECONDARY outcome

Timeframe: At baseline visit

Population: The Sensory Profile was not administered to all subjects at baseline due to the PI's decision to remove this assessment from the protocol partway through the study; due to staff oversight, however, this assessment remained listed among the measures in the protocol.

The Sensory Profile is designed to measure sensory-related difficulties. This measure will be administered to the primary caregiver of each subject to measure the caregiver's sensory ability and its impact on the subject. Of the four subscales scored in the Sensory Profile, the "Sensation Seeking" subscale mean raw scores for the placebo and treatment groups are reported here. This subscale has a raw scores range from 0 to 95, with scores 0-6 indicating that the child is sensation seeking much less than others, 7-19 less than others, 20-47 just like the majority of others, 48-60 more than others, and 61-95 much more than others.

Outcome measures

Outcome measures
Measure	Placebo n=22 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=18 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Sensory Profile - Sensation Seeking Subscale Raw Score	47.86364 units on a scale Standard Deviation 7.97195	47.83333 units on a scale Standard Deviation 7.69454

SECONDARY outcome

Timeframe: At baseline visit

Population: This assessment was introduced to the protocol partway through the study, and therefore there were only 20 subjects (10 placebo and 10 active) who were administered the Vineland-II at both their baseline and follow-up visits.

The Vineland-II measures the personal and social skills of individuals from birth through adulthood. It was designed to assess handicapped and non-handicapped persons in their personal and social functioning and is appropriate for individuals of all ages. The Vineland-II is a survey that is administered to a parent or caregiver using a semi-structured interview format and is organized around four Behavior Domains: Communication, Daily Living Skills, Socialization, and Motor Skills. Each subtest is scored with a standard score X=100 ± 15 and summed to calculate the Adaptive Behavior Composite (ABC) using age-adjusted scoring tables. Reported here are the ABC mean standard scores for the placebo and treatment groups baseline. The ABC ranges from 20 to 160 and indicates low (20-70), moderately low (70-85), adequate (85-115), moderately high (115-130), or high (130-160) overall adaptive functioning.

Outcome measures

Outcome measures
Measure	Placebo n=10 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=10 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) - Adaptive Behavior Composite Standard Score	73.3 units on a scale Standard Deviation 10.08905	66.5 units on a scale Standard Deviation 16.84076

SECONDARY outcome

Timeframe: At baseline visit

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. Shown here are the mean baseline raw scores from the Visual Reception scale. This scale's raw scores range from 0 to 50. The lower the score on this scale, the weaker the child's ability for visual reception; the higher the score, the greater the ability for visual reception.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=27 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Visual Reception Raw Score	28.9 units on a scale Standard Deviation 7.94	26.3 units on a scale Standard Deviation 9.50

SECONDARY outcome

Timeframe: At baseline visit

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. Shown here are the mean raw scores from the Fine Motor scale at the baseline visit. This scale's raw scores range from 0 to 49. The lower the score on this scale, the weaker the child's fine motor skills; the higher the score, the greater the child's fine motor skills.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=27 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Fine Motor Raw Score	24.8 units on a scale Standard Deviation 5.26	23.1 units on a scale Standard Deviation 7.13

SECONDARY outcome

Timeframe: At six month visit

Population: The ADOS was not administered to all subjects at the six-month visit due to the PI's decision to remove this assessment from the protocol partway through the study; due to staff oversight, however, the ADOS remained listed in the protocol. Also, 2 sertraline and 3 placebo subjects discontinued and were thus administered no follow-up ADOS.

The Autism Diagnostic Observation Schedule (ADOS-2) assesses and diagnoses autism spectrum disorder. This test was administered at baseline and at the six-month follow-up visit. The choice to administer Module 1 or Module 2 depends on the verbal ability of each subject: Module 1 is used for children who are 31 months and older and/or who do not consistently use phrase speech, and Module 2 is used for children of any age who use phrase speech but are not verbally fluent. The scoring algorithm gives an overall total, which ranges from 0 to 28. The higher the score, the higher the level of autism-related symptoms. The overall total ranges from 0 to 28. On Module 1, for children with few to no words, scores at 11 and above indicate autism spectrum; for children with some words, the cutoff is scores 8 and above. On Module 2, the cutoff for autism spectrum is 7 or above for kids under 5 years, and 8 or above for those 5 years and older.

Outcome measures

Outcome measures
Measure	Placebo n=26 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=24 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
The Autism Diagnostic Observation Schedule (ADOS-2)	11.00 units on a scale Standard Deviation 5.31	11.67 units on a scale Standard Deviation 6.59

SECONDARY outcome

Timeframe: At six-month visit

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent. An additional subject from the sertraline arm was not administered this measure at the 6-month visit due to staff oversight. Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Visual Analog Scale will be used to measure the severity of three specific behavioral symptoms chosen by the caregiver(s). Parents mark on a visual line measuring 10 cm with "worst behavior" at 0 cm and "best behavior" at 10 cm. The parents choose two key behaviors that they want to target for this trial (e.g., aggression, hyperarousal, anxiety, hyperactivity) and the third target measurement is language/communication. For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the 6-month visit. The calculated distance in cm between the baseline and 6-month visit marks thereby demonstrates whether each behavior improved, worsened, or stayed the same during the study, and by how much. Shown here is the mean distance in cm from the "worst behavior" side, at the 6-month visit. The smaller the value, the worse the behavior. The range is minimum 0 cm to maximum 10 cm.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=24 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
The Visual Analog Scale	5.16 units on a scale Standard Deviation 2.03	5.58 units on a scale Standard Deviation 2.58

SECONDARY outcome

Timeframe: At six-month visit

Population: Data were collected and analyzed on those participants who were compliant with the eye tracking protocol: 13 in the placebo group, and 9 in the active group.

There are several eye tracking measures, each intended to measure different outcomes including social gaze, social reciprocity, and attention. All stimuli are presented on a Tobii T120 binocular eye tracker monitor. The system consists of a high-resolution camera embedded in a 17-inch TFT monitor. Stimuli consist of sixty colored photographs of adult human face (equal numbers of males and females, different races and ethnicities) from the NimStim Face Stimulus Set, each showing a calm, happy, or fearful expression, and sixty scrambled versions of the face images. Shown here are the averaged response times (in seconds) to the presented stimuli, at the 6-month follow-up visit.

Outcome measures

Outcome measures
Measure	Placebo n=13 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=9 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Eye Tracking	0.505969231 seconds Standard Deviation 0.08	0.538312222 seconds Standard Deviation 0.095

SECONDARY outcome

Timeframe: At six-month visit

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Preschool Language Scale-fifth edition (PLS-5) is designed to measure auditory comprehension (AC) and expressive communication (EC) for children birth to 7 years 11 months. The measure examines the child's attention, play, gestures, social communication, semantics, language structure, integrative language skills and emergent literacy skills. The PLS-5 has expanded coverage of early play behaviors, concepts, Theory of Mind, as well as emergent literacy skills. The PLS-5 yields norm-referenced scores including standard scores, percentile ranks and age equivalents for the AC and EC scales as well as for Total Language (TL). Raw score ranges are 0 to 65 in AC, 0 to 67 in EC, and therefore 0 to 132 in TL (calculated by summing AC+EC raw scores). The higher the scores, the greater the language ability. Shown here are the mean TL raw scores from the 6-month follow-up visit.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=25 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Preschool Language Scale-fifth Edition (PLS-5): AC+EC Total Raw Score	59.89 units on a scale Standard Deviation 18.11	62.80 units on a scale Standard Deviation 21.70

SECONDARY outcome

Timeframe: At six-month visit

Population: 2 subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent. 3 subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent. The SPM-P was removed from the protocol after the trial was initiated and was therefore not administered to 4 placebo and 3 treatment recipients at the 6-month visit.

The Sensory Processing Measure - Preschool (SPM-P) is a questionnaire that was used to measure specific problems, including under- and over-responsiveness, sensory-seeking behavior, and perceptual problems in multiple environments (at home, at school, and in the community) for children aged 2 to 5 years old. The SPM-P provides norm-referenced standard scores for two higher level integrative functions (praxis and social participation) and five sensor sensory systems (visual, auditory, tactile, proprioceptive, and vestibular functioning). The SPM-P was administered to the caregiver at baseline and again at the 6-month follow-up visit. Reported here is the Social Participation subscale mean raw score from the 6-month visit, which ranges from 8 to 32. The lower the raw score, the more limited the child's level of social participation. The higher the score, the greater the child's level of social participation.

Outcome measures

Outcome measures
Measure	Placebo n=23 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=22 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Sensory Processing Measure-Preschool (SPM-P) Social Participation: Raw Score	19.7 units on a scale Standard Deviation 6.41	18.0 units on a scale Standard Deviation 6.23

SECONDARY outcome

Timeframe: At six-month visit

Population: The Sensory Profile assessment was not administered to any subjects at the follow-up visit due to revisions to the protocol.

The Sensory Profile is designed to measure sensory-related difficulties. This measure will be administered to the primary caregiver of each subject to measure the caregiver's sensory ability and its impact on the subject. Of the four subscales scored in the Sensory Profile, the "Sensation Seeking" subscale mean raw scores for the placebo and treatment groups are reported here. This subscale has a raw scores range from 0 to 95, with scores 0-6 indicating that the child is sensation seeking much less than others, 7-19 less than others, 20-47 just like the majority of others, 48-60 more than others, and 61-95 much more than others.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: At six-month visit

Population: This assessment was only introduced to the protocol partway through the trial. As such, only 20 subjects (10 placebo, 10 active) were administered the Vineland-2 at both baseline and follow-up visits.

The Vineland-II measures the personal and social skills of individuals from birth through adulthood. It was designed to assess handicapped and non-handicapped persons in their personal and social functioning and is appropriate for individuals of all ages. The Vineland-II is a survey that is administered to a parent or caregiver using a semi-structured interview format and is organized around four Behavior Domains: Communication, Daily Living Skills, Socialization, and Motor Skills. Each subtest is scored with a standard score X=100 ± 15 and summed to calculate the Adaptive Behavior Composite (ABC) using age-adjusted scoring tables. Reported here are the ABC mean standard scores for the placebo and treatment groups at the 6-month visit. The ABC ranges from 20 to 160 and indicates low (20-70), moderately low (70-85), adequate (85-115), moderately high (115-130), or high (130-160) overall adaptive functioning.

Outcome measures

Outcome measures
Measure	Placebo n=10 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=10 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Adaptive Behavior Composite Standard Score	74.5 units on a scale Standard Deviation 7.50185	66.4 units on a scale Standard Deviation 17.68364

SECONDARY outcome

Timeframe: At six-month visit

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. Shown here are the mean raw scores from the Visual Reception scale at the 6-month follow-up visit. This scale's raw scores range from 0 to 50. The lower the score on this scale, the weaker the child's ability for visual reception; the higher the score, the greater the ability for visual reception.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=25 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Visual Reception Raw Score	30.9 units on a scale Standard Deviation 6.73	32.4 units on a scale Standard Deviation 10.46

SECONDARY outcome

Timeframe: At baseline visit

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. Shown here are the mean baseline age-equivalent scores from the Visual Reception scale. This scale's age-equivalent scores for each of the five scales are calculated from the raw scores for each scale, using the MSEL Age Equivalents table. Age-equivalent scores for each scale range from 0 to 70 months, with lower scores indicating that a child's visual reception is at a level typical of younger ages, and higher scores indicating that a child's visual reception is at a level typical of older ages.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=27 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Visual Reception Age-equivalent Score	28.2 months Standard Deviation 10.53	25.3 months Standard Deviation 11.59

SECONDARY outcome

Timeframe: At six-month visit

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. Shown here are the mean age-equivalent scores from the Visual Reception scale at the 6-month follow-up visit. This scale's age-equivalent scores for each of the five scales are calculated from the raw scores for each scale, using the MSEL Age Equivalents table. Age-equivalent scores for each scale range from 0 to 70 months, with lower scores indicating that a child's visual reception is at a level typical of younger ages, and higher scores indicating that a child's visual reception is at a level typical of older ages.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=25 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Visual Reception Age-equivalent Score	30.6 months Standard Deviation 9.60	33.7 months Standard Deviation 15.06

SECONDARY outcome

Timeframe: At six-month visit

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. Shown here are the mean raw scores from the Fine Motor scale at the 6-month follow-up visit. This scale's raw scores range from 0 to 49. The lower the score on this scale, the weaker the child's fine motor skills; the higher the score, the greater the child's fine motor skills.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=25 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Fine Motor Raw Score	25.2 units on a scale Standard Deviation 4.96	27.3 units on a scale Standard Deviation 8.06

SECONDARY outcome

Timeframe: At baseline visit

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. Shown here are the mean baseline age-equivalent scores from the Fine Motor scale. This scale's age-equivalent scores for each of the five scales are calculated from the raw scores for each scale, using the MSEL Age Equivalents table. Age-equivalent scores for each scale range from 0 to 70 months, with lower scores indicating that a child's fine motor skills are at a level typical of younger ages, and higher scores indicating that a child's fine motor skills are at a level typical of older ages.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=27 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Fine Motor Age-equivalent Score	24.5 months Standard Deviation 6.97	22.7 months Standard Deviation 8.66

SECONDARY outcome

Timeframe: At six-month visit

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language, and expressive language. Shown here are the mean age-equivalent scores from the Fine Motor scale at the 6-month follow-up visit. This scale's age-equivalent scores for each of the five scales are calculated from the raw scores for each scale, using the MSEL Age Equivalents table. Age-equivalent scores for each scale range from 0 to 70 months, with lower scores indicating that a child's fine motor skills are at a level typical of younger ages, and higher scores indicating that a child's fine motor skills are at a level typical of older ages.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=25 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Fine Motor Age-equivalent Score	25.0 months Standard Deviation 6.91	28.4 months Standard Deviation 10.91

SECONDARY outcome

Timeframe: At baseline visit

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor (not administered because it was out of age range for most subjects), visual reception, fine motor, receptive language and expressive language. Based on the raw score obtained by the participant in each scale, the scoring software computes T scores for each scale separately. Each scale's T score has a range of 20 to 80, a mean of 50, and a standard deviation of 10, and the lower the T score, the lower the child's cognitive and developmental ability. Cognitive T score sum is the sum of the T scores for each scale administered; since 4 scales were administered, the sum's range is 80 to 320, with lower sums indicating lower overall ability. The MSEL was administered at the baseline visit and at the 6-month follow-up visit, and mean baseline cognitive T score sums for the placebo and treatment groups are shown here.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=27 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Cognitive T Score Sum	96.0 T scores Standard Deviation 21.97	99.7 T scores Standard Deviation 33.46

SECONDARY outcome

Timeframe: At six-month visit

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor (not administered because it was out of age range for most subjects), visual reception, fine motor, receptive language and expressive language. Based on the raw score obtained by the participant in each scale, the scoring software computes T scores for each scale separately. Each scale's T score has a range of 20 to 80, a mean of 50, and a standard deviation of 10, and the lower the T score, the lower the child's cognitive and developmental ability. Cognitive T score sum is the sum of the T scores for each scale administered; since 4 scales were administered, the sum's range is 80 to 320, with lower sums indicating lower overall ability. The MSEL was administered at the baseline and 6-month follow-up visits, and mean cognitive T score sums from the 6-month follow-up visit for the placebo and treatment groups are shown here.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=25 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Cognitive T Score Sum	93.0 T scores Standard Deviation 20.33	105.4 T scores Standard Deviation 40.27

SECONDARY outcome

Timeframe: At baseline visit

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language and expressive language. Based on the raw score obtained by the participant in each scale, the scoring software computes T scores, percentile ranks, and age equivalents for each scale separately, as well as a cognitive T score sum and summary age-equivalent score to characterize overall early developmental ability. Summary age-equivalent scores range from 0 to 70 months, with lower scores indicating that a child's ability is at a level typical of younger ages, and higher scores indicating that a child's ability is at a level typical of older ages. The MSEL was administered at the baseline visit and at the 6-month follow-up visit, and mean baseline summary age-equivalent scores for the placebo and treatment groups are shown here.

Outcome measures

Outcome measures
Measure	Placebo n=30 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=27 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Summary Age-equivalent Score	24.8 months Standard Deviation 9.33	26.8 months Standard Deviation 8.89

SECONDARY outcome

Timeframe: At six-month visit

Population: Two subjects from the sertraline arm discontinued - 1 lost to follow up, 1 withdrew consent Three subjects from the placebo arm discontinued - 1 lost to follow up, 2 withdrew consent

The Mullen Scales of Early Learning (MSEL) is a cognitive test to measure cognitive ability and language development. The test has five scales: gross motor, visual reception, fine motor, receptive language and expressive language. Based on the raw score obtained by the participant in each scale, the scoring software computes T scores, percentile ranks, and age equivalents for each scale separately, as well as a cognitive T score sum and summary age-equivalent score to characterize overall early developmental ability. Summary age-equivalent scores range from 0 to 70 months, with lower scores indicating that a child's ability is at a level typical of younger ages, and higher scores indicating that a child's ability is at a level typical of older ages. The MSEL was administered at the baseline visit and at the 6-month follow-up visit, and mean summary age-equivalent scores at the 6-month follow-up visit for the placebo and treatment groups are shown here.

Outcome measures

Outcome measures
Measure	Placebo n=27 Participants This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=25 Participants This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Mullen Scales of Early Learning - Summary Age-equivalent Score	23.6 months Standard Deviation 10.76	30.1 months Standard Deviation 12.64

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 26 other events

Deaths: 0 deaths

Active

Serious events: 0 serious events

Other events: 25 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Randi Hagerman

University of California, Davis, MIND Institute

Phone: 916-703-0247

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Other adverse events
Measure	Placebo n=30 participants at risk This arm will undergo identical treatment and assessments as the experimental group, with the exception of the active agent, sertraline. This group will be placed on a placebo. Placebo: The placebo will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid placebo once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid placebo once per day for a period of six months.	Active n=27 participants at risk This arm will undergo identical treatment and assessments as the placebo group. This group will receive the active agent, sertraline. Sertraline: Liquid sertraline (20 mg/mL) will be dosed in an age-dependent manner. Participants aged 2-3 years of age will be given 2.5 mg (0.125 mL) of liquid sertraline once per day for a period of six months. Participants aged 4 years to 5 years 8 months will be given 5 mg (0.25 mL) of liquid sertraline once per day for a period of six months.
Psychiatric disorders Tantrums	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Nervous system disorders Tremor	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Injury, poisoning and procedural complications Self-injurious behavior	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Nervous system disorders Seizures	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Psychiatric disorders Hand flapping	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Renal and urinary disorders Genital infection	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
General disorders Decreased verbalization	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
General disorders Deciduous teeth eruption	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Blood and lymphatic system disorders Bruising	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Investigations Abnormal Electroencephalogram	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Psychiatric disorders Irritability	0.00% 0/30 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	3.7% 1/27 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Injury, poisoning and procedural complications Falling	0.00% 0/30 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	3.7% 1/27 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Eye disorders Eye infection	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	3.7% 1/27 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Skin and subcutaneous tissue disorders Dry skin	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
General disorders Drooling	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	3.7% 1/27 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Eye disorders Dilated pupils	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
General disorders Biting clothing	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Psychiatric disorders Aggression	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	3.7% 1/27 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
General disorders Sleep disturbance	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	3.7% 1/27 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
General disorders Headache	6.7% 2/30 • Number of events 2 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Psychiatric disorders Nervousness	3.3% 1/30 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	3.7% 1/27 • Number of events 2 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Metabolism and nutrition disorders Loss of appetite	13.3% 4/30 • Number of events 5 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	14.8% 4/27 • Number of events 4 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Endocrine disorders Sweating	3.3% 1/30 • Number of events 2 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Gastrointestinal disorders Nausea	10.0% 3/30 • Number of events 3 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	3.7% 1/27 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Psychiatric disorders Anxiety	6.7% 2/30 • Number of events 2 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	0.00% 0/27 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
General disorders Bruxism	0.00% 0/30 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	3.7% 1/27 • Number of events 1 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Ear and labyrinth disorders Ear infection	16.7% 5/30 • Number of events 8 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	11.1% 3/27 • Number of events 5 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Psychiatric disorders Hyperactivity	13.3% 4/30 • Number of events 4 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	11.1% 3/27 • Number of events 4 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
General disorders Drowsiness/Tiredness	16.7% 5/30 • Number of events 6 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	11.1% 3/27 • Number of events 3 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Skin and subcutaneous tissue disorders Rash	6.7% 2/30 • Number of events 2 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	18.5% 5/27 • Number of events 6 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Gastrointestinal disorders Vomiting	33.3% 10/30 • Number of events 17 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	29.6% 8/27 • Number of events 8 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Gastrointestinal disorders GI upset	16.7% 5/30 • Number of events 5 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	18.5% 5/27 • Number of events 5 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Gastrointestinal disorders Diarrhea	56.7% 17/30 • Number of events 29 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	44.4% 12/27 • Number of events 20 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.
Infections and infestations Upper respiratory infection	66.7% 20/30 • Number of events 31 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.	51.9% 14/27 • Number of events 24 • The adverse event data were collected via non-systematic assessment (based on parent/caregiver reporting) throughout the 6-month period of each subject's participation in the study, as well as via systematic assessment (physical exams) at the baseline, 3-month, and 6-month timepoints.