A Controlled Trial of Sertraline in Young Children With Autism Spectrum Disorder
Phase: PHASE2
Conditions: Autism Spectrum Disorder
Sponsor: Randi J. Hagerman, MD

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1) Protocol Title 
A Controlled Trial of Sertraline in Young Children with ASD 
2) Author of Protocol 
 
Dr. Randi Hagerman,  MD 
 
3) IRB Review History 
This is a modification to an approved protocol. 
4) Objectives 
Aim 1:  
To evaluate the benefit of sertraline for treatment of social deficits and 
language delays in young children with ASD (2 through 5 years old, 
inclusive) in a double-blind, placebo-controlled trial. 
Hypothesis 1.1:  We hypothesize that sertraline will stimulate both language and 
socialization and improve behavior in young children with ASD compared 
to those who are not treated with sertraline.  
 
Aim 2:  
Explore biomarkers associated with response to early treatment with 
sertraline in children with ASD. 
Hypothesis 2.1:  Levels of BDNF at baseline and change in BDNF levels will correlate to the 
clinical response to sertraline in young children with ASD. 
Hypothesis 2.2:  Polymorphisms in the brain-derived neurotrophic factor (BDNF), within the 
serotonin transporter gene (SLC6A4) and serotonin-synthesizing 
tryptophan hydroxylase 2 (TPH2) gene will correlate with the clinical 
response to sertraline. 
Hypothesis 2.3:  Sertraline treatment may have an immunomodulatory effect through a 
decrease in the pro-inflammatory (such as cytokine IL-1) and an increase in 
the anti-inflammatory cytokines (i.e. IL-4 and TGF1).  
 
5) Background 
Autism Spectrum Disorder (ASD) is a behaviorally defined disorder with many causes 
including currently estimated over 1,000 gene mutations that can lead to deficits in synaptic 
plasticity, neuronal migration, transcription and translation changes in addition to many other 
processes that are important for synapse development, CNS connectivity and developmental 
change. Neuroimmune mechanisms may also be active in ASD and influenced by exposure to 
environmental toxins. Currently the CDC has reported that 1 in 68 children at age 8 years in the 
general population has ASD (CDC 2014 MMWR). Known specific genetic causes of ASD that are 

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over 2 to 3% include fragile X syndrome (FXS) and tuberous sclerosis (TS), although many more 
single gene mutations, duplications or deletions can cause 1% or less of ASD.  
We have chosen sertraline treatment in young children with ASD because our previous open 
label and our current controlled trial of sertraline in FXS+ASD have demonstrated significant 
benefit. There is evidence that young children with ASD demonstrate early deficits of serotonin 
synthesis compared to typically-developing children. There is also emerging evidence regarding 
the stimulation of brain-derived neurotrophic factor (BDNF) by an SSRI and the benefit of 
neurogenesis in animal models of intellectual disability (ID ). Preliminary open-label data in ASD 
have shown benefit of an SSRI in preschool children with ASD. Although a multicenter controlled 
trial of citalopram in children with ASD ages 5-17yo did not show benefit, there has never been a 
controlled trial of sertraline in children <5yo with ASD. In our experience in preschool children 
with ASD this is the optimal time to stimulate connectivity in the brain to improve social 
interaction and language, and this is the time that serotonin is deficient in the brain. This 
double-blind, placebo-controlled trial will assess behavioral and language benefits in ASD as well 
as whether variations in genes that affect the level of serotonin at the synapse can predict 
treatment response. This work will provide much-needed rigorous evidence of a scientifically 
validated treatment in young children with ASD and will provide biomarker evidence of who 
may respond. 
There is a great need to develop treatment programs early on in ASD because this is the 
time to rectify the synaptic abnormalities that are taking place with a developmental window 
which will impact the rest of their life. The benefit of early treatment with behavioral 
interventions has been dramatically demonstrated in young children with ASD most recently 
with the Early Start Denver Model (ESDM) with positive effects on behavior, cognition, and even 
EEG patterns. We believe the use of a low dose SSRI in early childhood in addition to the 
community behavioral and therapy programs will have a significant effect on behavior, 
language, and development in young children with ASD. Such early intervention is imperative to 
study at this time when the prevalence is ever higher at 1 in 68 children who are 8-years-old in 
the general population (CDC 2014 MMWR). 
Autism is a behaviorally-defined disorder (DSM-V) that arises through one or more of a large 
number of genetic and/or environmental factors. Mutations in numerous recognized genes are 
known to be highly associated with autism, operating through mechanisms that alter/disrupt 
critical functions, including synaptic plasticity, the balance of inhibitory and excitatory pathways, 
regulation of mTOR pathways, mitochondrial function, immune function, and neuronal 
migration. Similar mechanisms of dysfunction are known to occur in genetic subgroups of 
autism such as fragile X syndrome (FXS) where the lack of the Fragile X Mental Retardation 1 
Protein (FMRP) leads to dramatic up-regulation of protein production in the CNS, up-regulation 
of the metabotropic glutamate receptor 5 (mGluR5) pathway, and down-regulation of the 
GABAA pathways. This imbalance between the glutamate and GABA systems can also be seen in 
idiopathic autism and in the context of other mutations associated with autism. This coupling 
between FXS and autism suggests that treatments effective in FXS provide a rational basis for 

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potential efficacy in other forms of ASD. There is also preliminary evidence that low levels of 
FMRP occur in the brain of adults with ASD. We have seen a dramatic response of young 
children with FXS+ASD (2 to 6 years) to sertraline and in the interim analysis of the first 30 
children of our currently funded double-blind, placebo-controlled trial of sertraline in young 
children with FXS. The purpose of this study is to expand our studies to children with idiopathic 
ASD with further investigation of biomarkers that predict treatment response; thus, providing a 
foundation for individualized treatment based on the biomarker profile. 
Anxiety is a pervasive problem in ASD and FXS that may contribute to or exacerbate a 
number of the other symptoms, including deficits in reciprocal social interaction (e.g., gaze 
avoidance), stereotypies or repetitive behaviors (e.g., hand-flapping) and communication 
abnormalities (e.g. repetitive and perseverative speech) that characterize ASD. Higher ratings of 
anxiety were associated with more severe autism symptoms as independently rated by trained 
clinicians on the Autism Diagnostic Observation System (ADOS) in our study of children with FXS. 
Our extensive clinical experience and these findings indicate that effective anxiety treatment 
may reduce autism symptoms and improve social reciprocity in patients with ASD with or 
without FXS. 
We and others have been treating anxiety, repetitive, and compulsive behaviors in children 
with ASD with SSRIs, typically fluoxetine or sertraline, for many years. The utilization of SSRIs to 
treat ASD increased from 6.1% in 1993 to 21.4% in 2002, and in a review by Langworthy-Lam et 
al., fluoxetine, paroxetine, and sertraline accounted for 61% of SSRI prescriptions in children 
with autism. 
There have been no controlled trials of sertraline in children with ASD except for our study 
in FXS and ASD, which was also funded by HRSA.  Previous studies of sertraline use in ASD 
without FXS include an open label in 42 adults with ASD that demonstrated improved aggression 
and repetitive behavior, and an open-label study in 9 adults with ID and ASD by Hellings et al., 
which demonstrated improvement. Previous studies of SSRIs in children include a controlled 
trial of fluoxetine in 39 children 5 to 16 years (mean age 8.2 years) with 8 weeks in each arm and 
a 4 week washout in between. They saw improvement in obsessive compulsive behavior but not 
in language; however, it would be unlikely to see improvement in language in such a short 
treatment period. Overall, there is a 60%-70% response rate to fluoxetine in an open-label trial 
for ASD and ID and a 53% response rate to fluvoxamine in a placebo-controlled trial for ASD. A 
recent multicenter study of citalopram in children with ASD who were 5 to 17years old 
demonstrated no significant benefit for citalopram use (n=73) compared to placebo (n=76). This 
study has dampened the enthusiasm for SSRI treatments in children with ASD. However, this 
study did not include children under 5 years, and this is the age that we hypothesize will have 
the greatest response to an SSRI. Children under 5 years not only have a developmental window 
for connectivity in the CNS, but those with ASD have low serotonin during this time, which 
sertraline can improve. Sertraline can also stimulate neurogenesis, which may further enhance 
development. 

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Our preliminary data in a subgroup of ASD, specifically young children with FXS + ASD, has 
demonstrated a significant benefit of low-dose sertraline in a retrospective study.  In our 
controlled study of sertraline in FXS, the interim analysis of the data after the first 30 patients 
completed the trial has demonstrated a positive response with the CGI-I, demonstrating a 
significant benefit compared to placebo. Because of these beneficial effects, we have proposed 
the current study of a double-blind, placebo-controlled trial of sertraline in young children with 
idiopathic ASD. In 2016, the complete results of this study were published (Hess et al.), which 
showed that despite the fact that there was no statistically significant difference from placebo 
on the study’s primary outcomes (MSEL expressive language age equivalent and CGI-I), analyses 
of secondary measures showed significant improvements, particularly in motor and visual 
perceptual abilities and social participation. Furthermore, post hoc analysis found significant 
improvement in early expressive language development as measured by the MSEL among 
children with FXS + ASD on sertraline. Overall, sertraline was well tolerated, with no difference 
in side effects between sertraline and placebo groups, and no serious adverse events occurred. 
Sertraline is approved by the FDA for children 6 years and older for treatment of anxiety and 
obsessive compulsive disorder, but it is not approved for autism. We received an IND from the 
FDA to carry out our sertraline study in young children ages 2 to 6 with FXS with and without 
ASD, and this IND number is 113747, given to us in 2011. We have given the FDA yearly updates 
of our study. The PI of this study had an IND for this drug under fragile X syndrome, and this IND 
now includes ASD as a secondary indicated population (IND Number 113747-0001). 
Sertraline has been shown to help increase the levels of serotonin in hippocampal neurons 
and this correlated with increased levels of the brain derived neurotrophic factor (BDNF). BDNF 
is the most abundant neurotrophin in the brain playing an important role during brain 
development and in synaptic plasticity. It has been implicated in cognitive function as well as in 
the pathogenesis of various psychiatric disorders. A synergistic relationship has been proposed 
for serotonin (5-HT) and BDNF since BDNF promotes the survival and differentiation of 5-HT 
expressing neurons while the presence of SSRIs stimulates the expression of BDNF. This 
synergistic effect has a role in mood disorders, such as depression, and makes the BDNF gene 
and genes related to serotonin levels attractive candidates for the study of diseased brain 
function and behaviors. 
Besides neurogenesis, BDNF also regulates long term potentiation (LTP), and it is involved in 
synaptic plasticity. It primarily interacts with the protein tropomyosin-related kinase B (TrkB).  
Alterations in the expression of BDNF and TrkB are also associated with defects in learning and 
memory. Corroborating this role of BDNF, it has been shown that BDNF improves neurogenesis 
in animal models of Down syndrome. In the knock-out (KO) mouse model of FXS, dysregulation 
in BDNF/TrkB signaling affects differentiation of neural progenitor cells (NPC) and brain 
development.  
Despite the name, BDNF is found in tissues other than the brain, including peripheral blood 
as this neurotrophic factor functions in the central and peripheral nervous systems; thus, BDNF 
expression can be easily measured in plasma samples. In fact, a study showed that blood BDNF 

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concentrations reflect brain-tissue BDNF levels. Therefore, for Aim 2, we will measure BDNF 
expression in blood to see if this correlates with treatment response to sertraline. 
We will also investigate the response to sertraline in association with the different 
polymorphic variants, particularly in the serotonin transporter (SLC6A4), serotonin-synthesizing 
tryptophan hydroxylase 2 gene (TPH2), and BDNF genes, in our study patients. These genes have 
different polymorphic allelic variants that have been implicated in neurological conditions. Two 
BDNF variants have been associated with diagnosis and response to treatment in patients with 
neuropsychiatric disorders. Specifically, the BDNF Val66Met polymorphism has been associated 
with attenuated stress response in individuals suffering from depression as reviewed in a meta-
analysis that examined 22 studies. The consensus scientific finding is that individuals with the 
met-allele have more difficulty coping with stress and major depression than individuals with a 
homozygous val/val genotype. This same polymorphism has also been implicated in efficacy of 
response to fluoxetine in an Asian population group. Thus, the variable response rate to SSRI 
treatment in ASD could be associated with secondary gene effects that ultimately can regulate 
serotonin levels in the brain.  
Thus, the question we will investigate in Aim 2 is whether the allelic variation at BDNF, 
TPH2, or in the 5-HTTLPR have a correlation with treatment response to sertraline. As the 
pattern of response to SSRIs is variable it would be very advantageous if one could predict 
response and individually tailor and personalize a specific treatment. Studies of the gene for the 
serotonin transporter (SLC6A4), and in particular the 44 base pair insertion/deletion 
polymorphism within a repetitive unit in the promoter region (5-HTTLPR), have indicated that 
the long (L, insertion) form of 5-HTTLPR is functionally more active than the short (S, deletion) 
form. While the long allele (L) of the 5-HTT gene-linked polymorphic region (5-HTTLPR) has been 
correlated with shyness in grade school children, the short allele (S) has been shown to 
moderate the influence of stressful life events on depression. In addition, multiple studies 
document that individuals with social anxiety disorder or depressive disorders, who are 
homozygous for the high-transcribing long (L/L) genotype (which is most effective in clearing the 
synapse of serotonin), have consistently shown the best response to treatment with an SSRI. 
Several studies, although not always consistent, have examined the influences of the 5-HTTLPR 
polymorphism and demonstrated that individuals with the short allele (S) compared to those 
that are homozygous for the long allele (L/L) show increased vulnerability to develop anxiety-
related traits and depression. Also there is evidence that environmental insults such as 
significant stress exposure in those with the S allele are at more risk to develop depression. 
Thus, with Aim 2 we sought to demonstrate that patients with ASD homozygous for the L 
allele in the 5-HTTLPR will show a greater improvement in language and social reciprocity than 
those with the other genotype. This hypothesis is supported by studies that documented 
individuals with social anxiety disorder or depressive disorders that are homozygous for the 
high-transcribing long (L/L) genotype (which is most effective in clearing the synapse of 
serotonin), consistently have the best treatment response to SSRIs. Establishing a link between 

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treatment response and this polymorphism would identify a useful genetic trait that would be 
very important when selecting effective treatment options.  
BDNF, as described above, has been shown to play a role in intellectual disabilities, ADHD. 
Differences in BDNF expression due to the different activity of the allelic variants could lead to 
altered brain development in ASD at very early stages of development that contribute to the 
synaptic plasticity defects in ASD. Thus, we expect that the BDNF (Val/Met) may act as a 
modifier of disease severity and that those homozygous (Met/Met) and heterozygous (Val/Met) 
may have less response than those with the (Val/Val) genotype.  
We will also assess the contribution of the serotonin-synthesizing tryptophan hydroxylase 2 
(TPH2) gene, which is involved in serotonin biosynthesis in the brain, and has been associated 
with a number of psychiatric disorders, including ADHD, autism, and major depression. The 
rs1178997 SNP in the promoter of TPH2 results in disruption of a transcription factor binding 
site and has been reported to decrease promoter activity by 22%, so we will also assess this 
allelic variant.  
Mucosal serotonin (5-HT) has been shown to modulate the immune response potentially 
influencing intestinal inflammation.  In addition, serotonergic receptors have been characterized 
in lymphocytes, monocytes, macrophages, and dendritic cells suggesting a role for 5-HT in 
immune cell function. Several lines of evidence have identified the existence of immune 
dysfunction ASD that can affect core features of ASD that ultimately lead to altered 
neurodevelopmental processes. Cytokines are regulators of host responses to infection, immune 
responses, inflammation, and trauma. Some cytokines act to make disease worse (pro-
inflammatory); whereas, others serve to reduce inflammation and promote healing (anti-
inflammatory). Interleukin (IL)-1 and tumor necrosis factor (TNF) are pro-inflammatory 
cytokines. Pro-inflammatory cytokines and serotonergic homeostasis have both been implicated 
in the pathophysiology of major psychiatric disorders. It has been demonstrated that 
inflammatory cytokines can activate p38 mitogen-activated protein kinase (MAPK), which 
induces a catalytic activation of the serotonin transporter. 
The role of inflammation in ASD prompts us to investigate the cytokine response to 
sertraline treatment. We will document whether the abnormal cytokine profiles in ASD change 
with sertraline treatment and whether these changes correlate with treatment response.  
In the treatment of autism, Chugani has emphasized the importance of developmental 
windows for pharmacological intervention aimed at setting brain developmental programs back 
on course. In her PET studies using a 11C methyl-L-tryptophan as a tracer to estimate serotonin 
synthesis, she has demonstrated that humans undergo a period of high brain serotonin 
synthesis capacity during early childhood, in the first five years and that this developmental 
process is disrupted in children with autism. Children with autism show a gradual increase in 
serotonin synthesis capacity that is significantly lower on average than typically developing 
children in the first 6 years and then it becomes gradually higher by 7 years of age. Since 
serotonin is known to be an important factor involved in postnatal synaptogenesis, one 
approach to the treatment of autism would be the use of an SSRI in children less than the age of 

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5 years when serotonin synthesis capacity is lower in autistic children compared to non-autistic 
children. The goal of such treatment would be to provide a more normal modulation of synaptic 
plasticity for a finite period time when the serotonin input is critical for brain connectivity. 
Currently Chugani and colleagues have a multicenter study assessing the benefit of buspirone in 
children 2 through 5 years of age with autism.  
Our experience in using sertraline in young children with ASD comes from the clinical 
experience of the PI, Randi Hagerman MD, in the clinical follow-up of children with ASD who 
were started with an SSRI between 2 to 5 years. In addition, at the MIND Institute we have 
carried out a controlled trial of buspirone in young children with ASD as part of the multicenter 
trial of Dr Chugani, but her evaluation of the data is not yet complete.  
6) Inclusion and Exclusion Criteria 
Inclusion Criteria 
1. Documentation of ASD with DSM-V criteria as well as a standardized autism assessment 
such as the Autism Diagnostic Observation Schedule (ADOS) or the Autism Diagnostic 
Interview–Revised (ADI-R).  
2. Subject between the ages of 24-72 months of age. 
3. A reliable parent or caregiver who can report the side effects and communicate 
effectively with the research team. 
4. Stable medications during the two months prior to enrollment. 
5. Currently receiving interventions in the community or school for ASD. 
 
              Exclusion Criteria 
1. Current or past SSRI treatment. 
2. Other serious co-morbid medical disorders affecting brain function and behavior, 
including uncontrolled seizures. 
 
7) Number of Subjects 
We will recruit a total of 72 patients with ASD over three years, in hopes of having 20 
subjects complete the trial each year (for a total of 60 subjects completing the trial). Due to a 
delayed activation and several periods of low recruitment due to study staff turnover in the past 
few years, we will enter a no-cost extension year to reach enrollment targets by July 2018. 
 
8) Recruitment Methods 
Subjects will be recruited through the MIND Institute Subject Tracking System (STS) and 
referral from UCDHS clinicians. If needed, approved study flyers will be posted in the regional 
center, UCDHS clinics, social networking sites, community providers’ offices, and given to an 
autism support groups. Additionally, the investigator plans to do educational presentations on 
use of sertraline in neurodevelopmental disorders, which may lead to recruitment into this 
study.  

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Potential subjects who are interested in participating in the study will be pre-screened 
either via telephone or on site by the research team utilizing the approved Oral Informed 
Consent Script for Research. This will also allow potential subjects to ask study-related questions 
and discuss the study in depth with the research team. 
We are requesting a waiver of HIPAA Authorization for recruitment purposes only. The 
research team will identify potential subjects and access medical records to verify eligibility prior 
to the treating physician and research coordinator approaching the potential subject. Consent to 
participate and HIPAA Authorization to access additional information in the medical records will 
be obtained prior to enrollment into the study. The protected health information will not be 
reused or disclosed to outside persons or entities.  
The review of subjects' medical records is for limited information and only to determine 
eligibility. The data are derived from clinically indicated procedures and there is minimal risk to 
the subjects' status, employment, or insurability. Only research personnel will access medical 
records via EMR, and all personnel are required to use the “Quick Disclosure” function in EMR to 
document review. Without an initial review of the medical record for screening purposes, it 
would not be possible to identify potential subjects and confirm their applicability for study 
participation. Once eligibility in confirmed, subjects will be approached to obtain their 
authorization to access and use their health information for the research. 
9) Compensation to the Subjects 
There will not be any compensation available to subjects for completing any or all of the 
study procedures. 
 
10) 
Study Timelines 
Screening and enrollment began upon IRB approval of this protocol and associated 
documents. Enrollment has continued for approximately two and a half years and will be 
extended for an additional year in order to reach the full target and to have the final participant 
finish before the end of 2018. 
Each participant will be involved in this trial for a period of six months. This will include 
three visits to the UC Davis MIND Institute – a combined screening and baseline visit, a 3 month 
interim visit (+2 week), and a 6 month end-of-treatment visit (+2 week). Additionally, there will 
be weekly phone calls for the first month of treatment, and subsequent monthly phone calls if 
no visit is scheduled during that month.  
Participants will be active in this trial until about December of 2018, at which point we 
expect that the final participant will have completed the trial period. 
Final data analysis of data collected during the trial period of each participant will be 
analyzed after the final participant has completed the trial, which is expected to be about 
December 2018. 
11) 
Study Endpoints 
Our primary study endpoints will be changes, from baseline to 6 months, in both the 
expressive language raw scores and  the combined age equivalent scores as measured by the 
MSEL. All other measures listed below in Section 12 are secondary study endpoints.\ 

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12) 
Procedures Involved 
The schedule of assessments is listed below:  
 
Demographics: 
At Screening, basic demographic information will be collected on all study subjects, 
including but not limited to date of birth, race, ethnicity, socioeconomic status, education of 
parents, parental occupation, and parental salary range.  
Medical Examination:  
This will be carried out by Dr. Hagerman or her associate and will include growth 
percentiles, vitals, a detailed medical history, physical, neurological examination, and review of 
medical records, as applicable. In addition a detailed family history may be obtained, if medically 
Assessments 
Screening/ 
Baseline Visit 
Three 
month visit 
(+2 week) 
Six Month 
Final Visit 
(+2 week) 
Informed Consent 
X 
 
 
Inclusion/Exclusion Criteria 
X 
 
 
Medical History 
X 
 
 
Physical Exam 
X 
X 
X 
Adverse Events 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
Vital Signs 
X 
X 
X 
Blood Draw 
X 
Xa 
X 
Mullen Scales of Early Learning (MSEL) 
X 
 
X 
Preschool Language Scale, 5th ed. (PLS-5) 
X 
 
X 
Autism Diagnostic Observation Schedule (ADOS) or 
Autism Observation Scale for Infants (AOSI) 
X 
 
 
Vineland Adaptive Behavior Scale, 2nd ed. (VABS-II) 
X 
 
X 
Clinical Global Impression Scale (CGI) 
X 
X 
X 
Visual Analogue Scale (VAS) 
X 
X 
X 
Sensory Processing Measure, Preschool ed. (SPM-P) 
or  
Sensory Processing Measure (SPM) 
X 
 
X 
Preschool Anxiety Scale, Revised ed. (PAS-R) 
X 
 
X 
DSM V Checklist 
X 
 
 
Social Responsiveness Scale (SRS) 
X 
 
X 
Eye Trackingb 
X 
 
X 
Aberrant Behavior Checklist (ABC)c 
X 
X 
X 
Suicidality Checklistc 
X 
X 
X 
Dispense Study Drug 
X 
X 
 

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necessary. A medical history and exam will be conducted at the Screening/baseline visit. A 
medical exam and a review of recent history will take place at each subsequent visit. 
Mullen Scales of Early Learning (MSEL; Mullen, 1995):  
The MSEL was standardized in children from birth to 68 months of age. It includes five 
subscales: gross motor, fine motor, visual reception, expressive language, and receptive 
language. The subscales yield alpha coefficients between .75 and .83. Test-retest values range 
from .76 to .96 across ages and scales, and inter-rater reliability from .91 to .96. NVMA and 
NVIQ will be computed (with latter being twice the T score). The MSEL will be a baseline and 6-
month outcome measure. 
Preschool Language Scale-Fifth Edition:  
The PLS-5 assesses auditory comprehension and expressive communication 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 also has a means by which to track progress using 
Growth Scores to monitor a child’s skills. PLS-5 was standardized with a sample of 1400 children, 
including children with disabilities, selected to be representative of the U. S. population in terms 
of ethnicity, gender, geographic region, and parent education level based on U.S. Census figures 
(March 2008 update). Of the sample, 45% consisted of minorities, the largest percentage to 
date. The PLS-5 will be a baseline and 6-month outcome measure. 
Clinical Global Impression Scale (CGI):  
This scale is a standard assessment for medication studies because it allows the clinician to 
utilize the history from the parents or caretaker and incorporate it into a clinical rating for the 
clinical follow-up of the patient through the treatment trial. (Guy, 1976; Psychopharmacology, 
1985).  
The CGI-S is a 7-point scale that requires the clinician to rate the severity of the patient’s 
illness at the time of assessment, relative to the clinician’s past experience with subjects who 
have the same diagnosis. The CGI-S will be captured at Screening. The 7-point scale is as follows: 
 
Normal 
 
1 
Borderline Ill  
2  
Mildly Ill  
3  
Moderately Ill  
4  
Markedly Ill  
5  
Severely Ill  
6  
Extremely Ill  
7  
 
The CGI-I is a 7-point scale that requires the clinician to assess how much the subject has 
improved or worsened relative to a baseline status. The CGI-I will be captured at the 3-month 
visit and the 6-month visit. The response options include the following: 
 
Very Much Improved 
1 
Much Improved  
2  
Minimally Improved  
3  
No Change  
4  

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Minimally Worse  
5  
Much Worse  
6  
Very Much Worse  
7  
Visual Analogue Scale (VAS):  
Parents will mark on a visual line measuring 10 cm with one side marked “worst behavior” 
and the other side marked “best behavior”. They will assess 3 key behaviors that are targeted 
for this trial (e.g., aggression, hyperarousal with stimuli, anxiety, hyperactivity). For each 
behavior they will mark their impression of the behavior at each visit, demonstrating how they 
have changed from the baseline. The horizontal marks are measured in cm distance so that we 
can see improvements or worsening of behavior over this time period. The VAS will be a 
baseline, 3-month, and 6-month outcome measure. 
Autism Diagnostic Observation Scale (ADOS) or Autism Observation Scale for Infants (AOSI):  
The ADOS (Lord, et al., 2000) and AOSI are semi-structured standardized interviews 
administered directly for the purposes of diagnosing autism. The ADOS uses developmentally 
appropriate social and object-based interactions in a 30-45 minute interview to elicit symptoms 
of autism in four areas: social interaction, communication, play, and repetitive, restrictive 
behaviors. The ADOS consists of different modules, each directed at a particular level of 
language ability and is thus appropriate to use across subjects of varying ages and functioning 
levels. A previously completed ADOS or AOSI performed 6 months prior to the 
Screening/Baseline visit can be used to determine study eligibility. In this instance, the ADOS or 
AOSI will not need to be done at the Screening/Baseline visit. This assessment will not be 
repeated at the 3-month or 6-month visits because its purpose is solely for eligibility 
determination and characterization of the study population at baseline. 
Vineland Adaptive Behavior Scale-Second Edition (VABS-II):   
The VABS-II (Sparrow, Cicchetti, & Balla, 2005) is an update of the VABS developed by Carter 
et al., 1998 that was designed to assess handicapped and non-handicapped persons in their 
personal and social functioning and is appropriate for individuals of all ages. The VABS-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.  The 
VABS was successfully utilized to establish level of adaptive functioning for individuals with FXS 
(Berry-Kravis et al., 2006; Zingerevich et al., 2009).  Internal consistency for each domain was 
measured utilizing the split-half method and coefficients ranging from .83 to .90 were 
established. Test retest reliability was calculated to be .81 to .86 and inter-rater reliability was 
.62 to .78. The VABS will be a baseline and 6-month outcome measure. 
Sensory Processing Measure (SPM):  
The SPM is designed to measure sensory processing difficulties in multiple environments (at 
home, at school, and in the community) for children aged 5 to 12 years old. The SPM 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. Within each system, the SPM offers descriptive clinical information on 
processing vulnerabilities, including under- and over- responsiveness, sensory-seeking behavior, 
and perceptual problems. The SPM will be a baseline and 6-month outcome measure. 
Sensory Processing Measure-Preschool (SPM-P):  

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The SPM-P is designed to integrate seamlessly with the SPM (as described above) but is 
targeted for a younger population (ages 2 to 5 years old). For most patients we will use the SPM-
P; for those over 5 years old the SPM or the SPM-P will be used as appropriate based on the 
participant’s cognitive age and ability. As with the SPM, the SPM-P will be a baseline and 6-
month outcome measure. 
Preschool Anxiety Scale – Revised (PAS-R): 
The PAS-R is a revision of an earlier measure (Preschool Anxiety Rating Scale, Spence et al., 
2001). It is designed to assess symptoms of anxiety and fears in young children (aged 6 and 
below) as reported by their parents. The measure provides 4 subscales tapping generalized 
anxiety, social anxiety, separation anxiety, and specific fears. The total scale and 4 subscales 
showed strong internal consistency (alphas = .72-.92), 12-month stability (rs = .60-.75) and 
maternal/paternal agreement (rs = .60-.75). Scores on the scale also showed expected 
correlations with a measure of emotional distress, diagnosed anxiety disorders, and behavioral 
indicators of anxiety. The PAS-R will be a baseline and 6-month outcome measure. 
Diagnostic and Statistical Manual of Mental Disorders-V: 
Per the DSM-V (APA 2013), Autism Spectrum Disorder (ASD) is characterized by severe and 
pervasive impairment in several areas of development: reciprocal social interaction skills, 
communication skills, and the presence of stereotyped behavior, interests, and activities. The 
qualitative impairments that define these conditions are distinctly deviant relative to the 
individual’s developmental level or mental age. The DSM-V will not be repeated at the 3-month 
or 6-month visits because its purpose is solely for eligibility determination and characterization 
of the study population at baseline. 
Social Responsiveness Scale (SRS): 
The SRS distinguishes autism spectrum conditions from other child psychiatric conditions by 
identifying the presence and extent of autistic social impairment. This 65-item rating scale 
measures the severity of autism spectrum symptoms as they occur in natural social settings. 
Completed by a parent or teacher in 15 to 20 minutes, the SRS provides a clear picture of a 
child’s social impairments, assessing social awareness, social information processing, capacity 
for reciprocal social communication, social anxiety/avoidance, and autistic preoccupations and 
traits. The SRS will be a baseline and 6-month outcome measure. 
Eye Tracking: 
In a series of eye tracking tasks participants will be shown stimuli, either objects or 
emotional faces and their visual reaction times as measured by mean saccade latencies and 
overall fixations to predefined areas of interest will be recorded. The tasks aim to index 
visuospatial attention via passive viewing methods that will not overly tax the participants, and 
may be sensitive to subtle changes over time that will not be evident in more gross behavioral 
measures. The eye tracking protocol also includes collection of demographic information and 
completion of the Carey Temperament Scales (CTS). The CTS is a collection of parent-report 
questionnaires, each covering a specific age range between 1 month and 12 years, that 
examines nine categories of behavioral and temperamental style as defined in the New York 
Longitudinal Study (NYLS). Eye tracking will be a baseline and 6-month outcome measure. 
Aberrant Behavior Checklist-Community (ABC-C): 

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The ABC is a parental survey consisting of 58 questions designed to measure the severity of 
autism-associated behaviors, including irritability, lethargy, stereotypy, hyperactivity and 
inappropriate speech. The irritability subscale includes self-injurious and aggressive behavior. 
The total score range within the ABC is 0–174, with higher scores indicating more severely 
affected behavior. The ABC has been previously approved by the IRB as it is part of the MIND 
Institute Protocol Repository (MIPR, IRB # 200513093). The ABC will be captured at baseline, 3 
months, and 6 months. 
Clinical Assessment of Suicidal Ideation and Behavior: 
This assessment is a series of “yes” or “no” questions. The clinician will ask if the subject 
understands the concept of suicidal ideation. If the answer is “No”, the remaining questions 
about the subject’s behavior will be asked to the caregiver. If the answer is “Yes”, the remaining 
questions will be directed to the subject.  This assessment will be used in combination with the 
ABC irritability subscale to assist the clinician in assessing any possible suicidal ideation or 
behavior.  Although we have never seen this side effect in children under 6 years old, this has 
been added to follow the FDA draft Guidance for Suicidal Ideation and Behavior (attached for 
reference). This assessment will be administered at screening, 1 month, 3 months, and 6 
months.  
Additional Information Regarding Above Assessments: 
Measures administered may be audio or video recorded for future reference or coding. All 
recording will be stored in compliance with all applicable guidelines. 
The MSEL, CGI, ADOS, VABS-II, SPM, SPM-P, and VAS assessments listed above are part of 
the MIND Institute’s Protocol Repository (MIPR) and have been approved under the human 
subjects protocol #232909. The PLS-5 has been included as part of this protocol’s initial 
submission for approval. The remaining assessments are computer-based and are described in 
full above.  
Laboratory Blood Tests 
Laboratory assessments will be collected at the Screening/Baseline visit and the 6-month 
visit. If blood is unable to be completed at the Screening/Baseline visit, then sample collection 
will be attempted at the 3-month visit. Both safety blood samples and biomarker blood samples 
will be collected. Safety laboratory assessments include complete metabolic panel and complete 
blood count. Biomarker assessments will evaluate DNA, RNA, FMR1 mutation status, BDNF, 
SLC6A44, TPH2, 5-HTTLPR, and cytokine response. Approximately 30 mL (6 tsp) of blood will be 
collected per blood draw.  
13) 
Data and Specimen Banking 
Each sample will be coded by a unique numerical identifier. There will be a total of two 
blood draws throughout the study. Each blood draw will have a total volume of up to 30ml. 
Safety labs will be processed through the UC Davis Pathology Laboratory. Biomarker samples 
will be delivered to Dr. Tassone’s lab at the UC Davis MIND Institute’s Wet Lab for processing 
and storage. Samples will be kept until the end of the study and subsequent analysis, at which 
point they will be destroyed. Alternatively, on the study consent form, participants may indicate 
permission to allow for samples to be kept for a period of 15 years after the end of the study.  

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14) 
Data Management and Confidentiality 
The clinical study data will be entered into and stored in REDCap, which is managed by the 
Biomedical Informatics Program of the UC Davis Clinical and Translational Science Center. 
Vanderbilt University, with collaboration from a consortium of institutional partners, has 
developed a software toolset and workflow methodology for electronic collection and 
management of research and clinical trial data. REDCap (Research Electronic Data Capture) data 
collection projects rely on a thorough study-specific data dictionary defined in an iterative self-
documenting process by all members of the research team with planning assistance from the 
Biomedical Informatics Program. Iterative development and testing processes result in a well-
planned data collection strategy for individual studies. The REDCap system provides secure, 
web-based applications that are flexible enough to be used for a variety of types of research, 
provide an intuitive interface for users to enter data and have real time validation rules (with 
automated data type and range checks) at the time of entry. These systems offer easy data 
manipulation with audit trails for reporting, monitoring, and querying patient records as well as 
and automated export mechanism to common statistical packages (SPSS, SAS, Stata, R/S-Plus). 
REDCap servers are housed in a local data center at UC Davis Health System and all web-based 
information transmission is encrypted. REDCap was developed specifically around HIPAA-
Security guidelines. For example, upon login, an approved username and password is required. 
REDCap has been disseminated for use locally at other institutions and currently supports 240+ 
academic/non-profit consortium partners on six continents and over 26,000 research end-users 
(www.project-redcap.org). 
All research personnel on this IRB protocol will have some type of access to this database. 
The data management and biostatistics team (Patrick Adams and Dr. Danh Nguyen) will have full 
access since they will create the data dictionary and address data requests. Research 
coordinators, technicians, and assistants will enter the data into the database. All research 
personnel will have current GCP training for investigators and staff involved in research 
involving human subjects. 
Analysis will be based on the intention-to-treat principle. The analysis of treatment efficacy 
will be based on the analysis of covariance (ANCOVA) with outcomes (receptive and expression 
language at 6-month follow-up with corresponding baseline measure as a covariate). The 
chosen endpoint at 6-month, based on preliminary data, provides a reasonable treatment time 
period to assess changes in the response. The proposed method adjusts for potential baseline 
differences between treatment arms despite randomization, if any. The sample size/power for 
the ANCOVA is based on sample size needed for a t-test by a variance inflation factor 1-2 where 
there is the correlation between baseline and follow-up measures. From our preliminary data, 
the receptive and expressive scores have ranges from approximately 0.2 to 0.5. Thus, we 
provide the power for the t-test and power for the ANCOVA will be higher depending on this 
factor. We estimate clinically relevant effects sizes from our preliminary data at follow-up visit 
for (sertraline /placebo) as follows: receptive language score mean 18.1/23.8, SD=7.0; 
expressive language score mean 13.6/20.7, SD 8.4. For these effect sizes of the 2 primary 
measures, the ANCOVA will have power of at least 80% (or have between 0.2-0.5) at level 
alpha=0.016 with the proposed total sample size n = 60.  
For CGI, we will use the standard t-test for 6-month follow-up assessment. For n = 60 the t-
test to detect a one point CGI change (from 4 = no change to 3 = minimally improved) and 
conservatively assuming a SD = 1, the power is 91% at alpha level of 0.016. We will use similar 
regression and ANCOVA/ANOVA methods to analyze other secondary variables. 

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15) 
Provisions to Monitor the Data to Ensure the Safety of Subjects 
A DSMB will be established that will include two physicians who are independent of the 
study but who have significant expertise in carrying out psychopharmacological interventions in 
children with ASD. In addition, an independent statistician will be a member of the DSMB. The 
DSMB will examine unblinded adverse event(s) and clinical data annually to recommend 
whether the trial can be safely continued. The investigators and staff will remain blinded 
throughout the trial. 
16) 
Withdrawal of Subjects 
The study team reserves the right to withdraw subjects from the study for reasons including, 
but not limited to, adverse events and non-compliance. The caregivers of a subject may also 
withdraw their son or daughter from the study. 
If a subject is withdrawn from the study early, caregivers will be asked to return to the MIND 
Institute for a termination visit which will include a visit with a study physician who can assess 
for adverse events and general safety of the subject. 
17) 
Risks to Subjects 
Risks associated with participation in this study pertain to the study medication, the possible 
ineffectiveness of treatment, and the blood tests. A potential risk is the chance of infection or 
bleeding at the site where the venous blood draw is completed. This site will be carefully 
cleaned and a band aid will be applied. Other potential risks are the side effects of sertraline, 
which include hyperarousal, hyperactivity or activation especially if the dose is too high. 
 In adolescents, SSRIs have induced suicidal ideation in rare circumstances, but we have 
never seen this side effect in children under 6 years old. According to the FDA Draft Guidance 
for Suicidal Ideation and Behavior section III.C, this study falls under trials involving patients 
where it is reasonable to omit assessments of suicidal ideation. However, because the study 
does involve an antidepressant drug, we are implementing the irritability subscale of the ABC 
and the Clinical Assessment of Suicidal Ideation and Behavior Checklist to aid clinicians in this 
risk assessment. Clinicians will perform the assessments at each visit, and at the one-month 
phone call (scheduling a follow-up, face to face interaction if needed).  The study physician will 
discontinue the medication if there is any concern about suicidal ideation or behavior. 
Weekly phone calls during the first month will be made by study personnel to evaluate the 
presence of side effects. Subsequent phone calls will be monthly except for months 3 and 6, 
when a visit will take place. The study physician will perform a phone call after one month of 
treatment to assess for adverse events as well as perform the Clinical Assessment of Suicidality 
and ABC – Irritability Subscale.  Dr. Hagerman’s contact information will be provided to all 
subjects’ parents for emergencies related to the study. 
All the data obtained from this study will be kept confidential. Only research personnel on 
the IRB-approved protocol will have access to the data. Electronic data will be password 
protected and physical data will be stored in a locked file room. However, just like with other 
personal information kept by your health care providers, your banks, and others, even these 
safeguards cannot guarantee absolute protection of the data.  If private information gets into 
the wrong hands, it can cause harm.  Although rare, there are reported cases of breaches that 
have resulted in discrimination in insurance or employment.   

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18) 
Vulnerable Populations 
This study intends to enroll developmentally disabled children with ASD who will be too 
young to consent to participate to this study. As such, reliable and competent caregiver(s), such 
as (a) parent(s) or other legal guardian, must give consent to participate in this study. The 
caregivers of the participant will be informed of all known risks and potential benefits associated 
with the study. 
Because this study involves young children ages 2 through 5 years old (inclusive) with 
developmental disorders, all study staff will pay special attention to the potential for the 
extreme sensitivities, multiple stressors, and other possible risks associated with the vulnerable 
population under study. We have done research with developmentally disabled and cognitively 
impaired individuals of all ages for many years. Consent for individuals with cognitive disability is 
always signed by parent or caregiver, and no study-specific procedures will be done for any 
subject prior to consent. 
 
19) 
Multi-Site Research 
This is a single-site research study. 
 
20) 
Community-Based Participatory Research 
Not applicable. 
 
21) 
Sharing of Results with Subjects 
Participants may request a research report with scores from some of the cognitive testing 
completed at the baseline and final visits. Participants will not be unblinded at any point during 
their enrollment. This is to prevent unconscious biases that may present as the trial progresses 
and to ensure quality data. Subjects will be unblinded once all study procedures and all 
statistical analyses for all subjects have been completed. 
 
22) 
Setting 
The UC Davis MIND Institute:  
Participants will be evaluated at the MIND Institute Research Clinic. The MIND Institute is a 
multi-purpose research facility focusing on patients with autism spectrum disorders and other 
neurodevelopmental disorders. The basic (wet labs) and clinical buildings, total approximately 
100,000 ft2, were completed in 2002 and are co-localized on the UC Davis Medical Center 
campus in Sacramento. The MIND Institute is well equipped with multiple patient exam rooms 
available for screening IQ measures as well as questionnaires, surveys, and physical exams. This 
will be the main study site, as recruitment, screening, and patient visits will occur at the MIND 
Institute. The MIND MICRO committee has approved space usage for this study.  
 

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23) 
Resources Available 
For a full list of research personnel associated with this study, please refer to the associated 
personnel list. All study personnel will be familiar with the protocol and research procedures. 
Computers: All key personnel have up-to-date personal computers with high-speed internet 
and printer connections. 
Offices: The MIND Institute has office space available for all associated research personnel. 
All office space includes up-to-date computers, high-speed internet access, printers and 
telephones with private voice mail. 
 
24) 
Prior Approvals 
The Year 1 initial submission was submitted on 18-Sep-2014, and a response addressing 
analyst concerns from 7-Oct-2014 was subsequently submitted on 24-Oct-2014. Initial approval 
was granted on 25-Nov-2014. Year 2 renewal was submitted on 26-Aug-2015 and approved 14-
Sep-2015. Year 3 renewal was submitted on 29-Jul-2016 and approved on 9-Aug-2016. Year 4 
renewal submission is due by 23-Jun-2017. 
 
25) 
Provisions to Protect the Privacy Interests of Subjects 
Research charts will be kept on the subjects and subject information will be coded to 
protect confidentiality. All charts will be kept in a locked cabinet of a locked file room. The 
identifiers used to identify subjects will be kept in locked offices and/or locked cabinets, and the 
electronic database containing personal information will be kept on a secure computer network 
accessible only to PI’s research team. If information from the study is published or presented at 
scientific meetings, subject names and other information that could identify subjects will not be 
used. 
The subjects’ health information, along with the identifiers, will be kept with the 
investigator as mentioned, until the conclusion of the study, or when immediate access is no 
longer required. Thereafter, the information may be transferred to a records and information 
management company for long-term storage, or to a UCDMC long-term storage facility. 
Archiving, storage, and destruction of all study materials will comply with the MIND Institute’s 
Archiving SOP# 500-017. 
All study personnel will have access to study records, data, and specimens. If required, 
access to study records and data will be made available to representatives of HRSA. Enrolled 
subjects will be made aware that study personnel, and representatives of HRSA, will have access 
to their records. This will be included in the consent form and will also be thoroughly reviewed 
during the consenting process. In addition, every attempt will be made to ensure that the 
personal and medical information of the subject will be kept private; however, we cannot 
guarantee total privacy. The subject’s personal and medical information may be given out if 
required by law (for example, reporting sensitive information (such as child abuse) to state or 
local authorities if necessary). 
 

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26) 
Compensation for Research-Related Injury 
It is important that subjects promptly tell the person in charge of the research if they believe 
that they have been injured because of taking part in this study. If subjects are injured as a 
result of being in this study, the University of California will provide necessary medical 
treatment. Depending on the circumstances, the costs of the treatment may be covered by 
University or the study sponsor or may be billed to the subject’s insurance company just like 
other medical costs. The University and the study sponsor do not normally provide any other 
form of compensation for injury.  
27) 
Economic Burden to Subjects 
There is no charge for the subject to participate in this study. Neither the subject nor his or 
her insurance carrier will be charged for taking part in the research. All costs associated with the 
study will be paid by the sponsor/department.  
There may be indirect costs associated with participation including travel and time taken off 
work to meet appointments. Possible expenses to the subject’s family include time spent at the 
clinic as well as expenses for traveling. All eligible research subjects, who would not otherwise 
be able to participate due to the cost of traveling to the MIND Institute (e.g., flights, gas, 
lodging), will be offered up to $400 travel reimbursement per visit for actual costs incurred. 
Costs of travel may include, but are not limited to, economy airfare, car mileage, lodging, 
bridge tolls, parking garage fees, taxis, rental cars, and/or gas reimbursement for rental cars. 
Reimbursement will be based off of paid receipts submitted by families per UCDMC 
reimbursement policy. Travel reimbursement is based off of employee reimbursement 
guidelines enforced by the Department of Psychiatry and Behavioral Sciences and University 
policy. Reimbursement checks will be mailed 6-10 weeks from submission of paid receipts 
following the completed study visit. 
28) 
Consent Process 
If requested, the study consent form will be provided to potential subjects prior to visiting 
the MIND Institute. 
Consenting will take place at the UC Davis MIND Institute by research personnel 
delegated by the PI to consent.  Procedures for obtaining consent will be followed as 
outlined in HRP-090. Consenting and all study measures and assessments will be done in 
English, as some of the measures used through this study are only available in English. 
All participants will be under the age of 18; thus, we will require the consent of a parent, 
guardian, or other legally responsible adult with documentation of authority to sign on 
behalf of the participant in order to be enrolled in this study. All subjects, parents, or 
LARs (as applicable) will sign a HIPAA authorization for research.  
Consent to enroll in this study will preferentially be obtained from both 
parents/guardians of the participant; however, only one parent will be required to 
consent to participate in this study. The investigator feels that given the potential 
benefit and low-risk safety profile of the investigational product, it is sufficient to obtain 
permission from one parent.  
 

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29) 
Process to Document Consent in Writing. 
 
The consent will conform to HRP-090 “Informed Consent Process for Research” and HRP-
091 “Written Documentation of Consent”. 
 
30) 
Drugs or Devices 
We will treat children with ASD ages 24 to 72 months in a randomized, double-blind, 
placebo-controlled trial of sertraline (brand name Zoloft) for 6 months. Randomization to 
sertraline or placebo will be carried out by UCDMC Investigational Drug Services Pharmacy, and 
dosing will be determined based on patient age at enrollment. The study drug will be 
administered in liquid form (20 mg per cc). 
For patients aged 2 to 3 years (inclusive) at enrollment, sertraline liquid or placebo liquid in 
a dose of 2.5 mg per day (0.125 ml) will be used. For those aged 4 years through 5 years 
(inclusive) at enrollment, the starting dose will be 5.0 mg perday (0.25 ml). The liquid can be 
mixed with water, ginger ale, lemon or lime soda, lemonade, or orange juice, as per the package 
insert. The UCDMC Investigational Drug Services Pharmacy will store and dispense the study 
drug. 
As previously described, starting dose is assigned based on age at enrollment. After 
enrollment, dose modifications may be made at the discretion of the study physician; for 
example, if a subject aged 4-5 years (inclusive) at time of enrollment is experiencing an adverse 
event while at the 5 mg daily dose, the study physician may decrease the subject’s dose to 2.5 
mg daily if clinically indicated. However, subjects started at 2.5 mg based on enrollment age will 
not undergo dose increase to 5 mg during the trial. In other words, if a subject aged 2-3 years 
(inclusive) at time of enrollment turns 4 years of age during her study participation, she will 
nevertheless continue at the original dose of 2.5 mg per day. 
The PI of this study had an IND for this drug under fragile X syndrome, and this IND now 
includes ASD as a secondary indicated population (IND Number 113747-0001).