A Trial of Sertraline in Young Children With Autism Spectrum Disorder

Study Overview
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Brief Summary
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This study is a control trial of sertraline (Zoloft) in children aged 2 to 5 years old inclusive with Autism Spectrum Disorder. The trial is six months long, and each participant will receive a series of tests at both the beginning and end of the study. The researchers hope to show improvements in language and social deficits.

Detailed Description
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This is a single center study and the UC Davis MIND Institute for Autism Spectrum Disorder (ASD) patients aged between 2 years and 5 years old inclusive funded by the Health Resources and Services Administration (HRSA). It is a double-blind control trial of sertraline (Zoloft), an anti-depressant typically used in the treatment of depression, obsessive-compulsive disorder, panic disorder, and other conditions. The researchers are investigating the use of this selective serotonin reuptake inhibitor (SSRI) in ASD because a retrospective study has shown significant improvements in language and social deficits. There is also emerging evidence regarding the stimulation of brain-derived neurotrophic factor (BDNF) and the stimulation of neurogenesis when an SSRI is given early on in the development of animal models of Down syndrome. The researchers hope to see improvements in language stimulation, social gaze and social reciprocity, spatial attention, and a decrease in autistic behaviors. The aim of this study is to carry out a double-blind placebo controlled trial of sertraline in children with ASD who are between the ages of 2 years and 5 years old inclusive. At baseline, the researchers will assess behavioral and cognitive development. 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 and eight phone calls. The researchers will also assess the side effects of the sertraline treatment throughout the study.

Official Title
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A Controlled Trial of Sertraline in Young Children With Autism Spectrum Disorder

Conditions
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Autism Spectrum Disorder

Intervention / Treatment
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* Drug: Sertraline Liquid Placebo
* Drug: Sertraline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documentation of Autism Spectrum Disorder with Diagnostic and Statistical Manual for Mental Disorders-Fifth edition, criteria as well as a standardized autism assessment such as the Autism Diagnostic Observation Schedule or the Autism Diagnostic Interview-Revised. Subject between the ages of 24-72 months of age. A reliable parent or caregiver who can report the side effects and communicate effectively with the research team. Stable medications during the two months prior to enrollment. Currently receiving interventions in the community or school for Autism Spectrum Disorder Exclusion Criteria: Current or past Selective Serotonin Reuptake Inhibitor treatment. Other serious co-morbid medical disorders affecting brain function and behavior, including uncontrolled seizures.

Ages Eligible for Study
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Minimum Age: 24 Months
Maximum Age: 72 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Sertraline Liquid Placebo<br>The placebo will be dosed in an age depended manner. Participants aged 2-3 years of age will be given 2.5 mg of liquid placebo once per day for a period of six months. Participants aged 4 years to 6 years will be given 5 mg of liquid placebo once per day for a period of six months. | Drug: Sertraline Liquid Placebo<br>* Liquid placebo given in parallel to active medication<br>* Other names: Placebo;|
| Active Comparator: Sertraline Active Medication<br>Liquid sertraline (20 mg/cc) will be dosed in an age depended manner. Participants aged 2-3 years of age will be given 2.5 mg of liquid sertraline once per day for a period of six months. Participants aged 4 years to 6 years will be given 5 mg of liquid sertraline once per day for a period of six months. | Drug: Sertraline<br>* Active medication<br>* Other names: Zoloft;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Mullen Scales of Early Learning - Expressive Language Raw Score | 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. | From baseline visit to six-month visit | 
| Change in Mullen Scales of Early Learning - Combined Age Equivalent Score | 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 combined age equivalent scores, calculated as the sum of the age equivalent scores from each scale. The combined score ranges from 0 to 280. 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. | From baseline visit to six-month visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Adaptive Behavior Composite Standard Score | 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 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. | At baseline visit | 
| Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Adaptive Behavior Composite Standard Score | 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 six-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. | At six-month visit | 
| Preschool Anxiety Scale-Revised - Total Score | Preschool Anxiety Scale-Revised (PAS-R) is a questionnaire designed to assess symptoms of anxiety and fears in young children aged 6 and below as reported by their parents. The PAS-R consists of 34 questions, each with a rating option of 0 to 4 where 0=not true at all, 1=seldom true, 2=sometimes true, 3=quite often true, and 4=very often true. The total score is calculated as the sum of all responses and therefore ranges from 0 to 136. Lower scores indicate less anxiety/fear; higher scores indicate more anxiety/fear. Reported here are the mean total scores for the placebo and treatment groups at baseline. | At baseline visit | 
| Preschool Anxiety Scale-Revised - Total Score | Preschool Anxiety Scale-Revised (PAS-R) is a questionnaire designed to assess symptoms of anxiety and fears in young children aged 6 and below as reported by their parents. The PAS-R consists of 34 questions, each with a rating option of 0 to 4 where 0=not true at all, 1=seldom true, 2=sometimes true, 3=quite often true, and 4=very often true. The total score is calculated as the sum of all responses and therefore ranges from 0 to 136. Lower scores indicate less anxiety/fear; higher scores indicate more anxiety/fear. Reported here are the mean total scores for the placebo and treatment groups at the six-month visit. | At six-month visit | 
| Preschool Language Scale-Fifth Edition - Total Language Raw Score | The Preschool Language Scale-Fifth Edition (PLS-5) is designed to measure auditory comprehension (AC) and expressive communication (EC) for children from 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, and 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. | At baseline visit | 
| Preschool Language Scale-Fifth Edition - Total Language Raw Score | The Preschool Language Scale-Fifth Edition (PLS-5) is designed to measure auditory comprehension (AC) and expressive communication (EC) for children from 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, and 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 six-month visit. | At six-month visit | 
| Sensory Processing Measure-Preschool - Social Participation Raw Score | The Sensory Processing Measure-Preschool (SPM-P) is a questionnaire measuring 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, as reported by the parent/caregiver. 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 at baseline, 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. | At baseline visit | 
| Sensory Processing Measure-Preschool - Social Participation Raw Score | The Sensory Processing Measure-Preschool (SPM-P) is a questionnaire measuring 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, as reported by the parent/caregiver. 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 at the six-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. | At six-month visit | 
| Clinical Global Impression Scale-Severity (CGI-S) | The Clinical Global Impression-Severity (CGI-S) is a 7-point scale completed by a clinician that yields a rating of the patient's illness severity at the time of assessment, relative to the clinician's past experience with patients who have the same diagnosis. The 7-point scale ranges from: 1 = Normal; 2 = Borderline Ill; 3 = Mildly Ill; 4 = Moderately Ill; 5 = Markedly Ill; 6 = Severely Ill; and 7 = Extremely Ill. Therefore, the higher the score, the greater the severity of the patient's illness. The CGI-S was administered at baseline only for the purpose of characterizing the study population. Shown here are the CGI-S mean scores from the baseline visit. | At baseline visit | 
| Clinical Global Impression Scale-Improvement (CGI-I) | The Clinical Global Impression-Improvement (CGI-I) is a 7-point scale completed by a clinician that yields a score measuring the overall behavioral change of an individual and their therapeutic response. The 7-point scale ranges from: 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 clinician. The CGI-I was administered at the three-month and six-month visits. Shown here are the CGI-I mean scores from the 3-month follow-up visit. | At three-month visit | 
| Clinical Global Impression Scale-Improvement (CGI-I) | The Clinical Global Impression-Improvement (CGI-I) is a 7-point scale completed by a clinician that yields a score measuring the overall behavioral change of an individual and their therapeutic response. The 7-point scale ranges from: 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 clinician. The CGI-I was administered at the three-month and six-month visits. Shown here are the CGI-I mean scores from the 6-month follow-up visit. | At six-month visit | 
| Visual Analog Scale - Language/Communication Score | The Visual Analog Scale measures the severity of three specific behavioral symptoms as reported by the parent/caregiver: Language/Communication, Anxiety/Obsessive Compulsive Behaviors, and Aggression/Hyperactivity/Hyperarousal. Caregivers mark on a visual line measuring 10 cm with worst behavior at 0 cm and best behavior at 10 cm. For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the six-month visit. The calculated distance in cm between the marks drawn at the baseline and six-month visits 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 for the Language/Communication scale, at baseline. The smaller the value, the worse the behavior. The range is minimum 0 cm to maximum 10 cm. | At baseline visit | 
| Visual Analog Scale - Language/Communication Score | The Visual Analog Scale measures the severity of three specific behavioral symptoms as reported by the parent/caregiver: Language/Communication, Anxiety/Obsessive Compulsive Behaviors, and Aggression/Hyperactivity/Hyperarousal. Caregivers mark on a visual line measuring 10 cm with worst behavior at 0 cm and best behavior at 10 cm. For each behavior the caregiver is instructed to mark their impression of the behavior at baseline visit and again at the six-month visit. The calculated distance in cm between the marks drawn at the baseline and six-month visits 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 for the Language/Communication scale, at the six-month visit. The smaller the value, the worse the behavior. The range is minimum 0 cm to maximum 10 cm. | At six-month visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Autism Spectrum Disorder, Behavior, sertraline, treatment