Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders

Study Overview
=================
Brief Summary
-----------------
There are currently no approved medications for the treatment of anxiety in children and youth with neurodevelopmental disorders (NDDs), both common and rare. Sertraline, a selective serotonin reuptake inhibitor, has extensive evidence to support its use in children's and youth with anxiety but not within NDDs. More research is needed to confirm whether or not sertraline could help improve anxiety in children and youth with common and rare neurodevelopmental conditions. This is a pilot study, in which we plan to estimate the effect size of reduction in anxiety of sertraline vs. placebo. across rare and common neurodevelopmental disorders, and determine the best measure(s) to be used as a primary transdiagnostic outcome measure of anxiety, as well as diagnosis specific measures in future, larger-scale clinical trials of anxiety in NDDs.

Official Title
-----------------
A Randomized Placebo-Controlled Trial of Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders

Conditions
-----------------
Neurodevelopmental Disorders, Autism, Autism Spectrum Disorder, Fragile X Syndrome, Tuberous Sclerosis, 22Q11 Deletion Syndrome, 22Q11 Deletion, ADHD, Tic Disorders, Tourette Syndrome, Tourette Syndrome in Children, Tourette Syndrome in Adolescence, ADHD - Combined Type, ADHD Predominantly Inattentive Type, ADHD, Predominantly Hyperactive - Impulsive, Provisional Tic Disorder, Anxiety, Anxiety Disorders, Agoraphobia, Generalized Anxiety, Generalized Anxiety Disorder, Social Anxiety, Social Anxiety Disorder, Unspecified Anxiety Disorder, Other Specified Anxiety Disorders, Separation Anxiety

Intervention / Treatment
-----------------
* Drug: Sertraline
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Outpatients 8-17 years of age, inclusive Females of child bearing potential who are sexually active and agree to use medically acceptable birth control throughout the study and at least one week post last dose of study drug. Meet Diagnostic and Statistical Manual of Mental Disorders - DSM-5 criteria for ASD, ADHD, Tic Disorders, or genetic diagnosis of Fragile X, tuberous sclerosis or 22q11 deletions. CALM Study Page 13 of 38 Version 5.0 June 26th, 2023 Meet DSM-5 criteria for one of the following anxiety disorders: Separation Anxiety Disorder, Social Anxiety Disorder, Agoraphobia, Generalized Anxiety Disorder, or Unspecified Anxiety Disorder, based on expert clinical interview, supported by the Kiddie Schedule for Affective Disorders and Schizophrenia (KSADS; Kaufman et al., 2016). Other specified anxiety disorder is included to account for youth with impairing anxiety symptoms who may not meet criteria for one of the other anxiety disorders. Have a Clinician's Global Impression-Severity for anxiety (CGI-S; Guy, 1976)) score ≥ 4 (moderately ill) (inter-rater reliability will be done prior to initiation of enrollment, using videotapes of interviews and vignettes) Have at least phrase speech, to allow for some self-report. So that results can be generalized to children and youth with NDD and various levels of ability, no IQ cut-off will be employed. Full-scale IQ (as measured by the Stanford-Binet) is measured to explore its effect on efficacy and safety* If already receiving interventions, must meet the following criteria: If receiving concomitant medications affecting behaviour, must be on a stable dose during the month prior to screening and will not electively modify ongoing medications for study duration If already receiving stable non-pharmacological behavioural interventions, have stable participation during 3 months prior to screening, and will not electively modify ongoing interventions Ability to complete assessments in English/French Exclusion Criteria: Receiving other SSRIs within four weeks of randomization (6 weeks for fluoxetine) Previous treatment with sertraline, at an adequate dose (at least 100mg for 6 weeks, or lower dose and duration if not well-tolerated), associated with no response or significant-to-the-participant side effects. Received more than 2 previous appropriate trials of SSRIs with no adequate response Pregnant females or sexually active females on inadequate contraception Serious medical condition that, based on Investigator judgment, might interfere with the conduct of the study, confound interpretation of the study results, or endanger participant. In addition diabetic patients on medications for glycemic control will be excluded as sertraline may interfere with glycemic control. Hypersensitivity to sertraline or any components of its formulation On Monoamine Oxidase Inhibitors or pimozide (as per product monograph) On concomitant medications known to significantly increase QT interval where this would result in unacceptable risk per Investigator judgment. Known congenital QT prolongation HIV, hepatitis B or C, hemophilia, abnormal blood pressure, substance abuse, immunity disorder, major depressive episode or psychosis (as required by Health Canada) Unable to tolerate venipuncture Unable to swallow capsules Enrolled in another intervention study

Ages Eligible for Study
-----------------
Minimum Age: 8 Years
Maximum Age: 17 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sertraline<br> | Drug: Sertraline<br>* Oral capsule (25mg, 50mg, 100mg, 200mg)<br>* Other names: Serotonin Reuptake Inhibitor;|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* Oral placebo capsule<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Screen for Child Anxiety Related Emotional Disorders (SCARED) - parent version | The SCARED is a 41-item measure of anxiety symptoms, with both child and parent versions. The parent version will be used as a primary outcome measure. The minimum overall score is 0 while the maximum overall score is 82. A score greater than or equal to 25 may indicate the presence of an Anxiety Disorder. Higher scores indicate a higher instance of anxiety symptoms while a lower score indicates a lower instance of anxiety symptoms. | 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impressions - Improvement Scale - Global (CGI-I) | The CGI-I is a clinician reported scale which will be used to examine the effect of sertraline vs. placebo on measures of global function. The CGI-Improvement Scale employs a seven point (1 = very much improved to 7 = very much worse) to determine the participant's improvement in response to treatment. | 16 weeks | 
| The Safety Monitoring Uniform Report Form (SMURF) | The SMURF will be administered by the clinician at each visit to examine the safety and tolerability of sertraline. This rating covers a range of behavioural and physical AEs that are relevant to SSRIs. | 16 weeks | 
| Pediatric Quality of Life Inventory (PedsQL) | The PedsQL will be used to examine the effect of sertraline vs. placebo on measures of quality of life. The PedsQL is measuring health-related quality of life (HRQOL) in 2- to 18-year-olds. The PedsQL 4.0 Generic Core Scales are multidimensional child self-report and parent-proxy report scales that have been used extensively as an outcome measure, including in ASD. We will use the parent-proxy report scale, and optionally, age-appropriate child self-report scale. Each item is is rated between a 0 (Never a problem) to 4 (Almost always a problem). | 16 weeks | 
| The Health Utilities Index-3 (HUI-3) | The HUI-3 will be used to examine the effect of sertraline vs. placebo on measures of general health status and health-related quality of life. The study is using the parent-proxy version of the HUI-3. The HUI-3 is a 15-item questionnaire to classify a subject's health status. | 16 weeks | 
| Whole blood serotonin (5-HT) assessment | A whole blood serotonin assessment will be completed to examine the effect of sertraline vs. placebo on biomarkers of serotonin. 3mL of blood will be drawn at screening and week 16 visits for the purpose of this assessment. High performance liquid chromatography will be performed using fluorometric detection of 5-HT, tryptophan (TRP), and 5-hydroxyindole acetic acid (5-HIAA), using N-methylserotonin as an internal standard. Using this method, 5-HT intra- and inter- assay coefficients of variation are reliably less than 5% and 10%, respectively. | 16 weeks |