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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Anxiety Disorders; Anxiety; Tuberous Sclerosis; ADHD; Neurodevelopmental Disorders; Autism Spectrum Disorder; Fragile X Syndrome; Tourette Syndrome; Tic Disorders; Autism; ADHD Predominantly Inattentive Type; ADHD - Combined Type; ADHD, Predominantly Hyperactive - Impulsive; Tourette Syndrome in Children; Tourette Syndrome in Adolescence; 22Q11 Deletion Syndrome; 22Q11 Deletion
• Intervention / Treatment: Drug: Sertraline; Other: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 130
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Faiza Khawaja; Phone Number: 3526 4164256220; Email: fkhawaja@hollandbloorview.ca

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada
      • Recruiting
      • Alberta Children's Hospital - University of Calgary
      • Contact: Thomas Qiao; Email: qingqi.qiao@ucalgary.ca
      • Principal Investigator: Dr. Kara Murias
    • Edmonton, Alberta, Canada
      • Recruiting
      • University of Alberta-Glenrose
      • Contact: Jacob Bennett; Email: metcoord@ualberta.ca
      • Principal Investigator: Dr. Francois Bolduc
  • Nova Scotia
    • Halifax, Nova Scotia, Canada
      • Recruiting
      • Dalhousie University - IWK Health Centre
      • Contact: Stacey MacWilliam; Email: Stacey.MacWilliam@iwk.nshealth.ca
      • Principal Investigator: Dr. Megan Thomas
  • Ontario
    • Hamilton, Ontario, Canada, L8S4K1
      • Recruiting
      • McMaster University
      • Contact: Nancy Selman; Phone Number: 9057415479; Email: nselman@mcmaster.ca
      • Principal Investigator: Dr. Elisabetta Trinari
    • Kingston, Ontario, Canada, K7M8A6
      • Not yet recruiting
      • Queen's University
      • Contact: Kelly Estrada Piedrahita; Phone Number: 76903 613-533-6000; Email: kaep@queensu.ca
      • Principal Investigator: Dr. Sarosh Khalid-Khan
    • London, Ontario, Canada, N6A 5W9
      • Recruiting
      • University of Western Ontario, Lawson Health Research Institute
      • Contact: Ahsan Ahmad; Phone Number: 74906 (519) 685-8500; Email: ahsan.ahmad@lhsc.on.ca
      • Principal Investigator: Dr. Robert Nicolson
    • Toronto, Ontario, Canada, M4G 1R8
      • Recruiting
      • Holland Bloorview Kids Rehabilitation Hospital
      • Contact: Karly Janisse; Phone Number: 3297 4164256220; Email: kjanisse@hollandbloorview.ca
      • Principal Investigator: Dr. Evdokia Anagnostou
  • Quebec
    • Montréal, Quebec, Canada
      • Not yet recruiting
      • Ste Justine Hospital - Universite de Montreal
      • Contact: Baudouin Forgeot D'Arc
      • Principal Investigator: Dr. Baudouin Forgeot D'Arc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Outpatients 8-17 years of age, inclusive
2. 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.
3. 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.
4. 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.
5. 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)
6. 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*

7. If already receiving interventions, must meet the following criteria:

   1. 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
   2. If already receiving stable non-pharmacological behavioural interventions, have stable participation during 3 months prior to screening, and will not electively modify ongoing interventions
8. Ability to complete assessments in English/French

Exclusion Criteria:

1. Receiving other SSRIs within four weeks of randomization (6 weeks for fluoxetine)
2. 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.
3. Received more than 2 previous appropriate trials of SSRIs with no adequate response
4. Pregnant females or sexually active females on inadequate contraception
5. 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.
6. Hypersensitivity to sertraline or any components of its formulation
7. On Monoamine Oxidase Inhibitors or pimozide (as per product monograph)
8. On concomitant medications known to significantly increase QT interval where this would result in unacceptable risk per Investigator judgment.
9. Known congenital QT prolongation
10. HIV, hepatitis B or C, hemophilia, abnormal blood pressure, substance abuse, immunity disorder, major depressive episode or psychosis (as required by Health Canada)
11. Unable to tolerate venipuncture
12. Unable to swallow capsules
13. Enrolled in another intervention study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Other: Placebo; Oral placebo capsule
Active Comparator: Sertraline	Drug: Sertraline; Oral capsule (25mg, 50mg, 100mg, 200mg); Other Names: Zoloft; Sertraline Hydrochloride; Serotonin Reuptake Inhibitor

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
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
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
Clinical Global Impressions- Improvement Scale (CGI-I) focused on anxiety	The CGI-I is a clinician reported scale which will be used to examine the effect of sertraline vs. placebo on measures of global anxiety. 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
Adverse events	Adverse events as elicited by the SMURF.	16 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Multidimensional Anxiety Scale for Children - 2nd addition (MASC-2)	The MASC-2 will be used as an additional anxiety measure to examine the effect of sertraline vs. placebo on measures of anxiety. The MASC-2 can be rated by parents or completed as a self-report. The parent rated version will be used and if the participant has adequate language ability, the self-report will also be used. The MASC-2 is a 50-item questionnaire. Each item is rated from 0 (Never) to 3 (Often). A higher score is indicative of higher symptoms of anxiety.	16 weeks
Clinical Global Impressions - Severity Scale - Global (CGI-S) focused on anxiety	The CGI-S is a clinician reported scale which will be used to examine the effect of sertraline vs. placebo on measures of global function. The CGI-Severity Scale employs a seven point (1 = Normal, not at all ill to 7 = among the most extremely ill patients) to determine the participant's initial level of severity of impairment.	16 weeks
The Screen for Child Anxiety Related Emotional Disorders (SCARED) - child version	The SCARED is a 41-item measure of anxiety symptoms, with both child and parent versions. The Child version will be used as an exploratory 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
Clinical Global Impressions- Improvement Scale (CGI-I) focused on anxiety	The CGI-I is a clinician reported scale which will be used to examine the effect of sertraline vs. placebo on measures of global anxiety. 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 Parent Chief Complaint	The Parent Chief Complaint will be used to examine the effect of sertraline vs. placebo on individualized target symptoms. The objective of this measure is to have the parent describe the frequency and severity of one or two primary concerns of their child's behavior at the baseline visit and again at the end of treatment. Frequency is rated as Very Often (3), Often (2), Sometimes (1), or Rarely (0), and Severity is rated as Mild (1; behaviour occurs and is a mild problem), Moderate (2; behaviour occurs and is a moderate problem), and Severe (3; behaviour occurs and is a severe problem).	16 weeks
Parent Rated Anxiety Scale in ASD (PRAS-ASD)	The PRAS-ASD will be used to examine the effect of sertraline vs. placebo on measures of anxiety in ASD. It is completed by the parents and includes 25 questions rated on a scale for 0-3 (none-severe problem).	16 weeks
Anxiety Depression and Mood Scale (ADAMS)	The ADAMS is designed to assess anxiety and depression in children with and without intellectual disability. The ADAMS is a 28 item questionnaire which is rated by the parent. Each item is rated from 0 (behaviour has not occurred, or is not a problem) to 3 (behaviour occurs a lot, or is a severe problem).	16 weeks

Collaborators and Investigators

• Sponsor: Holland Bloorview Kids Rehabilitation Hospital
• Collaborators: The Hospital for Sick Children; Alberta Health services; University of Alberta; McMaster University; Unity Health Toronto; University of Toronto; Queen's University; Dalhousie University; St. Justine's Hospital; Western University; Maternal, Infant, Child and Youth Research Network (MICYRN); Azrieli Foundation (Funder); Canadian Institutes of Health Research (Funder); Ontario Brain Institute (Funder)
• Investigators: Principal Investigator: Dr. Evdokia Anagnostou, Holland Bloorview Kids Rehab Hospital

Study record dates

Study Major Dates

• Study Start (Actual): September 16, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: September 27, 2023
• First Submitted That Met QC Criteria: October 11, 2023
• First Posted (Actual): October 13, 2023

Study Record Updates

• Last Update Posted (Actual): July 16, 2025
• Last Update Submitted That Met QC Criteria: July 14, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neurologic Manifestations; Endocrine System Diseases; Musculoskeletal Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Cardiovascular Diseases; Mental Disorders; Pathologic Processes; Neoplasms; Heart Diseases; Genetic Diseases, Inborn; Disease; Neurobehavioral Manifestations; Neurodegenerative Diseases; Lymphatic Diseases; Craniofacial Abnormalities; Musculoskeletal Abnormalities; Congenital Abnormalities; Child Development Disorders, Pervasive; Parathyroid Diseases; Cardiovascular Abnormalities; Heart Defects, Congenital; Movement Disorders; Abnormalities, Multiple; Heredodegenerative Disorders, Nervous System; Neoplastic Syndromes, Hereditary; Neurocutaneous Syndromes; Mental Retardation, X-Linked; Intellectual Disability; Genetic Diseases, X-Linked; Basal Ganglia Diseases; Hamartoma; Neoplasms, Multiple Primary; Malformations of Cortical Development, Group I; Malformations of Cortical Development; Nervous System Malformations; Sex Chromosome Disorders; Chromosome Disorders; Lymphatic Abnormalities; Hypoparathyroidism; Autism Spectrum Disorder; Syndrome; Anxiety Disorders; Autistic Disorder; Neurodevelopmental Disorders; Tuberous Sclerosis; Fragile X Syndrome; Tic Disorders; Tourette Syndrome; DiGeorge Syndrome; 22q11 Deletion Syndrome; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Neurotransmitter Agents; Membrane Transport Modulators; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Antidepressive Agents; Serotonin Agents; Serotonin Receptor Agonists; Serotonin; Selective Serotonin Reuptake Inhibitors; Sertraline
• Other Study ID Numbers: SER-11-2020

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Time Frame: After publication
• IPD Sharing Access Criteria: Through Brain Code
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No