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

Anxiety Clinical Trial

— CALM  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06081348
• Other study ID #: SER-11-2020
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: October 2023
• Est. completion date: April 2024

Study information

• Verified date: October 2023
• Source: Anagnostou, Evdokia, M.D.
• Contact: Karly Janisse
• Phone: 4164256220
• Email: kjanisse[@]hollandbloorview.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 130
• Est. completion date: April 2024
• Est. primary completion date: April 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years to 17 Years

Eligibility

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. CALM Study Page 13 of 38 Version 5.0 June 26th, 2023

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

Related Conditions & MeSH terms

• 22Q11 Deletion Syndrome
• ADHD
• ADHD - Combined Type
• ADHD Predominantly Inattentive Type
• ADHD, Predominantly Hyperactive - Impulsive
• Agoraphobia
• Anxiety
• Anxiety Disorders
• Anxiety, Separation
• Autism
• Autism Spectrum Disorder
• Autistic Disorder
• DiGeorge Syndrome
• Fragile X Syndrome
• Generalized Anxiety
• Generalized Anxiety Disorder
• Neurodevelopmental Disorders
• Phobia, Social
• Provisional Tic Disorder
• Separation Anxiety
• Social Anxiety
• Social Anxiety Disorder
• Syndrome
• Tic Disorders
• Tics
• Tourette Syndrome
• Tourette Syndrome in Adolescence
• Tourette Syndrome in Children
• Tuberous Sclerosis

Intervention

Drug:
• Sertraline
Oral capsule (25mg, 50mg, 100mg, 200mg)

Other:
• Placebo
Oral placebo capsule

Locations

Country	Name	City	State
Canada	Alberta Children's Hospital - University of Calgary	Calgary	Alberta
Canada	University of Alberta-Glenrose	Edmonton	Alberta
Canada	Dalhousie University - IWK Health Centre	Halifax	Nova Scotia
Canada	McMaster University	Hamilton	Ontario
Canada	Queen's University	Kingston	Ontario
Canada	University of Western Ontario, Lawson Health Research Institute	London	Ontario
Canada	Ste Justine Hospital - Universite de Montreal	Montréal	Quebec

Sponsors (15)

Lead Sponsor	Collaborator
Anagnostou, Evdokia, M.D.	Alberta Health services, Azrieli Foundation, Canadian Institutes of Health Research (CIHR), Dalhousie University, Holland Bloorview Kids Rehabilitation Hospital, McMaster University, Ontario Brain Institute, Queen's University, St. Justine's Hospital, The Hospital for Sick Children, Unity Health Toronto, University of Alberta, University of Toronto, Western University

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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