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

Primary Purpose

Neurodevelopmental Disorders, Autism, Autism Spectrum Disorder

Status
Not yet recruiting
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Sertraline
Placebo
Sponsored by
Anagnostou, Evdokia, M.D.
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Neurodevelopmental Disorders

Eligibility Criteria

8 Years - 17 Years (Child)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Alberta Children's Hospital - University of Calgary
  • University of Alberta-Glenrose
  • Dalhousie University - IWK Health Centre
  • McMaster University
  • Queen's University
  • University of Western Ontario, Lawson Health Research Institute
  • Ste Justine Hospital - Universite de Montreal

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Sertraline

Placebo

Arm Description

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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.
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.
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).
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.
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.

Full Information

First Posted
September 27, 2023
Last Updated
October 18, 2023
Sponsor
Anagnostou, Evdokia, M.D.
Collaborators
Azrieli Foundation, Canadian Institutes of Health Research (CIHR), Ontario Brain Institute, Holland Bloorview Kids Rehabilitation Hospital, McMaster University, Western University, Queen's University, University of Alberta, Alberta Health services, St. Justine's Hospital, Dalhousie University, Unity Health Toronto, University of Toronto, The Hospital for Sick Children
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1. Study Identification

Unique Protocol Identification Number
NCT06081348
Brief Title
Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
Acronym
CALM
Official Title
A Randomized Placebo-Controlled Trial of Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
October 2023 (Anticipated)
Primary Completion Date
April 2024 (Anticipated)
Study Completion Date
April 2024 (Anticipated)

3. Sponsor/Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
130 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Sertraline
Arm Type
Active Comparator
Arm Title
Placebo
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Sertraline
Other Intervention Name(s)
Sertraline Hydrochloride, Zoloft, Serotonin Reuptake Inhibitor
Intervention Description
Oral capsule (25mg, 50mg, 100mg, 200mg)
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
Oral placebo capsule
Primary Outcome Measure Information:
Title
The Screen for Child Anxiety Related Emotional Disorders (SCARED) - parent version
Description
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.
Time Frame
16 weeks
Secondary Outcome Measure Information:
Title
Clinical Global Impressions - Improvement Scale - Global (CGI-I)
Description
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.
Time Frame
16 weeks
Title
The Safety Monitoring Uniform Report Form (SMURF)
Description
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.
Time Frame
16 weeks
Title
Pediatric Quality of Life Inventory (PedsQL)
Description
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).
Time Frame
16 weeks
Title
The Health Utilities Index-3 (HUI-3)
Description
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.
Time Frame
16 weeks
Title
Whole blood serotonin (5-HT) assessment
Description
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.
Time Frame
16 weeks
Other Pre-specified Outcome Measures:
Title
Multidimensional Anxiety Scale for Children - 2nd addition (MASC-2)
Description
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.
Time Frame
16 weeks
Title
Clinical Global Impressions - Severity Scale - Global (CGI-S) focused on anxiety
Description
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.
Time Frame
16 weeks
Title
The Screen for Child Anxiety Related Emotional Disorders (SCARED) - child version
Description
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.
Time Frame
16 weeks
Title
Clinical Global Impressions- Improvement Scale (CGI-I) focused on anxiety
Description
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.
Time Frame
16 weeks
Title
The Parent Chief Complaint
Description
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).
Time Frame
16 weeks
Title
Parent Rated Anxiety Scale in ASD (PRAS-ASD)
Description
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).
Time Frame
16 weeks
Title
Anxiety Depression and Mood Scale (ADAMS)
Description
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).
Time Frame
16 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
8 Years
Maximum Age & Unit of Time
17 Years
Accepts Healthy Volunteers
No
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Karly Janisse
Phone
4164256220
Ext
3297
Email
kjanisse@hollandbloorview.ca
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Evdokia Anagnostou
Organizational Affiliation
Holland Bloorview Kids Rehab Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Alberta Children's Hospital - University of Calgary
City
Calgary
State/Province
Alberta
Country
Canada
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Paul Arnold
First Name & Middle Initial & Last Name & Degree
Paul Arnold
Facility Name
University of Alberta-Glenrose
City
Edmonton
State/Province
Alberta
Country
Canada
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Francois Bolduc
First Name & Middle Initial & Last Name & Degree
Francois Bolduc
Facility Name
Dalhousie University - IWK Health Centre
City
Halifax
State/Province
Nova Scotia
Country
Canada
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Megan Thomas
First Name & Middle Initial & Last Name & Degree
Megan Thomas
Facility Name
McMaster University
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8S4K1
Country
Canada
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Alessia Greco
Phone
9057415479
Email
algreco@mcmaster.ca
First Name & Middle Initial & Last Name & Degree
Elisabetta Trinari
Facility Name
Queen's University
City
Kingston
State/Province
Ontario
ZIP/Postal Code
K7M8A6
Country
Canada
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ramona Rego
Phone
6135484417
Ext
1165
First Name & Middle Initial & Last Name & Degree
Sarosh Khalid-Khan
Facility Name
University of Western Ontario, Lawson Health Research Institute
City
London
State/Province
Ontario
ZIP/Postal Code
N6A 5W9
Country
Canada
Facility Name
Ste Justine Hospital - Universite de Montreal
City
Montréal
State/Province
Quebec
Country
Canada
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Baudouin Forgeot D'Arc
First Name & Middle Initial & Last Name & Degree
Baudouin Forgeot D'Arc

12. IPD Sharing Statement

Plan to Share IPD
No

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

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