Cognitive Rehabilitation (Mega Team) and Its Effects on Emotional and Behavioral Regulation in ADHD, ASD, and CHD

Study Overview
=================
Brief Summary
-----------------
Children with disorders that impact neurodevelopment often have difficulties with executive functions and regulating emotions. Cognitive-based video game training has been shown to improve outcomes, however, this training has been expensive, has required professional supervision, and has been investigated only within a narrow group of children. The Mega Team study will test the effects of a highly engaging, take-home video game-based intervention designed to improve executive functioning in children with various brain-based developmental disorders.

Detailed Description
-----------------
The target population for this study will be children between the ages of 6-12 with a diagnosis of ADHD, ASD or CHD. Potential subjects for this study will be recruited from the clinical teams within SickKids and partnering institutions (e.g., CAMH and Holland Bloorview). Participants will be identified by a psychiatrist, psychologist or specialist physician as meeting diagnostic criteria for one of the three disorders; 1) ADHD, 2) ASD, 3) CHD. Families of children who have expressed interested in this study will be contacted by research staff to discuss the study in more detail and will coordinate the logistics of an initial consent and enrollment appointment. Parent(s)/guardian(s) of participants will be required to consent and children will be required to assent to take in this study. This protocol is divided into 3 studies: sub-study 1 (ADHD), sub-study 2 (ASD) and sub-study 3 (CHD) each consisting of a pre-post treatment design with 6 month follow-up. Each sub-study includes an active treatment and wait -list arm. Please see study visit schedule (pg. 11) for time-line of events and measures by participant at each time point. Participants will be tested at SickKids at pre-treatment, post-treatment and follow-up. Participants will train at home with weekly calls from research staff. Assessors at all clinic visits will be blind to treatment status. All pre, post and following-up clinic assessments will be conducted off stimulant medication with a washout period of 48 hours. Stratification: Participants may be taking medications at the time of the study (stimulants and non-stimulants including SSRI or antipsychotic medications). Families will be asked to be stabilized on their current dose of medication for at least for a month before commencing the study and to maintain the same medication and dosage during the 5 week study. If a change in the type of medication or dosage takes place during the study it will be recorded. Due to the established impact of stimulant medications on EF 20 21 this class of medication will be used as part of the randomization process to attain equal proportions of participants using stimulant medications in the Mega Team and TAU groups. As some medication use is anticipated in all disorder groups the same randomization approach will be used in all three studies. Sample Size: The sample size for sub-study 1 (ADHD) will be 220 participants with 110 randomized into each group from initial estimated recruitment pool of 250. The sample size will provide 80% power to declare statistical significance if the true difference between treatment groups is 0.43 standard deviations or greater, using a two-sided, 5% level test of hypothesis, Bonferroni corrected for three comparisons. A pilot study of Mega Team is currently underway (Dr. Crosbie PI, a registered clinical trial) and results from that pilot will provide final estimates of the standard deviations before commencement of the current study. The planned sample for each of sub-study 2 (ASD) and sub-study 3 (CHD) will be 120 (60 per arm) given the novelty of investigating cognitive rehabilitation targeting EFs in these populations. Information from sub-study 1, which will happen first, and the results from the Mega Team pilot study, will allow adjustment in sample size of sub-study 2 and sub-study 3. All aspects of enrollment, randomization, and attrition will be monitored and documents using CONSORT flow diagram22. Randomization: Participants within each sub-study who have consented/ assented to the study and meet all inclusion criterion will be randomized to either Mega Team or TAU waitlist stratified by medication status (yes or no)) using random block sizes. Randomization will be carried out using RedCAP23. Blinding: Assessors at all clinic visits will be blind to treatment status. Participants and parents will be asked not to make mention of their treatment status during visits. They will be reminded of this regularly. Assessors will indicate their blinded status at the end of all visits. Parents and children will be asked not to inform teachers of the treatment status. At the time of questionnaire completion, teachers will be asked if they are aware of the treatment status of the child. Intervention Conditions: Mega Team Training Sessions: Mega Team is highly engaging video game based cognitive intervention that trains multiple executive functions: response inhibition, verbal working memory and visual working memory in the context of a single game with increasing difficulty based on the individual performance. Children in the treatment group will train at home on their own tablet or on a study tablet provided to the family (if needed). They will be instructed to practice Mega Team for 15 minutes a day, approximately 5 days a week for a targeted minimum of 21 sessions and a maximum of 25 sessions. The minimum value of 21 sessions has been selected based on findings of prior research. Majority of studies using other models of intervention have been able to capture significant training-induced improvements after 21 sessions 24-26. The maximum training of 25 sessions has been set to control for variability within and between our groups. Performance on Mega Team will automatically upload to a secure portal hosted by eHave for monitoring of enrolment, adherence and for data analyses. Scoring algorithms will track how often and how long the participants trained on Mega Team as well as their performance. Weekly calls from research staff will provide motivation and address barriers to game play. TAU waiting list Control: Children in the control group will not be provided with any overt intervention but continue with treatment recommendations as provided by their clinical care team. They will be asked to complete a video game usage log weekly to record the type and duration of their regular video game playing, and will receive weekly calls from research staff, as will participants assigned to Mega Team. Participants on in the TAU group will be given access to the game at the completion of the 6 month follow-up visit.

Official Title
-----------------
Cognitive Rehabilitation (Mega Team) and Its Effects on Emotional and Behavioral Regulation in ADHD, ASD, and CHD

Conditions
-----------------
ADHD, ASD, CHD - Congenital Heart Disease

Intervention / Treatment
-----------------
* Other: Mega Team - video game


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Sub-Study 1 Inclusion Criteria Must be 6-12 years of age Have IQ above 70 as estimated by two subtests of the Wechsler Abbreviated Scale of intelligence, Second Edition (WASI II) or equivalent. Diagnosed with ADHD based upon DSM 5 criteria by a referring clinician confirmed by semi structured interview with the parents using PICS, including information from parent and teacher ratings of an established measure of ADHD symptoms. Does not have a diagnosis of ASD or CHD [in this case, individuals can be enrolled into Study 2 (ASD) or Study 3 (CHD)]. Have reliable access to the internet Sub-Study 2 inclusion criteria Must be 6-12 years of age Have IQ above 70 as estimated by two subtests of the Wechsler Abbreviated Scale of intelligence, Second Edition (WASI II) or equivalent Meets clinical diagnosis of ASD by referral services (Holland Bloorview, CAMH) supported by ADOS. Have reliable access to the internet Sub-Study 3 inclusion criteria Must be 6-12 years of age Have IQ above 70 as estimated by two subtests of the Wechsler Abbreviated Scale of intelligence, Second Edition (WASI II) or equivalent Must have a diagnosis of Transposition of the Great Arteries (TGA) or Hypoplastic left heart syndrome Must have received cardiac surgery before 6 weeks of age. Have reliable access to the internet Exclusion Criteria: Sub-Study 1 Exclusion Criteria Younger than 6 years or older than 12 IQ below 70 as estimated by two subtests of the Wechsler Abbreviated Scale of intelligence, Second Edition (WASI II) or equivalent Does not meet consensus diagnosis of DSM 5 criteria for ADHD based on a semi structured interview with the parents using PICS-6, including information from parent and teacher ratings of an established measure of ADHD symptoms. Has a diagnosis of ASD or CHD [in this case, individuals can be enrolled into Study 2 (ASD) or Study 3 (CHD)]. Sub-Study 2 exclusion criteria Younger than 6 years or older than 12 IQ below 70 as estimated by two subtests of the Wechsler Abbreviated Scale of intelligence, Second Edition (WASI II) or equivalent Does not meet confirmed diagnosis of ASD based on ADOS Sub-Study 3 exclusion criteria Younger than 6 years or older than 12 IQ below 70 as estimated by two subtests of the Wechsler Abbreviated Scale of intelligence, Second Edition (WASI II) or equivalent Does not have a diagnosis of Transposition of the Great Arteries (TGA) or Hypoplastic left heart syndrome Did not receive cardiac surgery before 6 weeks of age.

Ages Eligible for Study
-----------------
Minimum Age: 6 Years
Maximum Age: 12 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>Subjects randomly assigned to this arm will train on the Mega Team video game. | Other: Mega Team - video game<br>* Subjects randomly assigned to the treatment group will be instructed to practice Mega Team for 15 minutes a day, 5 days a week for a minimum of 21 days and a maximum of 25 days.<br>* Other names: Mega Team;|
| No Intervention: Control- wait list group<br>Subjects randomly assigned to this arm will be the wait-list group. They are allowed to play the video games that they usually play. | |

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Response Inhibition | Inhibitory control will be measured using the Stop Signal Task (SST). The SST measures the ability to cancel an already initiated motor response. The primary outcome measure will be the participants' average stop signal reaction time (SSRT). | Baseline, Post-training study visit #1 (4-5 weeks after baseline), Post-training study visit #2 (6 months after baseline) | 
| Change in Working Memory | Verbal and Spatial N-back (1, 2 conditions) will be used to assess central executive working memory. The N-Back task requires on-line monitoring, updating, and manipulation of information and measures key processes within working memory. In the N-Back task, the participant is required to monitor a series of stimuli and to respond whenever a stimulus is presented that is the same as the one presented n trials previously, where n is a pre-specified integer, usually 0, 1, or 2. The current study will use letters (verbal) and spatial location (spatial) paradigms. Visual and spatial working memory span will be assessed using the Spatial Span subtest and the Digit Span item from the WISC-IV Integrated. The primary outcome measure will be the overall score. | Baseline, Post-training study visit #1 (4-5 weeks after baseline), Post-training study visit #2 (6 months after baseline) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Planning and Organization | The Tower Test from the Delis-Kaplan Executive Function System (D-KEFS;28 is a test of planning and problem solving abilities. Participants are asked to construct towers of discs on a set of pegs corresponding to a model. Raw scores reflect the participant's ability to use the fewest possible moves to achieve the tower depicted in the model. | Baseline, Post-training study visit #1 (4-5 weeks after baseline), Post-training study visit #2 (6 months after baseline) | 
| Everyday functioning and impairment | Parent and teacher rating of behaviours and impairments associated with executive functions will be assessed using The Behavior Rating Inventory of Executive Function (BRIEF;29). This is a 86 item questionnaires with solid psychometric properties (ref) with correlations with other measures of emotional and behavioral functioning29. | Baseline, Post-training study visit #1 (4-5 weeks after baseline), Post-training study visit #2 (6 months after baseline) | 
| Inattentive and Hyperactivity Behaviour rated by parent and teacher | Items associated with inattentiveness and hyperactivity from the SNAP IV will be used to estimate behavioural symptoms associated with ADHD. The SNAP-IV (SNAP-IV; Swanson IV, 2003) is an 18-item scale that includes the DSM-IV criteria for ADHD with items 1-9 representing the inattentive subset of symptoms and items 10-18 representing the Hyperactivity/Impulsivity subset. | Baseline, Post-training study visit #1 (4-5 weeks after baseline), Post-training study visit #2 (6 months after baseline) | 
| Academic accuracy and efficiency | Academic efficiency and accuracy will be assessed using the fluency measures from the Woodcock Johnson III30 test of achievement. The fluency tasks measure the accuracy of completing academic tasks within a time limit. Reading, math and writing fluency subtests will be included. | Baseline, Post-training study visit #1 (4-5 weeks after baseline), Post-training study visit #2 (6 months after baseline) |