The Effects of ADHD Medication (TEAM) Study

Study Overview
=================
Brief Summary
-----------------
This study evaluates the effects of receiving and then discontinuing methylphenidate (MPH) in children with ADHD. After receiving MPH for 8 weeks, participants will be randomized to either discontinue MPH (and receive placebo) OR remain on MPH for 4 weeks.

Detailed Description
-----------------
The stimulant methylphenidate (MPH) is the most commonly prescribed psychoactive medication in children. An abundance of studies attest to the efficacy of MPH for attenuating inattentive, hyperactive, and impulsive symptoms in children with ADHD. Despite its efficacy, most children with ADHD who are prescribed MPH have poor continuity of treatment for a variety of reasons, including forgetting to administer the medication and delays obtaining refills. In addition, it is an accepted clinical practice for physicians to omit MPH for periods of time, such as during the summer or on weekends (i.e., drug holidays). Since MPH discontinuation is considered to be benign, many clinicians do not employ any special procedures or inform families of any special precautions in regard to its cessation. However, increasing evidence suggests that the pharmacological effects of MPH cause lasting changes in brain neurochemistry that persist beyond medication discontinuation. Moreover, these neurobiological effects of discontinuation appear to have neurobehavioral consequences. There is a critical need to better understand the breadth and magnitude of the neurobehavioral effects caused by MPH discontinuation as well as to better understand the temporal trajectory of these deleterious effects. Hence, the primary goal of the proposed research is to conduct the first randomized, double-blind, placebo-controlled trial specifically designed to study the negative effects of MPH discontinuation at multiple time points. 180 children diagnosed with ADHD will participate across two recruitment sites. After undergoing a 4-week MPH titration trial and 4-week MPH maintenance phase, participants will be randomized to either discontinue MPH (and receive placebo) OR remain on MPH for 4 weeks. Comprehensive multi-time point, multi-informant (parents, teachers, study staff) and multi-modal (behavior/mood/affect ratings scales, direct behavior observations, standardized testing) assessments will be used to assess a broad range of neurobehavioral outcomes. We will examine the magnitude and time course of effects of MPH discontinuation on behavioral as well as cognitive and academic functioning in children with ADHD. Furthermore, we will examine moderators of the adverse effects of MPH discontinuation on these outcomes to aid in the identification of those who are at increased risk.

Official Title
-----------------
The Effects of ADHD Medication (TEAM) Study: Neurobehavioral Effects of Abrupt Methylphenidate Discontinuation

Conditions
-----------------
ADHD

Intervention / Treatment
-----------------
* Drug: OROS-Methylphenidate (MPH)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: ADHD Diagnostic Status: Meets DSM-V criteria for ADHD, with Clinical Global Impression (CGI) rating corresponding to at least moderately ill. Cognitive and Academic Functioning: Intelligence Quotient (IQ) of >80 as estimated by Vocabulary and Block Design subtests of the Wechsler Intelligence Scale for Children-4th Edition and scaled scores >80 on the Wechsler Individual Achievement Test-2nd edition Reading and Math subtests Physical Health: Physical exam and ECG findings are judged to be normal for age and sex by study physician and/or medical consultant, and there is no co-existing condition for which MPH is contraindicated 4. School: Enrolled in a school setting rather than a home-school program. This ensures that we can obtain parent and teacher ratings from separate individuals for diagnosis and outcome assessment Exclusion Criteria: Psychiatric Medications: Current or prior use of any medication for psychological/psychiatric problems Behavioral Interventions: Current active participation in ADHD-related behavioral interventions, given that improvements due to these interventions may confound our group comparisons Psychiatric or Neurobehavioral Conditions: Children with mania/hypomania, schizophrenia, or severe depressive disorder, as determined by the K-SADS, will be excluded since ADHD medications may not be an appropriate first line of treatment for children with these comorbid disorders Organic Brain Injury: History of head trauma, neurological disorder (including epilepsy), or other disorder affecting brain function due to potential differences in neurophysiology of ADHD phenotype Cardiovascular Risk Factors: Children with a personal history or family history of cardiovascular risk factors will be excluded, or given the option of participating in the study after obtaining an EKG and verification from a pediatric cardiologist regarding the safety of their participation in a trial of methylphenidate. In this case, families will be responsible for the costs of EKG and any necessary cardiologist evaluation Pregnancy: The safety of MPH use during pregnancy has not been established

Ages Eligible for Study
-----------------
Minimum Age: 7 Years
Maximum Age: 11 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 |
| --- | --- |
| Placebo Comparator: MPH Discontinuation<br>Double-blind (DB) placebo-controlled 4-week methylphenidate (MPH) titration trial. Pts will receive 3 active dosages of MPH (children <25kg: 18mg, 27mg, 36mg; children >25kg: 18mg, 36mg, 54mg for) as well as 1 random week of placebo, given qAM. Pts will begin on the lowest dose (or a randomized placebo week) and proceed through all dose conditions in an incremental fashion. DB 4-week MPH maintenance phase. The clinician, parent, and teacher ratings of behavior and side effects from the titration trial weeks will be graphed. Two doctors will blindly review the graphs and judge which week was the optimal dose week. Pts will then receive their optimal dose of MPH (qAM) for 4 weeks. DB 4-week MPH Discontinuation Phase. Pts in this arm will receive placebo (qAM). | Drug: OROS-Methylphenidate (MPH)<br>* OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA.<br>* Other names: Concerta;|
| Active Comparator: Sustained MPH<br>Double-blind (DB) placebo-controlled 4-week methylphenidate (MPH) titration trial. Pts will receive 3 active dosages of MPH (children <25kg: 18mg, 27mg, 36mg; children >25kg: 18mg, 36mg, 54mg for) as well as 1 random week of placebo, given qAM. Pts will begin on the lowest dose (or a randomized placebo week) and proceed through all dose conditions in an incremental fashion. DB 4-week MPH maintenance phase. The clinician, parent, and teacher ratings of behavior and side effects from the titration trial weeks will be graphed. Two doctors will blindly review the graphs and judge which week was the optimal dose week. Pts will then receive their optimal dose of MPH (qAM) for 4 weeks. DB 4-week MPH Discontinuation Phase. Pts in this arm will continue their optimal MPH dose (qAM). | Drug: OROS-Methylphenidate (MPH)<br>* OROS-methylphenidate will be taken orally once daily at doses that have been approved for the study age group by the U.S. FDA.<br>* Other names: Concerta;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parent ADHD Total Symptom Scores | Parent Vanderbilt ADHD Rating Scale Total Symptom Score, minimum=0, maximum=54, higher scores indicate more/worse ADHD symptoms | baseline, study weeks 8, 9, 10, 12 | 
| Inhibitory Control Reaction Time Variability (SD of the Reaction Time) | Assessed via the Go/No-Go computerized measure of inhibitory control reaction time variability (with standard deviation of the reaction time being the indicator variability variability). Unit of measure is msec. Minimum is 0, Maximum is 500. Higher scores indicate more variability (higher standard deviation) in reaction time, indicating worse outcome (more characteristic of individuals with ADHD and less characteristic of typically developing individuals). | baseline, study weeks 8, 9, 10 & 12 | 
| Math Computation - Number of Problems Completed Correctly | Math Computation Curriculum-Based Measure - Number of Problems Completed Correctly. Minimum=0, Maximum=600. Higher scores indicate improved/better performance | baseline, study weeks 8, 9, 10 & 12 | 
| % Time on Task | Participants were videotaped while completing the 20-minute Analogue Math task. Their behavior was coded in 20-second intervals by trained coders who determined if the children were on-task or off-task during each interval. The amount of time coded as on-task was divided by the total amount of time and then multiplied by 100 to generate the % of time on task variable. | baseline, study weeks 8, 9, 10, 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Barkley Sluggish Cognitive Tempo (SCT) Ratings | assessed via parent-completed Barkley Sluggish Cognitive Tempo Scale. Minimum=12, Max=48, higher scores indicate worse outcome. | baseline, study weeks 8, 9, 10 &12 | 
| Parent Ratings of Emotional Regulation | assessed via parent-completed Emotion Regulation Checklist (ERC). Outcome assessed is ERC total mean score: minimum value=1, max value=4, higher scores indicate worse outcome | baseline, study weeks 8, 9, 10 &12 | 
| Spatial Working Memory | Spatial working memory was assessed via the Corsi Computerized Spatial Span Task, which requires the participant to reproduce a sequence of movements by tapping a series of blocks on a computer screen in the same order demonstrated by the examiner. Outcome of interest is total trials correct. Minimum score=0, max score=10. Higher scores indicate better performance. | baseline, study weeks 8, 9, 10 &12 | 
| Math Reasoning | Math reasoning was assessed by child completion of the AIMSWEB curriculum based measure (CBM) test of Math Concepts and Applications. At baseline (week 1), child's performance was assigned a value of 1.0. The child's performance at weeks 8, 9, 10, and 12 was derived by dividing actual score on the test by the score predicted at that time point after applying the measure's normed rate of improvement (ROI) metric to the baseline score. For example, a score of 1.5 at week 8 would indicate that the child's actual score at week 8 was 50% higher than the predicted score at week 8 (which was derived by applying the normed ROI metric to the baseline score). Scores at weeks 8, 9, 10, 12 that are >1.0 indicate greater improvement than expected (so better outcome), while scores at weeks 8, 9, 10, 12 that are <1.0 indicate less improvement than expected (so worse outcome). | baseline, study weeks 1, 8, 9, 10 &12 | 
| Reading Comprehension | Reading Comprehension was assessed by child completion of the AIMSWEB curriculum based measure (CBM) test of Reading Comprehension. At baseline (week 1), child's performance was assigned a value of 1.0. The child's performance at weeks 8, 9, 10, and 12 was derived by dividing actual score on the test by the score predicted at that time point after applying the measure's normed rate of improvement (ROI) metric to the baseline score. For example, a score of 1.5 at week 8 would indicate that the child's actual score at week 8 was 50% higher than the predicted score at week 8 (which was derived by applying the normed ROI metric to the baseline score). Scores at weeks 8, 9, 10, 12 that are >1.0 indicate greater improvement than expected (so better outcome), while scores at weeks 8, 9, 10, 12 that are <1.0 indicate less improvement than expected (so worse outcome). | baseline, study weeks 8, 9, 10 &12 | 
| Written Expression | Assessed by child completion of the AIMSWEB curriculum based measure (CBM) test of Written Expression, with the measure assessing number of words written by the child after receiving a prompt. At baseline (week 1), child's performance was assigned a value of 1.0. The child's performance at weeks 8, 9, 10, and 12 was derived by dividing actual score (# of words written) on the test by the score predicted at that time point after applying the measure's normed rate of improvement (ROI) metric to the baseline score. For example, a score of 1.5 at week 8 would indicate that the child's actual score at week 8 was 50% higher than the predicted score at week 8 (which was derived by applying the normed ROI metric to the baseline score). Scores at weeks 8, 9, 10, 12 that are >1.0 indicate greater improvement than expected (so better outcome), while scores at weeks 8, 9, 10, 12 that are <1.0 indicate less improvement than expected (so worse outcome). | baseline, study weeks 1, 8, 9, 10 &12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ADHD, inattention, hyperactivity, methylphenidate