Novel Approach to Stimulant Induced Weight Suppression and Its Impact on Growth

Study Overview
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Brief Summary
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Previous NIH funded Attention Deficit Hyperactivity Disorder (ADHD) trials in children found that daily stimulant therapy produced sustained growth deficits. However, no federally funded studies have examined the growth suppression associated with modern once a day stimulant medications. Therefore, this study will precisely estimate the risks of stimulant induced growth suppression (SIGS), examine the underlying mechanisms and develop treatments for it. While drug holidays and caloric supplementation are two common treatments for SIGS, there has been little systematic investigation of either. It is unknown if they are effective or feasible. Therefore, using a randomized adaptive design, we will evaluate the efficacy and feasibility of these two practices vs. routine monitoring of growth in 180 prepubertal children with ADHD. An additional 50 subjects will be treated solely with behavioral therapies to evaluate for growth abnormalities associated with ADHD. The study will assess will the risk of SIGS with ER stimulants and the underlying mechanisms while providing evidenced-based treatments for its management.

Detailed Description
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The study will consist of 4 parts: Screening assessment to determine if a child has ADHD and would be a good candidate to have their ADHD treated with an extended release (ER) stimulant medication. If the answer to step one is yes, then the child will be randomly assigned to receive either medication treatment with an extended release MPH product (OROS MPH). 78% of children with start with this option with 22% assigned to behavioral therapy/counseling treatments for ADHD. There will be no placebo treatments used in this study. All children must be between the ages of 5 and 12 and never have taken stimulant medications for ADHD for more than one week to be eligible for the study. Initial Treatment Phase: The dose of the assigned treatment option will be gradually adjusted over the course of the first 3 months until the child's ADHD is well controlled. If the child is assigned to medication, he/she will start with a low dose of the ER MPH product, and it will be gradually increased until his/her ADHD is in good control. Children assigned to medication will be asked to take it every day of the week for at least the first 6 months. Children assigned to behavior therapy will be asked to avoid using medication for the first 6 months of the study. After month 6 if the first treatment is not effective, the child will be given the chance to try the other option. If any treatment is causing a concerning side effect, he/she can stop taking it at any time and we will provide him/her with other treatment options as part of the study. Ongoing Treatment Phase: We will continue to provide these ADHD treatments for a total of 30 months (2 1/2 years). The dose or type of therapy may be adjusted if needed. The child will be monitored every 1-3 months over this time span. Monitoring includes doctor visits to assess growth and side effects of medication, regular contact with his/her teacher to assess function at school and with you to assess function at home. In total, the child will receive study treatments for approximately 30 months and will be required to come to our center for a minimum of 18 follow up visits over this time. The average visit should take 30 minutes or less. Weight Recovery Phase: Any child whose body mass index or BMI declines by a concerning amount will be randomly assigned to receive 1 of 3 weight promotion treatments to stabilize his/her BMI in order to see if this prevents suppression of height (keeps them growing to be as tall as they should be). We do not expect children assigned to the behavior therapy arm to need these treatments, but the identical weight promotion treatments will be available for children in this group if the need arises. A) Extra monitoring: A doctor will check the child's growth every month (instead of every 3 months) until his/her BMI has returned to normal.The child will stay on the current daily dose of medication or behavior therapy. B) Caloric supplementation: Parents will be provided with a flavored calorie drink to give to your child every night and continue on the same daily dose and frequency of medication or behavior therapy. The child will have their growth monitored monthly by a study doctor. C) Drug Holiday: Participants will now only take medication on school days. Children assigned to behavior therapy will not participate in this treatment as they are not taking any study medication. The child will have their growth monitored monthly by a study doctor. Once the child's weight recovers, these extra treatments will end and he/she will return to the prior medication treatment (medication7 days a week or behavior therapy) in step 3 and to every 3 month growth assessments. Any time the child's BMI declines again, the extra treatments will restart again.

Official Title
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Novel Approach to Stimulant Induced Weight Suppression and Its Impact on Growth

Conditions
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ADHD, Growth

Intervention / Treatment
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* Behavioral: behavior therapy
* Drug: Extended release (ER) methylphenidate product
* Other: monitoring
* Other: drug holiday
* Dietary Supplement: caloric supplement


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: children meeting criteria for any subtype of ADHD between the ages of 5-12 who are stimulant naive Exclusion Criteria: Children who meet any of the following criteria will not be eligible to participate in this study: children with a Full Scale Intelligence Quotient (I below 70 as children with IQs less than this would likely not benefit from the behavior therapy intervention not in full time school or less than 5 or older than 12 years at the time of the screening visit children who have a history of seizures or other neurological problems and are taking medication to prevent seizures as stimulants could worsen seizures children with a history of other medical problems for whom psychostimulant treatment may involve considerable risk including cardiac arrhythmias, hypertension, Tourette's Disorder or history of severe tic exacerbations secondary to stimulant exposure children with a history of other medical problems that could impact appetite or weight such as hypothyroidism, diabetes mellitus, liver or renal disease. Also, children using prescription medication that can significantly impact appetite or weight are excluded children with a childhood history or diagnosis of any of the following mental health disorders: pervasive developmental disorder, schizophrenia or other psychotic disorders, bipolar disorder, post traumatic stress disorder, major depression with serious suicidal thoughts or an eating disorder as stimulants are not safe and effective treatments for these conditions, and these diseases could affect eating habits children whose Body Mass Index is very low (too light for safe use of stimulant medication) or is too high (overweight so not suitable for weight promotion treatments) children allergic to milk proteins as they are in the caloric supplement (lactose intolerance okay) children previously treated with stimulant medications for more than 30 days as this study is focusing on children who have never used stimulant medication before.

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: initial randomization to behavior or extended release stimulant (ER stimulant) arms. Participants in either arm meting criteria for a weight recovery intervention (based on change in zBMI) will be adaptively randomized to one of three weight recovery arms (Monitoring, Drug Holiday, Caloric Supplementation)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: weight recovery treatment- monitoring<br>Subjects in either the behavior therapy arm or the medication arm will be assigned to one of 3 treatments if subject does not meet projected BMI goals. In the monitoring arm , participants will continue on their ER stimulant 7 days a week and have their weight, height and BMI checked monthly. | Other: monitoring<br>* monthly weight, height and BMI checks<br>* Other names: monitoring arm;|
| Active Comparator: behavior therapy<br>10 week basic parent training, advanced 8 week parent training course. monthly boosters, option for individual parent training sessions, school consultant assigned to each subject | Behavioral: behavior therapy<br>* combination of individual and group parent training plus school consultation<br>* Other names: behavior modification;|
| Experimental: ER stimulant<br>daily use of 12 hour extended release methylphenidate product | Drug: Extended release (ER) methylphenidate product<br>* medication to be taken daily for duration of study unless assigned to weight promotion arm<br>* Other names: Central Nervous Systemt (CNS) stimulants;|
| Experimental: weight recovery treatment- caloric supplement<br>Subjects in either the behavior therapy arm or the medication arm will be assigned to one of 3 treatments if subject does not meet projected BMI goals. In the caloric supplement arm, participants will continue on their ER stimulant 7 days a week, have their weight, height and BMI checked monthly and be prescribed a 150 kcal caloric supplement to be consumed every evening. | Dietary Supplement: caloric supplement<br>* continue current ADHD regimen and add one 8oz liquid caloric supplement at night<br>|
| Experimental: weight recovery treatment- drug holiday<br>Subjects in either the behavior therapy arm or the medication arm will be assigned to one of 3 treatments if subject does not meet projected BMI goals. In the drug holiday arm, participants will only take their ER stimulant on school days a week and have their weight, height and BMI checked monthly. | Other: drug holiday<br>* switch from seven day a week dosing to medication only on school days<br>* Other names: Ritalin based product, CNS stimulants;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change Score for Z-height Baseline to Endpoint | The primary endpoint will be change in z-height at month 30 which is study endpoint. Measured as a zscore with more negative units reflecting smaller incremental height gain. Z units used to account for differences between groups in gender and age with both impact height at a fixed time. | month 30 or last assessment point | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change Score for z Weight | difference between baseline and endpoint (month 30 or last assessment point if did not finish study). Measured as a zscore with more negative units reflecting lesser weight gain. Z units used to account for differences between groups in gender and age with both impact weight at a fixed time. | baseline to month 30 or to last assessment point | 
| Change in zBody Mass Index (BMI) | BMI will be calculated at endpoint (month 30). Difference between baseline and endpoint (month 30 or last assessment point if did not finish study). Measured as a zscore with more negative units reflecting less BMI gain. Z units used to account for differences between groups in gender and age with both impact BMI at a fixed time. | baseline to month 30 or last assessment point | 
| Treatment Adherence for Caloric Supplement | percent of days caloric supplement were taken versus prescribed in caloric supplement arm | from entry to exit of caloric supplement arm | 
| ADHD Symptoms- Parent Rated | sum of score on 10 item IOWA Conners with range from 0 to 30 and higher values indicating more symptoms. Collected at end point or last assessment point. | at month 30 or last collected assessment point | 
| Change Score for Zheight Months 0 to 6 | in addition to the primary outcome of height at month 30, change in z-height from baseline to study month 6 post is also reported. Subjects who were still moderately impaired after 6 months in their initial treatment arm were allowed to cross over and receive the treatments in the other arm so prior to month 6 no participants randomized to behavior arm were prescribed study medication. This outcome includes all participants with 2+ growth assessments from the behavior therapy and ER stimulant arms. Doesn't include adaptive randomization arms (drug holiday, cal supplement, monitoring) as they didn't exist until 2nd randomization which did not occur until after this assessment period was over. Height converted to z score to account for differences in age and gender. More negative values reflecting smaller incremental height gain. If participant dropped out prior to month 6, then the last assessment point was used. | baseline to month 6 | 
| ADHD Symptoms- Teacher Rated | sum of items on 10 item IOWA Conners with range from 0-30 and larger values indicating greater symptoms. Collected at endpoint or last assessment point. | month 30 or last assessment point | 
| Medication Adherence | % of study days that study ADHD medication was taken when prescribed to be taken; behavior group could be prescribed medication if moderately impaired still after month 6. Once prescribed, all medication was prescribed to be taken 7 days a week except for in the drug holiday weight recovery arm. | denominator is number of days in study for which study med was prescribed | 
| Number of Behavior Therapy Sessions | Raw number of behavior therapy sessions attended; participants could cross over to other treatment arm if moderately impaired after 6 months in initial randomly assigned arm | months 0 through 30 | 
| Change in Height z Score During Weight Recovery Phase (Second Randomization) | difference in height z score from entry into weight recovery phase to exit from weight recovery phase (exact duration varied by participant). Randomization could not occur before month 6 (equaling a 24 month duration) but could start as late as month 29 (equaling a 1 month duration) of treatment based on the pattern of zBMI change by the individual participant. Z scores used to account for differences in age and gender. More negative values reflecting less incremental height gain. | between 1 month and 24 months | 
| Change in Weight z Score During Weight Recovery Phase (Second Randomization) | difference in weight z score from entry into weight recovery phase to exit from weight recovery phase (exact duration varied by participant). Randomization could not occur before month 6 (equaling a 24 month duration) but could start as late as month 29 (equaling a 1 month duration) of treatment based on the pattern of zBMI change by the individual participant. Z scores used to account for differences in age and gender. Larger values reflect a greater incremental weight gain. | 1 to 24 months duration | 
| Change in Zscore for BMI During Weight Recovery Phase (Second Randomization) | difference in BMI z score from entry into weight recovery phase to exit from weight recovery phase (exact duration varied by participant). Randomization could not occur before month 6 (equaling a 24 month duration) but could start as late as month 29 (equaling a 1 month duration) of treatment based on the pattern of zBMI change by the individual participant. Z scores used to account for differences in age and gender. Larger values reflecting a greater incremental BMI gain. | between 1 month and 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADHD, growth, BMI, stimulant medication