Management of ADHD in Autism Spectrum Disorder

Study Overview
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Brief Summary
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This study is a pragmatic clinical trial examining the comparative effectiveness of two stimulant medications (methylphenidate and amphetamine) in the treatment of ADHD in children and adolescents with autism. Using a sequential, multiple assignment randomization trial (SMART) design the study will not only assess these two medications but also the role of an increasingly popular class of ADHD medication, the alpha-2 agonists. Findings from this study will help improve clinicians' approach to medication selection and reduce the repeated trials of multiple medications that are current standard care.

Detailed Description
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Current data shows that 1 in 54 children in the United States are diagnosed with autism spectrum disorder (ASD). Additional data shows that those diagnosed with autism are also at risk for being diagnosed with a co-occurring condition such as attention deficit/hyperactivity disorder (ADHD). Managing the symptoms of each can be challenging for providers, patients, and parents. Patients with ASD who are diagnosed with ADHD often face the challenge of finding the best medication options to treat symptoms. It is known that children with ASD and ADHD frequently respond differently to these treatments than typically developing (TD) children. Currently, no clear recommendations exist for parents or providers to follow to guide best medication options for patients with ASD and ADHD. This lack of medication knowledge and suboptimal medication management can lead to poor results and have substantial negative life impact for patients and their families. The main goal of this study is to determine if the most prescribed medications for ADHD in TD children are similarly effective for patients who also have a diagnosis of autism. The results of this study will improve provider understanding of first-line stimulant medicines, methylphenidate and amphetamine compound, with ASD patients. Parents will determine medication effectiveness through discussion with their child and with their doctor as well as their own observations and will drive the medication adjustment process. Parents will provide ratings of effectiveness using the Clinical Global Impression measure every two weeks and the Aberrant Behavior Checklist and the Vanderbilt Parent Rating Scale will be completed monthly. For those patients who do not respond to first-line medicines, this study will further develop the understanding of second-line medication options, the alpha2 agonists guanfacine and clonidine. Parents will provide ratings using the same measures as before. Additional study measures will collect and review parent/caregiver input in the process of determining medication continuation. Most measures will be completed through electronic portals, reducing the need for families to come to the hospital to participate in this study. While these medications are routinely prescribed to treat ADHD in children and adolescents with ASD, their relative effectiveness is not known. Randomizing participants to these different medicines in this format, called a SMART (Sequential Multiple Assignment Randomization Trial) design, will provide data on how well these medications work in children with ASD and ADHD, how they work compared to each other, and how their side effects differ from use in TD children. This study will also examine the effect of these medicines on target problems identified by parents, such as oppositional behavior. Parents/caregivers will be a significant part of the data and input captured to determine if medication should continue or be discontinued. The care team of patient, parent, and provider is solid in this project and will lead to optimal decision pathways for future patients with autism. The aims outlined in this study are beneficial to patients with autism and their families/caregivers who often help navigate health care with them for life. Having access to evidence-based best practices when making medication decisions can impact and expedite positive outcomes in managing the symptoms of ADHD. When symptoms are managed at optimal levels, patients can focus on building life skills and accessing opportunities toward meaningful life outcomes. Coproduced with parents and providers, this study is designed to reduce the trial and error aspect of prescribing ADHD medications and build provider and parent knowledge in best practice. The patient and family voice are an integral part of the study design process. This coproduction of treatment evidence helps ensure best outcomes for the patient and is supported by the inclusion of stakeholders. Participants will be children 4 to 17 years of age recruited from The Autism Care Network, the first and only network of its kind focused on better autism care, delivered at scale and at speed, to improve health and quality of life for children with autism and their families throughout North America. Twelve of the 20 network sites will participate in this study, each with providers and patients' parents committed to ensuring more than 500 patients will be part of this study and who are also committed to continuously improving whole-person and whole-family autism care.

Official Title
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Efficacy of Pharmacologic Management of ADHD in Children and Youth With Autism Spectrum Disorder

Conditions
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ADHD, Autism Spectrum Disorder

Intervention / Treatment
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* Drug: Randomization to either Amphetamine (AMP) class of stimulant medication or Methylphenidate (MPH) class of stimulant medication
* Drug: Randomization to either Alpha 2 agonist class of medication or alternate class of stimulant.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient and/or legally authorized representative must be willing and able to give informed consent/assent for participation in this study. Patient and their caregiver must be willing and able (in the Investigator's opinion) to comply with all study requirements. Patient must be between 4 and 17 years of age (inclusive) at time of enrollment. Patient must have a confirmed diagnosis of ASD based on supportive evidence (e.g. referring physician's report, medical records, such as ADOS (Autism Diagnostic Observation Schedule) or CARS (Childhood Autism Rating Scale), etc.). Patient must have the ability to consistently take medication (via pill, liquid or mixed with food/liquid). Patient must have a confirmed diagnosis of ADHD (based upon DSM-5 criteria and supportive evidence). Patient must have a consistent reporter (e.g., parent) who spends regular time with the child. Patient can be on other psychotropic medications (selective serotonin reuptake inhibitor (SSRI), atypical antipsychotic, anticonvulsant) if dose has been stable for > 4 weeks prior to consent with no plans for a dose change during the study. Patient with prior trial of ADHD medication more than one year before enrollment, based on clinician judgement of reason for prior trial failure. Patient and/or family/caregiver must be sufficiently fluent in English or Spanish to be able to complete questionnaires relevant to this study. Exclusion Criteria: Patient history of more than one prior trial of an ADHD medication within the past year. Less than 4 weeks since last ADHD medication was taken. Any other risk factor that might prevent patient from safely taking the study medications. There are no inclusion/exclusion criteria based upon participant IQ. We will include individuals across the entire range of cognition, just as practitioners are asked to treat ADHD in children with ASD across the entire IQ range.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 17 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: Health Services Research
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Stage 1 - Stimulant<br>This proposed naturalistic, pragmatic clinical trial does not involve investigational drugs. Sequential, multiple assignment randomized trial (SMART) pragmatic clinical trial. Stage 1 - randomization to either Amphetamine (AMP) or Methylphenidate (MPH). The specific medication prescribed by the physician will be determined by discussion between physician and parent / caregiver and review of the subject's insurance coverage. Subjects will receive their medication from their pharmacy. | Drug: Randomization to either Amphetamine (AMP) class of stimulant medication or Methylphenidate (MPH) class of stimulant medication<br>* Amphetamine (AMP) medication names: Adderall, Adderall XR, Adzenys ER, Adzenys XR-ODT, Dayanavel XR, Dexedrine (spansule), Dexedrine (tablet), Mydayis, Procentra liquid Methylphenidate (MPH) medication names: Adhansia XR, Aptensio XR, Azstarys, Concerta, Cotempla XR-ODT, Daytrana, Focalin, Focalin XR, Jornay PM. Metadate CD, Methylin (liquid), Ritalin, Ritalin LA, Quillichew ER, Quillivant XR (liquid)<br>|
| Active Comparator: Stage 2 - Alpha-2 Agonist or Alternate Stimulant<br>Stage 2 - randomization to either Alpha-2 Agonist or other stimulant not randomized to in Stage 1: Amphetamine (AMP) or Methylphenidate (MPH). (frequency, dosage, format, and duration dependent on participant and study doctor discussion). | Drug: Randomization to either Alpha 2 agonist class of medication or alternate class of stimulant.<br>* If first line stimulant therapy (Amphetamine/Methylphenidate) is deemed not effective or tolerable, re-randomization to the alternate stimulant or alpha-2 agonist will occur. If participant is satisfied with first line stimulant treatment, first-line stimulant therapy will continue. Catapres, Clonidine, Guanfacine, Intuniv, Kapvay, Tenex<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Vanderbilt Parent Rating Scale | The primary outcome measure is The Vanderbilt Parent Rating Scale for ADHD consists of 18 item, each scored from 0 to 3. It has a minimum score of 0, maximum score of 54. Higher scores indicate worse outcome. | 16 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parent reported Clinical Global Impression | Parent reported Clinical Global Impression - Improvement is a Likert scale ranging from 1 to 7. Higher scores indicate worse outcome. | 16 Weeks | 
| Aberrant Behavior Checklist- Hyperactivity/Impulsivity subscale | Aberrant Behavior Checklist- Hyperactivity/Impulsivity subscale consists of 16 items, each scored from 0 to 3. It has a minimum score of 0, maximum score of 48. Higher scores indicate worse outcome. | 16 Weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADHD, Autism, ASD