drugset / Trial / NCT05916339
AWARE: Management of ADHD in Autism Spectrum Disorder
Phase 4
Recruiting
500 enrolled
Daniel Coury
Children's Hospital Los Angeles · collabChildren's Hospital Medical Center, Cincinnati · collabChildren's Hospital of Philadelphia · collabHolland Bloorview Kids Rehabilitation Hospital · collabMaineHealth · collabMassachusetts General Hospital · collabNationwide Children's Hospital · collabPatient-Centered Outcomes Research Institute · collabUniversity of Alberta · collabUniversity of California, Irvine · collabUniversity of Michigan · collabUniversity of Pittsburgh · collabUniversity of Rochester · collabUniversity of Virginia · collab
RandomizedParallel-groupOpen-labelHealth-services research
Summary
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.
Timeline
- Start
- 2023-10-01
- Primary completion
- 2027-01-01
- Completion
- 2027-12-30
Publications
- Background Soke GN, Maenner MJ, Christensen D, Kurzius-Spencer M, Schieve LA. Prevalence of Co-occurring Medical and Behavioral Conditions/Symptoms Among 4- and 8-Year-Old Children with Autism Spectrum Disorder in Selected Areas of the United States in 2010. J Autism Dev Disord. 2018 Aug;48(8):2663-2676. doi: 10.1007/s10803-018-3521-1.
- Background Maenner MJ, Shaw KA, Baio J; EdS1; Washington A, Patrick M, DiRienzo M, Christensen DL, Wiggins LD, Pettygrove S, Andrews JG, Lopez M, Hudson A, Baroud T, Schwenk Y, White T, Rosenberg CR, Lee LC, Harrington RA, Huston M, Hewitt A; PhD-7; Esler A, Hall-Lande J, Poynter JN, Hallas-Muchow L, Constantino JN, Fitzgerald RT, Zahorodny W, Shenouda J, Daniels JL, Warren Z, Vehorn A, Salinas A, Durkin MS, Dietz PM. Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2016. MMWR Surveill Summ. 2020 Mar 27;69(4):1-12. doi: 10.15585/mmwr.ss6904a1.
- Background Loomes R, Hull L, Mandy WPL. What Is the Male-to-Female Ratio in Autism Spectrum Disorder? A Systematic Review and Meta-Analysis. J Am Acad Child Adolesc Psychiatry. 2017 Jun;56(6):466-474. doi: 10.1016/j.jaac.2017.03.013. Epub 2017 Apr 5.
- Background Neumeyer AM, Anixt J, Chan J, Perrin JM, Murray D, Coury DL, Bennett A, Farmer J, Parker RA. Identifying Associations Among Co-Occurring Medical Conditions in Children With Autism Spectrum Disorders. Acad Pediatr. 2019 Apr;19(3):300-306. doi: 10.1016/j.acap.2018.06.014. Epub 2018 Jul 24.
- Background Davignon MN, Qian Y, Massolo M, Croen LA. Psychiatric and Medical Conditions in Transition-Aged Individuals With ASD. Pediatrics. 2018 Apr;141(Suppl 4):S335-S345. doi: 10.1542/peds.2016-4300K.
- Background Spencer D, Marshall J, Post B, Kulakodlu M, Newschaffer C, Dennen T, Azocar F, Jain A. Psychotropic medication use and polypharmacy in children with autism spectrum disorders. Pediatrics. 2013 Nov;132(5):833-40. doi: 10.1542/peds.2012-3774. Epub 2013 Oct 21.
- Background Kuhlthau KA, McDonnell E, Coury DL, Payakachat N, Macklin E. Associations of quality of life with health-related characteristics among children with autism. Autism. 2018 Oct;22(7):804-813. doi: 10.1177/1362361317704420. Epub 2017 Jul 9.
- Background Lai MC, Kassee C, Besney R, Bonato S, Hull L, Mandy W, Szatmari P, Ameis SH. Prevalence of co-occurring mental health diagnoses in the autism population: a systematic review and meta-analysis. Lancet Psychiatry. 2019 Oct;6(10):819-829. doi: 10.1016/S2215-0366(19)30289-5. Epub 2019 Aug 22.
- Background Danielson ML, Bitsko RH, Ghandour RM, Holbrook JR, Kogan MD, Blumberg SJ. Prevalence of Parent-Reported ADHD Diagnosis and Associated Treatment Among U.S. Children and Adolescents, 2016. J Clin Child Adolesc Psychol. 2018 Mar-Apr;47(2):199-212. doi: 10.1080/15374416.2017.1417860. Epub 2018 Jan 24.
- Background Pastor P, Reuben C, Duran C, Hawkins L. Association between diagnosed ADHD and selected characteristics among children aged 4-17 years: United States, 2011-2013. NCHS Data Brief. 2015 May;(201):201.
- Background Wolraich ML, Hagan JF Jr, Allan C, Chan E, Davison D, Earls M, Evans SW, Flinn SK, Froehlich T, Frost J, Holbrook JR, Lehmann CU, Lessin HR, Okechukwu K, Pierce KL, Winner JD, Zurhellen W; SUBCOMMITTEE ON CHILDREN AND ADOLESCENTS WITH ATTENTION-DEFICIT/HYPERACTIVE DISORDER. Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics. 2019 Oct;144(4):e20192528. doi: 10.1542/peds.2019-2528.
- Background Newcorn JH, Kratochvil CJ, Allen AJ, Casat CD, Ruff DD, Moore RJ, Michelson D; Atomoxetine/Methylphenidate Comparative Study Group. Atomoxetine and osmotically released methylphenidate for the treatment of attention deficit hyperactivity disorder: acute comparison and differential response. Am J Psychiatry. 2008 Jun;165(6):721-30. doi: 10.1176/appi.ajp.2007.05091676. Epub 2008 Feb 15.
- Background Attention deficit hyperactivity disorder: diagnosis and management. London: National Institute for Health and Care Excellence (NICE); 2019 Sep. Available from http://www.ncbi.nlm.nih.gov/books/NBK493361/
- Background Bolea-Alamanac B, Nutt DJ, Adamou M, Asherson P, Bazire S, Coghill D, Heal D, Muller U, Nash J, Santosh P, Sayal K, Sonuga-Barke E, Young SJ; British Association for Psychopharmacology. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: update on recommendations from the British Association for Psychopharmacology. J Psychopharmacol. 2014 Mar;28(3):179-203. doi: 10.1177/0269881113519509. Epub 2014 Feb 12.
- Background Kooij SJ, Bejerot S, Blackwell A, Caci H, Casas-Brugue M, Carpentier PJ, Edvinsson D, Fayyad J, Foeken K, Fitzgerald M, Gaillac V, Ginsberg Y, Henry C, Krause J, Lensing MB, Manor I, Niederhofer H, Nunes-Filipe C, Ohlmeier MD, Oswald P, Pallanti S, Pehlivanidis A, Ramos-Quiroga JA, Rastam M, Ryffel-Rawak D, Stes S, Asherson P. European consensus statement on diagnosis and treatment of adult ADHD: The European Network Adult ADHD. BMC Psychiatry. 2010 Sep 3;10:67. doi: 10.1186/1471-244X-10-67.
- Background Pliszka S; AACAP Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007 Jul;46(7):894-921. doi: 10.1097/chi.0b013e318054e724.
- Background Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality Improvement and Management; Wolraich M, Brown L, Brown RT, DuPaul G, Earls M, Feldman HM, Ganiats TG, Kaplanek B, Meyer B, Perrin J, Pierce K, Reiff M, Stein MT, Visser S. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011 Nov;128(5):1007-22. doi: 10.1542/peds.2011-2654. Epub 2011 Oct 16.
- Background Biederman J, Melmed RD, Patel A, McBurnett K, Konow J, Lyne A, Scherer N; SPD503 Study Group. A randomized, double-blind, placebo-controlled study of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. Pediatrics. 2008 Jan;121(1):e73-84. doi: 10.1542/peds.2006-3695.
- Background Sallee FR, Lyne A, Wigal T, McGough JJ. Long-term safety and efficacy of guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2009 Jun;19(3):215-26. doi: 10.1089/cap.2008.0080.
- Background Jain R, Segal S, Kollins SH, Khayrallah M. Clonidine extended-release tablets for pediatric patients with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2011 Feb;50(2):171-9. doi: 10.1016/j.jaac.2010.11.005.
- Background Sallee FR, McGough J, Wigal T, Donahue J, Lyne A, Biederman J; SPD503 STUDY GROUP. Guanfacine extended release in children and adolescents with attention-deficit/hyperactivity disorder: a placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2009 Feb;48(2):155-65. doi: 10.1097/CHI.0b013e318191769e.
- Background Biederman J, Melmed RD, Patel A, McBurnett K, Donahue J, Lyne A. Long-term, open-label extension study of guanfacine extended release in children and adolescents with ADHD. CNS Spectr. 2008 Dec;13(12):1047-55. doi: 10.1017/s1092852900017107.
- Background Clemow DB, Bushe C, Mancini M, Ossipov MH, Upadhyaya H. A review of the efficacy of atomoxetine in the treatment of attention-deficit hyperactivity disorder in children and adult patients with common comorbidities. Neuropsychiatr Dis Treat. 2017 Feb 3;13:357-371. doi: 10.2147/NDT.S115707. eCollection 2017.
- Background Sikora DM, Vora P, Coury DL, Rosenberg D. Attention-deficit/hyperactivity disorder symptoms, adaptive functioning, and quality of life in children with autism spectrum disorder. Pediatrics. 2012 Nov;130 Suppl 2:S91-7. doi: 10.1542/peds.2012-0900G.
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- Background Mittal S, Boan AD, Kral MC, Lally MD, van Bakergem K, Macias MM, LaRosa A. Young Children with Attention-Deficit/Hyperactivity Disorder and/or Disruptive Behavior Disorders Are More Frequently Prescribed Alpha Agonists Than Stimulants. J Child Adolesc Psychopharmacol. 2020 Mar;30(2):81-86. doi: 10.1089/cap.2019.0105. Epub 2019 Oct 17.
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- Background Ghuman JK, Aman MG, Lecavalier L, Riddle MA, Gelenberg A, Wright R, Rice S, Ghuman HS, Fort C. Randomized, placebo-controlled, crossover study of methylphenidate for attention-deficit/hyperactivity disorder symptoms in preschoolers with developmental disorders. J Child Adolesc Psychopharmacol. 2009 Aug;19(4):329-39. doi: 10.1089/cap.2008.0137.
- Background Pearson DA, Santos CW, Aman MG, Arnold LE, Casat CD, Mansour R, Lane DM, Loveland KA, Bukstein OG, Jerger SW, Factor P, Vanwoerden S, Perez E, Cleveland LA. Effects of extended release methylphenidate treatment on ratings of attention-deficit/hyperactivity disorder (ADHD) and associated behavior in children with autism spectrum disorders and ADHD symptoms. J Child Adolesc Psychopharmacol. 2013 Jun;23(5):337-51. doi: 10.1089/cap.2012.0096.
- Background Scahill L, Bearss K, Sarhangian R, McDougle CJ, Arnold LE, Aman MG, McCracken JT, Tierney E, Gillespie S, Postorino V, Vitiello B. Using a Patient-Centered Outcome Measure to Test Methylphenidate Versus Placebo in Children with Autism Spectrum Disorder. J Child Adolesc Psychopharmacol. 2017 Mar;27(2):125-131. doi: 10.1089/cap.2016.0107. Epub 2016 Nov 28.
- Background Harfterkamp M, van de Loo-Neus G, Minderaa RB, van der Gaag RJ, Escobar R, Schacht A, Pamulapati S, Buitelaar JK, Hoekstra PJ. A randomized double-blind study of atomoxetine versus placebo for attention-deficit/hyperactivity disorder symptoms in children with autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2012 Jul;51(7):733-41. doi: 10.1016/j.jaac.2012.04.011. Epub 2012 May 25.
- Background Kilincaslan A, Mutluer TD, Pasabeyoglu B, Tutkunkardas MD, Mukaddes NM. Effects of Atomoxetine in Individuals with Attention-Deficit/Hyperactivity Disorder and Low-Functioning Autism Spectrum Disorder. J Child Adolesc Psychopharmacol. 2016 Nov;26(9):798-806. doi: 10.1089/cap.2015.0179. Epub 2016 May 26.
- Background Handen BL, Aman MG, Arnold LE, Hyman SL, Tumuluru RV, Lecavalier L, Corbett-Dick P, Pan X, Hollway JA, Buchan-Page KA, Silverman LB, Brown NV, Rice RR Jr, Hellings J, Mruzek DW, McAuliffe-Bellin S, Hurt EA, Ryan MM, Levato L, Smith T. Atomoxetine, Parent Training, and Their Combination in Children With Autism Spectrum Disorder and Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2015 Nov;54(11):905-15. doi: 10.1016/j.jaac.2015.08.013. Epub 2015 Sep 3.
- Background Scahill L, McCracken JT, King BH, Rockhill C, Shah B, Politte L, Sanders R, Minjarez M, Cowen J, Mullett J, Page C, Ward D, Deng Y, Loo S, Dziura J, McDougle CJ; Research Units on Pediatric Psychopharmacology Autism Network. Extended-Release Guanfacine for Hyperactivity in Children With Autism Spectrum Disorder. Am J Psychiatry. 2015 Dec;172(12):1197-206. doi: 10.1176/appi.ajp.2015.15010055. Epub 2015 Aug 28.
- Background Mahajan R, Bernal MP, Panzer R, Whitaker A, Roberts W, Handen B, Hardan A, Anagnostou E, Veenstra-VanderWeele J; Autism Speaks Autism Treatment Network Psychopharmacology Committee. Clinical practice pathways for evaluation and medication choice for attention-deficit/hyperactivity disorder symptoms in autism spectrum disorders. Pediatrics. 2012 Nov;130 Suppl 2:S125-38. doi: 10.1542/peds.2012-0900J.
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- Background Blum NJ, Shults J, Harstad E, Wiley S, Augustyn M, Meinzen-Derr JK, Wolraich ML, Barbaresi WJ. Common Use of Stimulants and Alpha-2 Agonists to Treat Preschool Attention-Deficit Hyperactivity Disorder: A DBPNet Study. J Dev Behav Pediatr. 2018 Sep;39(7):531-537. doi: 10.1097/DBP.0000000000000585.
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- Background Spencer TJ, Wilens TE, Biederman J, Weisler RH, Read SC, Pratt R. Efficacy and safety of mixed amphetamine salts extended release (Adderall XR) in the management of attention-deficit/hyperactivity disorder in adolescent patients: a 4-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2006 Feb;28(2):266-79. doi: 10.1016/j.clinthera.2006.02.011.
- Background Schumi J, Wittes JT. Through the looking glass: understanding non-inferiority. Trials. 2011 May 3;12:106. doi: 10.1186/1745-6215-12-106.
- Background D'Agostino RB Sr, Massaro JM, Sullivan LM. Non-inferiority trials: design concepts and issues - the encounters of academic consultants in statistics. Stat Med. 2003 Jan 30;22(2):169-86. doi: 10.1002/sim.1425.
- Background Zhang S, Faries DE, Vowles M, Michelson D. ADHD Rating Scale IV: psychometric properties from a multinational study as a clinician-administered instrument. Int J Methods Psychiatr Res. 2005;14(4):186-201. doi: 10.1002/mpr.7.
- Background Wangge G, Roes KC, de Boer A, Hoes AW, Knol MJ. The challenges of determining noninferiority margins: a case study of noninferiority randomized controlled trials of novel oral anticoagulants. CMAJ. 2013 Feb 19;185(3):222-7. doi: 10.1503/cmaj.120142. Epub 2012 Aug 20. No abstract available.
Drugs
| Evaluation | Drug | Modality | Dose | Route |
|---|---|---|---|---|
| Comparator | Amphetamine | Unknown | — | — |
| Comparator | Clonidine | Other / unclassified | — | — |
| Comparator | Guanfacine | Small molecule | — | — |
| Comparator | Methylphenidate | Small molecule | — | — |