Clinical trial NCT00796302: Treatment of Severe Childhood Aggression (The TOSCA Study)
Official title: Stimulant and Risperidone in Children With Severe Physical Aggression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Attention Deficit Disorder With Hyperactivity
Keywords: Conduct Disorder
Attention Deficit and Disruptive Behavior Disorders
Lead sponsor: Ohio State University
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2008-11-24
Enrollment: 168
Sex: ALL
Minimum age (years): 6
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will determine the safety and effectiveness of two medications for treating aggression in children with attention deficit hyperactivity disorder (ADHD).

Detailed description: ADHD is characterized by inattention, impulsivity, and hyperactivity. Children with ADHD sometimes also have disruptive behavior disorders (DBDs), such as conduct disorder (CD), which is estimated to develop in 20% to 40% of children with ADHD, and oppositional defiant disorder (ODD), which is estimated to develop in 33% to 50% of children with ADHD. These two disorders place youth at risk of other psychiatric disorders, especially substance abuse disorders. Several medications have been tested to treat conduct disorders in aggressive children, and, among these, risperidone and methylphenidate hydrochloride (HCl) have relatively good records of safety and tolerability. Psychostimulants, such as methylphenidate HCl, can reduce the symptoms in some, but not all, children with DBDs. Combining methylphenidate HCl with risperidone may be one way to increase the effectiveness of drug treatments. This study will compare the effectiveness of methylphenidate HCl alone versus methylphenidate HCl combined with risperidone for treating aggressive behavior in children with ADHD. Participation in this study will last 1 year. The child participant and a parent will attend all study visits. Two initial visits will involve a battery of baseline tests, including a psychological clinical interview, physical examination, lab tests, and an electrocardiogram (ECG). The parents will undergo a parent education session and complete questionnaires about their child's behavior, emotions, and medication side effects. The child will have his or her vital signs measured and complete tests of verbal memory and attention and impulsiveness. After the second visit, the child participant will be randomly assigned to receive either methylphenidate HCl alone or methylphenidate HCl plus risperidone.

For the next 3 weeks, all child participants will take methylphenidate HCl at a dose that will start low and gradually be increased until the most effective dose is determined. For the next 6 weeks, child participants will add either risperidone or a placebo to their regimen of methylphenidate HCl. This second medication will also be started at a low dose and raised to appropriate levels of tolerability. During the 9 weeks of medication adjustment, participants will attend weekly study visits to complete questionnaires and have their vital signs measured. Parents will attend education sessions at each of these visits. The child's teacher will also fill out weekly questionnaires on the child's behavior. Every 3 weeks, child participants will be tested on verbal memory, attention, and impulsiveness. After the 9-week period, child participants will again undergo a physical exam, lab tests, and an ECG.

At this point, if the child's behavior has improved, the child will continue the same treatment for the next 3 months. Monthly study visits will include parent education sessions and recording of parent and teacher evaluations of the child. All participants will attend a 1-year follow-up visit that will include previous assessments.

Eligibility criteria: Inclusion Criteria:

* DSM-IV diagnosis of ADHD, any subtype
* DSM-IV diagnosis of a disruptive behavior disorder, including CD or ODD
* Evidence of serious physical aggression, as rated on the Overt Aggression Scale-Modified, and as determined by parent or guardian ratings on the NCBRF D-Total Score. In addition, the blinded clinician must assign a clinical global impressions severity score of 4 or greater for aggression.
* Prior to random assignment, participants must be free of all psychotropic medicines for 2 weeks for most drugs (such as most antidepressants, alpha agonists, beta blockers, anxiolytics, mood stabilizers, and antihistamines), and 4 weeks for depot antipsychotics and fluoxetine.

Exclusion Criteria:

* Full-scale IQ below 71
* Pregnancy or a history of seizure disorder or other neurological or medical disorders for which medication may present a considerable risk
* Abnormal liver function
* Pervasive developmental disorder, schizophrenia or other psychotic disorders, or eating disorders
* Currently taking other psychotropic medications from which discontinuation would present a significant risk. Participants may not discontinue a satisfactory medication to participate.
* Presence or history of major depressive disorder
* Diagnosis of bipolar disorder
* A hypomanic/biphasic score of 36 or greater as rated by child's parent on the General Behavior Inventory and confirmed by clinician as indication of mood disorder
* Active substance abuse disorder or lack of control of substance use that does not allow for safe medication administration
* Evidence of current child abuse or neglect
* History of suicide attempt in the past year or current suicidal ideation with plan and/or intent
* Family history of type II diabetes in two or more first degree relatives, defined as biological parents and/or full biological siblings

Primary outcomes:
measure: NCBRF-TIQ D-Total Score
timeFrame: Measured at baseline and Weeks 3, 4, 5, 6, 7, 8, 9
Secondary outcomes:
Other outcomes:
measure: Antisocial Behavior Scale - Reactive Aggression Subscale
timeFrame: Measured at baseline and Week 9
measure: Clinical Global Impressions Scale for Improvement
timeFrame: Measured at endpoint visit
measure: Clinical Global Impressions Scale for Severity of Illness
timeFrame: Measured at endpoint visit
Locations:
city: Stony Brook
country: United States
facility: State University of New York Stony Brook
state: New York
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Nisonger Center
state: Ohio
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
Study officials:
affiliation: Ohio State University
name: Michael G. Aman, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Pittsburgh
name: Oscar G. Bukstein, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: State University of New York Stony Brook
name: Kenneth D. Gadow, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Case Western Reserve University
name: Robert L. Findling, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Aman MG, Bukstein OG, Gadow KD, Arnold LE, Molina BS, McNamara NK, Rundberg-Rivera EV, Li X, Kipp H, Schneider J, Butter EM, Baker J, Sprafkin J, Rice RR Jr, Bangalore SS, Farmer CA, Austin AB, Buchan-Page KA, Brown NV, Hurt EA, Grondhuis SN, Findling RL. What does risperidone add to parent training and stimulant for severe aggression in child attention-deficit/hyperactivity disorder? J Am Acad Child Adolesc Psychiatry. 2014 Jan;53(1):47-60.e1. doi: 10.1016/j.jaac.2013.09.022. Epub 2013 Nov 18.
citation: Kaat A, Farmer C, Gadow K, Findling RL, Bukstein O, Arnold LE, Bangalore S, McNamara N, Aman M. Factor Validity of a Proactive and Reactive Aggression Rating Scale. J Child Fam Stud. 2015 Sep 1;24(9):2734-2744. doi: 10.1007/s10826-014-0075-5. Epub 2014 Nov 27.
citation: Farmer CA, Brown NV, Gadow KD, Arnold LE, Kolko DG, Findling RL, Molina BS, Buchan-Page KA, Rice RR Jr, Bangalore SS, Bukstein O, Rundberg-Rivera EV, McNamara N, Aman MG. Comorbid symptomatology moderates response to risperidone, stimulant, and parent training in children with severe aggression, disruptive behavior disorder, and attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol. 2015 Apr;25(3):213-24. doi: 10.1089/cap.2014.0109.
citation: Rundberg-Rivera EV, Townsend LD, Schneider J, Farmer CA, Molina BB, Findling RL, Gadow KD, Bukstein OG, Arnold LE, Kolko DJ, Buchan-Page KA, McNamara NK, Michel C, Austin A, Kipp H, Rice RR, Aman MG. Participant satisfaction in a study of stimulant, parent training, and risperidone in children with severe physical aggression. J Child Adolesc Psychopharmacol. 2015 Apr;25(3):225-33. doi: 10.1089/cap.2014.0097.
citation: Arnold LE, Gadow KD, Farmer CA, Findling RL, Bukstein O, Molina BS, Brown NV, Li X, Rundberg-Rivera EV, Bangalore S, Buchan-Page K, Hurt EA, Rice R, McNamara NK, Aman MG. Comorbid anxiety and social avoidance in treatment of severe childhood aggression: response to adding risperidone to stimulant and parent training; mediation of disruptive symptom response. J Child Adolesc Psychopharmacol. 2015 Apr;25(3):203-12. doi: 10.1089/cap.2014.0104.
citation: Gadow KD, Arnold LE, Molina BS, Findling RL, Bukstein OG, Brown NV, McNamara NK, Rundberg-Rivera EV, Li X, Kipp HL, Schneider J, Farmer CA, Baker JL, Sprafkin J, Rice RR Jr, Bangalore SS, Butter EM, Buchan-Page KA, Hurt EA, Austin AB, Grondhuis SN, Aman MG. Risperidone added to parent training and stimulant medication: effects on attention-deficit/hyperactivity disorder, oppositional defiant disorder, conduct disorder, and peer aggression. J Am Acad Child Adolesc Psychiatry. 2014 Sep;53(9):948-959.e1. doi: 10.1016/j.jaac.2014.05.008. Epub 2014 Jun 12.
citation: Grondhuis SN, Farmer CA, Arnold LE, Gadow KD, Findling RL, Molina BSG, Kolko DJ, Buchan-Page KA, Rice RR , Jr, Butter EM, Aman MG. Standardized Observation Analogue Procedure in the Treatment of Severe Childhood Aggression Study. J Child Adolesc Psychopharmacol. 2020 Feb;30(1):48-54. doi: 10.1089/cap.2019.0109. Epub 2019 Nov 15.
citation: Barterian JA, Arnold LE, Brown NV, Farmer CA, Williams C, Findling RL, Kolko DJ, Bukstein OG, Molina BSG, Townsend L, Aman MG. Clinical Implications From the Treatment of Severe Childhood Aggression (TOSCA) Study: A Re-Analysis and Integration of Findings. J Am Acad Child Adolesc Psychiatry. 2017 Dec;56(12):1026-1033. doi: 10.1016/j.jaac.2017.09.426. Epub 2017 Oct 6.
citation: Farmer CA, Epstein JN, Findling RL, Gadow KD, Arnold LE, Kipp H, Kolko DJ, Butter E, Schneider J, Bukstein OG, McNamara NK, Molina BS, Aman MG. Risperidone Added to Psychostimulant in Children with Severe Aggression and Attention-Deficit/Hyperactivity Disorder: Lack of Effect on Attention and Short-Term Memory. J Child Adolesc Psychopharmacol. 2017 Mar;27(2):117-124. doi: 10.1089/cap.2016.0040. Epub 2016 Jun 27.
citation: Gadow KD, Brown NV, Arnold LE, Buchan-Page KA, Bukstein OG, Butter E, Farmer CA, Findling RL, Kolko DJ, Molina BS, Rice RR Jr, Schneider J, Aman MG. Severely Aggressive Children Receiving Stimulant Medication Versus Stimulant and Risperidone: 12-Month Follow-Up of the TOSCA Trial. J Am Acad Child Adolesc Psychiatry. 2016 Jun;55(6):469-78. doi: 10.1016/j.jaac.2016.03.014. Epub 2016 Apr 13.
citation: Farmer CA, Arnold LE, Bukstein OG, Findling RL, Gadow KD, Li X, Butter EM, Aman MG. The treatment of severe child aggression (TOSCA) study: Design challenges. Child Adolesc Psychiatry Ment Health. 2011 Nov 10;5(1):36. doi: 10.1186/1753-2000-5-36.