Treatment of Severe Childhood Aggression (The TOSCA Study)

NCT00796302 | Completed Phase 4 Results DMC

• 6 other identifiers: R01MH077907DSIR 84-CTS1R01MH077907-01A21R01MH077676-01A21R01MH077750-01A21R01MH077997-01A2
• Study Type: interventional
• Target: 168
• Locations: 1 country
• Sites: 4

Brief Summary

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

Conditions

Attention Deficit Disorder With Hyperactivity

Keywords

Conduct Disorder; Attention Deficit and Disruptive Behavior Disorders

Outcome Measures

Primary Outcomes (1)

• NCBRF-TIQ D-Total Score

  Parent ratings of aggression and hostility on the Nisonger Child Behavior Rating Form-Typical IQ (NCBRF-TIQ) D-Total Score. The NCBRF provides 1 prosocial subscale (Positive/Social) and 6 problem behavior subscales (Conduct Problem, Oppositional Behavior, Hyperactive, Inattentive, Overly Sensitive, and Withdrawn/Dysphoric). The NCBRF has excellent internal consistency, distinguishes between controls and subjects with DBDs. Conduct Problem and Oppositional Behavior subscales map closely to DSM-IV-TR symptoms of CD and ODD; they were scored together to form a variable called the D-Total. For the NCBRF D-Total, higher scores reflect worse behavior. Each subscale is scored by taking the rating (0 \[did not occur or was not a problem\] to 3 \[occurred a lot or was a very severe problem\]) for all component items. The D-Total score was computed by adding the 6 scores from the Oppositional subscale and the 10 items from the Conduct Problem subscale. Thus D-Total scores could range from 0-69.

  Measured at baseline and Weeks 3, 4, 5, 6, 7, 8, 9

Other Outcomes (3)

• Antisocial Behavior Scale - Reactive Aggression Subscale

  Measured at baseline and Week 9

• Clinical Global Impressions Scale for Improvement

  Measured at endpoint visit

• Clinical Global Impressions Scale for Severity of Illness

  Measured at endpoint visit

Study Arms (2)

1

EXPERIMENTAL

Children will receive active methylphenidate HCl and active risperidone. Parents will receive parent management training.

Drug: Methylphenidate HCl; Drug: Risperidone; Behavioral: Parent Management Training (PMT)

2

ACTIVE COMPARATOR

Children will receive methylphenidate HCl and placebo instead of the active risperidone. Parents will receive parent management training.

Drug: Methylphenidate HCl; Behavioral: Parent Management Training (PMT); Drug: Placebo

Interventions

Methylphenidate HCl DRUG

For children weighing less than 25 kg, the dose will be titrated at 18 mg for the first 7 days, 36 mg for the next 4 days, and, if needed, 54 mg for the next 4 days. For children weighing more than 25 kg, the dose will be titrated at 18 mg for the first 4 days, 36 mg for the next 3 days, 54 mg for the next 4 days, and 72 mg for the next 3 days. Once the child's optimal dose is established, he or she will continue on that dose for the rest of the 21-week trial. One pill is taken once daily.

Also known as: Concerta

1; 2

Risperidone DRUG

For children weighing less than 45 kg, the dose will start at 0.5 mg at night. After 4 days, the child's dose may be increased to 1 mg a day. On Day 8, the child's dose may be increased to 1.5 mg a day. On Day 16, the child's dose may be increased to 2.0 mg a day. On Day 22, the child's dose may be increased to 2.5 mg a day. For children weighing more than 45 kg, the dose will start at 0.5 mg at night. After 4 days, the child's dose may be increased to 1.0 mg a day. On Day 8, the child's dose may be increased to 1.5 mg a day. On Day 12, the child's dose may be increased to 2.0 mg a day. On Day 15, the child's dose may be increased to 2.5 mg a day. On Day 18, the child's dose may be increased to 3 mg a day. On Day 23, the child's dose may be increased to 3.5 mg a day.

Also known as: Risperdal

1

Parent Management Training (PMT) BEHAVIORAL

PMT will include individual parent sessions held weekly for 9 weeks, with two booster sessions to be completed during the 3-month extension. Sessions will include development of problem-solving skills and behavior management strategies, practice activities, and role-playing with the behavioral therapist.

Also known as: Community Parent Education Program

1; 2

Placebo DRUG

One pill will be taken once daily for the first 4 days and then twice daily until Week 21.

2

Eligibility Criteria

• Age: 6 Years - 12 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Michael Aman: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (4)

State University of New York Stony Brook

Stony Brook, New York, 11794, United States

Location

Case Western Reserve University

Cleveland, Ohio, 44106, United States

Location

Ohio State University Nisonger Center

Columbus, Ohio, 43210, United States

Location

University of Pittsburgh

Pittsburgh, Pennsylvania, 15213, United States

Location

Related Publications (11)

• 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.

  PMID: 24342385 RESULT

• 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.

  PMID: 26504369 RESULT

• 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.

  PMID: 25885011 RESULT

• 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.

  PMID: 25885012 RESULT

• 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.

  PMID: 25885010 RESULT

• 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.

  PMID: 25151418 RESULT

• 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.

  PMID: 31730370 DERIVED

• 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.

  PMID: 29173736 DERIVED

• 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.

  PMID: 27348211 DERIVED

• 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.

  PMID: 27238065 DERIVED

• 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.

  PMID: 22074813 DERIVED

MeSH Terms

Conditions

Attention Deficit Disorder with Hyperactivity; Conduct Disorder; Attention Deficit and Disruptive Behavior Disorders

Interventions

Methylphenidate; Risperidone

Condition Hierarchy (Ancestors)

Neurodevelopmental Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Phenylacetates; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidinones; Pyrimidines

Limitations and Caveats

These results were obtained with children selected for severity of aggression and disruptive behavior, and the risk-benefit ratio may well be decreased for children with milder disruptive behavior or no physical aggression.

Results Point of Contact

• Title: Michael Aman
• Organization: Ohio State University

Aman.1@osu.edu

614-688-4196

Study Officials

• Michael G. Aman, PhD

  Ohio State University

  PRINCIPAL INVESTIGATOR

• Oscar G. Bukstein, MD, MPH

  University of Pittsburgh

  PRINCIPAL INVESTIGATOR

• Kenneth D. Gadow, PhD

  State University of New York Stony Brook

  PRINCIPAL INVESTIGATOR

• Robert L. Findling, MD

  Case Western Reserve University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Retiree-Faculty

Study Record Dates

• First Submitted: November 21, 2008
• First Posted: November 24, 2008
• Study Start: August 1, 2008
• Primary Completion: November 1, 2012
• Study Completion: November 1, 2012
• Last Updated: July 26, 2017
• Results First Posted: April 20, 2016

Record last verified: 2017-06

Locations

US (4)