Treatment of Severe Childhood Aggression (The TOSCA Study) - Full Text View

Purpose

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

Condition	Intervention	Phase
Attention Deficit Disorder With Hyperactivity	Drug: Methylphenidate HCl Drug: Risperidone Behavioral: Parent Management Training (PMT) Drug: Placebo	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Stimulant and Risperidone in Children With Severe Physical Aggression

Resource links provided by NLM:

MedlinePlus related topics: Attention Deficit Hyperactivity Disorder Premenstrual Syndrome

Drug Information available for: Methylphenidate Methylphenidate hydrochloride Risperidone

U.S. FDA Resources

Further study details as provided by Ohio State University:

Primary Outcome Measures:

Parent ratings of aggression and hostility on the Nisonger Child Behavior Rating Form-Typical IQ (NCBRF-TIQ) D-Total Score [ Time Frame: Measured at baseline and Weeks 3, 5, 7, 9, 13, 17, 21, and 52 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

The NCBRF-TIQ Version Subscales [ Time Frame: Measured at baseline and Weeks 3, 5, 7, 9, 13, 17, 21, and 52 ] [ Designated as safety issue: No ]
Clinical Global Impressions Scale for Improvement [ Time Frame: Measured at baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 13, 17, 21, and 52 ] [ Designated as safety issue: No ]
Standard Observation Analogue Procedures [ Time Frame: Measured at baseline and Weeks 9 and 52 ] [ Designated as safety issue: No ]
Antisocial Behavior Scale [ Time Frame: Measured at baseline and Weeks 9 and 52 ] [ Designated as safety issue: No ]
Adverse Events Log [ Time Frame: Measured at baseline and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 13, 17, 21, and 52 ] [ Designated as safety issue: Yes ]
Cognitive Battery [ Time Frame: Measured at baseline and Weeks 3, 9, 21, and 52 ] [ Designated as safety issue: No ]

Enrollment:	168
Study Start Date:	August 2008
Estimated Study Completion Date:	July 2013
Primary Completion Date:	November 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 1 Children will receive active methylphenidate HCl and active risperidone. Parents will receive parent management training.	Drug: Methylphenidate HCl 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. Other Name: Concerta Drug: Risperidone 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. Other Name: Risperdal Behavioral: Parent Management Training (PMT) 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. Other Name: Community Parent Education Program
Active Comparator: 2 Children will receive methylphenidate HCl and placebo instead of the active risperidone. Parents will receive parent management training.	Drug: Methylphenidate HCl 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. Other Name: Concerta Behavioral: Parent Management Training (PMT) 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. Other Name: Community Parent Education Program Drug: Placebo One pill will be taken once daily for the first 4 days and then twice daily until Week 21.

Arms

Assigned Interventions

Experimental: 1

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

Drug: Methylphenidate HCl

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.

Other Name: Concerta

Drug: Risperidone

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.

Other Name: Risperdal

Behavioral: Parent Management Training (PMT)

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.

Other Name: Community Parent Education Program

Active Comparator: 2

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

Drug: Methylphenidate HCl

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.

Other Name: Concerta

Behavioral: Parent Management Training (PMT)

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.

Other Name: Community Parent Education Program

Drug: Placebo

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

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

Ages Eligible for Study:	6 Years to 12 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00796302

Locations

United States, New York
State University of New York Stony Brook
Stony Brook, New York, United States, 11794
United States, Ohio
Case Western Reserve University
Cleveland, Ohio, United States, 44106
Ohio State University Nisonger Center
Columbus, Ohio, United States, 43210
United States, Pennsylvania
University of Pittsburgh
Pittsburgh, Pennsylvania, United States, 15213

Sponsors and Collaborators

Michael Aman

Investigators

Principal Investigator:	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

More Information

No publications provided

Responsible Party:	Michael Aman, Retiree-Faculty, The Ohio State University
ClinicalTrials.gov Identifier:	NCT00796302 History of Changes
Other Study ID Numbers:	R01 MH077907, DSIR 84-CTS, 1R01MH077907-01A2, 1R01MH077676-01A2, 1R01MH077750-01A2, 1R01MH077997-01A2
Study First Received:	November 21, 2008
Last Updated:	May 16, 2013
Health Authority:	United States: Federal Government

Keywords provided by Ohio State University:

Conduct Disorder
Attention Deficit and Disruptive Behavior Disorders

Additional relevant MeSH terms:

Aggression
Attention Deficit Disorder with Hyperactivity
Hyperkinesis
Behavioral Symptoms
Attention Deficit and Disruptive Behavior Disorders
Mental Disorders Diagnosed in Childhood
Mental Disorders
Dyskinesias
Neurologic Manifestations
Nervous System Diseases
Signs and Symptoms
Methylphenidate
Risperidone
Dopamine Uptake Inhibitors
Dopamine Agents

Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Neurotransmitter Uptake Inhibitors
Physiological Effects of Drugs
Central Nervous System Stimulants
Central Nervous System Agents
Therapeutic Uses
Serotonin Antagonists
Serotonin Agents
Antipsychotic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs
Dopamine Antagonists

ClinicalTrials.gov processed this record on May 16, 2013