Treatment of Severe Childhood Aggression (The TOSCA Study)

Michael Aman

Status and phase: Completed; Phase 4

Conditions: Attention Deficit Disorder With Hyperactivity

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

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00796302

1R01MH077907-01A2 (U.S. NIH Grant/Contract)

DSIR 84-CTS

1R01MH077750-01A2 (U.S. NIH Grant/Contract)

1R01MH077676-01A2 (U.S. NIH Grant/Contract)

1R01MH077997-01A2 (U.S. NIH Grant/Contract)

R01MH077907

Details and patient eligibility

About

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

Full 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.

Enrollment: 168 patients

Sex: All

Ages: 6 to 12 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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168 participants in 2 patient groups

1

Experimental group

Description:

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

Treatment:

Behavioral: Parent Management Training (PMT)

Drug: Risperidone

Drug: Methylphenidate HCl

2

Active Comparator group

Description:

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

Treatment:

Behavioral: Parent Management Training (PMT)

Drug: Methylphenidate HCl

Drug: Placebo