Intuniv vs Placebo in the Treatment of Childhood Intermittent Explosive Disorder

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Brief Title

Intuniv vs Placebo in the Treatment of Childhood Intermittent Explosive Disorder

Official Title

Intuniv vs Placebo in the Treatment of Childhood Intermittent Explosive Disorder

Brief Summary

      Children with explosive aggression are often rejected by their peers, placed in special
      classroom, and contribute to family discord. When psychotherapy and family therapy is
      unsuccessful, medications are often used. Current medications are stimulants (e.g.
      methylphenidate, dextroamphetamine), anticonvulsants (e.g. Divalproex) and antipsychotics
      (olanzapine, risperidone). At this time, the available medications are of limited usefulness,
      either because they do not always work or because they have side effects such as weight gain
      or insomnia. There is a clear need for new medications to treat explosive aggression when
      psychotherapy is unsuccessful.

      The hypothesis of this study is the medication Intuniv when combined with psychotherapy will
      be more helpful to children with explosive aggression than placebo combined with
      psychotherapy. Intuniv is a long acting form of guanfacine, a medication approved by the FDA
      for treatment of Attention Deficit Hyperactivity Disorder. Intuniv is not a stimulant, nor is
      it an anticonvulsant, nor is it an antipsychotic.

      The children in this study will be between the ages of 6 and 12 and meet Diagnostic and
      Statistical Manual of Psychiatry Fourth Edition, Text Revision (DSM-IV-TR) criteria for
      Intermittent Explosive Disorder.
    

Detailed Description

      Aggressive children are often alienated from parents, separated from peers, placed in special
      education and segregated with other aggressive children. While predatory (i.e. planned, goal
      directed, reward driven) aggression is not responsive to pharmacologic treatment, non
      predatory (impulsive, paranoid, irritable) aggression (DSM-IV-TR "Intermittent Explosive
      Disorder") often is. Intermittent Explosive Disorder is characterized by discrete episodes of
      failure to resist aggressive impulses resulting in serious assaults or destruction of
      property. In children, due to their limited ability to damage or hurt others, the seriousness
      of the aggressive impulses are indicated by (a) the frequency and severity of tantrums (b)
      the fact that the severity is out of proportion to the provocation, and (c) the intent to
      damage and hurt is present and (d) this pattern of events causes impairment.

      The level of aggression being studied is equivalent to that in moderate to severe
      Oppositional Defiant Disorder with the severity due to the tantrums rather than passive
      aggression (Modified Overt Aggression Score between 15-50). For 20 years a blood pressure
      medication, guanfacine (Tenex), has also been used for impulse control (e.g. in Attention
      Deficit Disorder, in Tourette's Syndrome) and to calm the sympathetic nervous system when it
      is hyper-aroused (e.g. in opiate and nicotine withdrawal]. Both impulsivity and hyper arousal
      can also promote intermittent explosive aggression. If guanfacine treats impulsivity and
      hyper arousal, it is logical to ask if guanfacine can treat intermittent explosive
      aggression.

      Shire Pharmaceuticals modified the guanfacine molecule to create a long acting preparation
      (Intuniv) that the FDA recently judged safe and effective for Attention Deficit Hyperactivity
      Disorder (ADHD) in children ages 6-17. Secondary analysis of data from the pivotal studies
      that led to this indication revealed that in ADHD children, Intuniv also reduced
      oppositional-defiant symptoms. Better impulse control (these were all ADHD children) and/or
      decreased sympathetic arousal (common to all intermittent explosive aggression) are plausible
      explanations.

      This Investigator Sponsor Protocol (ISP) seeks to replicate prospectively the anti-aggression
      finding. Since Intuniv could benefit non-ADHD aggressive children, any child with mild to
      moderate Intermittent Explosive Disorder is eligible. Anti-psychotic and anti-convulsant
      medications (current treatments for Intermittent Explosive Disorder) have serious side
      effects (weight gain, metabolic syndrome) and are not always effective. Intuniv is neither a
      stimulant, nor an antipsychotic, nor an anticonvulsant. Intuniv is not FDA approved for
      treatment of Intermittent Explosive Disorder.

      In addition to medication or placebo, all children will receive a modified form of Parent
      Management Training, the standard psychotherapy for oppositional symptoms, administered by a
      child psychiatrist. It addresses the coercive reciprocal social interactions that
      characterize microenvironment of oppositional children.

      Fifty children, ages 6-12 with Intermittent Explosive Disorder will be randomly assigned to
      eight weeks of double blind Intuniv plus Parent Management Training or placebo Parent
      Management Training. Titrated over four weeks to a maximum dose of 4 mgs or .09-.12
      mgs/kg/day, they will be maintained on that dose for four weeks. At the end of treatment, the
      treating physician will break the blind and offer open label treatment for eight weeks.
    

Study Phase

Phase 4

Study Type

Interventional


Primary Outcome

Number of Participants That Were Responders


Condition

Intermittent Explosive Disorder

Intervention

Parent Management Training

Study Arms / Comparison Groups

 Placebo plus Parent Management Training
Description:  Pills matching Intuniv Tablets without active medication combined with weekly Parent Management Training

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Behavioral

Estimated Enrollment

11

Start Date

July 2011

Completion Date

December 2014

Primary Completion Date

November 2014

Eligibility Criteria

        Inclusion Criteria:

          1. Age 6-12

          2. Meets DSM-IV TR Criteria for Intermittent Explosive Disorder

               1. several discreet episodes of failure to resist aggressive impulses that result in
                  serious assaultive acts or destruction of property

               2. the degree of aggressiveness is grossly out of proportion to any precipitating
                  psychosocial stressors

               3. the aggressive episode is not better accounted for by another mental disorder

               4. duration of at least six months

               5. impairment in home, peer relations and / or school

          3. Modified Overt Aggression Scale (MOAS) score > 15

          4. Parent and child willing to consent to study

          5. Inadequate response to psycho-social interventions (including school interventions)

          6. Medically healthy with

               1. weight > 55 lb (25 kg)

               2. body mass index < 35

               3. normal blood pressure as defined by National Heart Lung and Blood Institute
                  (below 95th percentile for age height and weight)

               4. normal response to orthostatic changes (no persistent fall in systolic/diastolic
                  BP > 20/10 mm Hg within 3 minutes of assuming the upright position)

               5. normal electrocardiogram

               6. normal vital signs

               7. no history of intolerance of guanfacine.

          7. If on another medication, willingness to discontinue if medication is judged
             ineffective after adequate trial or to remain on a constant optimized dose if it is
             partially effective

        Exclusion Criteria:

          1. Current Treatment with another alpha 2 blocker e.g. clonidine

          2. Puberty

          3. Meets criteria for Pervasive Developmental Disorder or Childhood schizophrenia

          4. MOAS score > 50

          5. weight < 55 lb or body mass index > 35

          6. hypertension (Blood Pressure above 95th percentile for age height and weight)

          7. Chronic hypotension (Blood Pressure at or below 5th percentile for age height and
             weight)

          8. Orthostatic Hypotension fall in systolic/diastolic BP > 20/10 mm Hg within 3 minutes
             of assuming the upright position

          9. QTc interval of > 440 milliseconds; Bradycardia; heart block diagnosed

         10. history of seizure during the past 2 years (exclusive of febrile seizures)

         11. Patients who had taken an investigational drug within 28 days

         12. Intelligence Quotient < 70

         13. Physical exam, EKG or laboratory results with any other significant abnormalities
             until reviewed by medicine.

         14. Active suicidal or homicidal ideation or history of suicide attempts

         15. Unequivocal manic or hypomanic Episode

         16. Patients who meet criteria for Major Depression in pre-puberty will not be eligible
             for this study.

         17. Axis I disorders that are current, severe and uncontrolled. Children with moderate
             Axis I pathology will be evaluated on a case by case basis and excluded if the other
             diagnosis is not ADHD but could still be the cause of the temper dyscontrol and the
             treatment is judged substandard.

         18. Any other history of cardiovascular dysfunction

         19. Positive Urine Toxicology

         20. Children who have experienced prior adverse effects (physical or psychological) to
             either Tenex or clonidine

         21. Any child who previously received Tenex and either did not tolerate it, or failed to
             respond to an adequate trial
      

Gender

All

Ages

6 Years - 12 Years

Accepts Healthy Volunteers

No

Contacts

Stephen J Donovan, MD, , 

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT02048241

Organization ID

#6068


Responsible Party

Principal Investigator

Study Sponsor

New York State Psychiatric Institute

Collaborators

 Shire

Study Sponsor

Stephen J Donovan, MD, Principal Investigator, New York State Psychiatric Institute


Verification Date

June 2018