Language-based Learning Skills and Attention Deficit Hyperactivity Disorder (ADHD): Impact of Treatment With Sustained-release Guanfacine
Condition: Attention-deficit/Hyperactivity Disorder
MeSH terms: Hyperkinesis; Attention Deficit Disorder with Hyperactivity
Study type: Interventional
Phase: Phase 4

Summary: 
      This study is investigating the effect of sustained-release guanfacine (Intuniv) on
      language-based learning skills in children age 6-12 who are diagnosed with attention deficit
      hyperactivity disorder (ADHD).
    

Detailed description: 
      LANGUAGE-BASED LEARNING SKILLS AND ADHD: IMPACT OF TREATMENT WITH SUSTAINED-RELEASE
      GUANFACINE

      Background:

      Children with attention-deficit/hyperactivity disorder (ADHD) often do poorly in school
      (1,2,3). Their slow academic progress is typically attributable to inattention, restlessness,
      disorganization and distractibility, all of which diminish their ability to learn.
      Additionally, these manifestations of ADHD may worsen an underlying specific learning
      disability (SLD), which is a common comorbidity of ADHD (1,4,5).

      Treatment for ADHD is often initiated with the goal of enhancing learning and fostering
      academic success. Yet changes in academic achievement resulting from the pharmacological
      treatment of ADHD have been less evaluated in clinical research than changes in specifically
      defined behaviors. Such behaviors typically include lack of attention to task, fidgeting,
      calling out, disorganization and hyperactivity. These behaviors, rather than overall academic
      improvement, are also what are measured with typical ADHD rating scales (6).

      A relatively small number of clinical studies have assessed the impact of medications for the
      treatment of ADHD on academic progress during childhood or adolescence. Some of these studies
      (3,7) have focused on long-term measures, such as lack of grade retention and ultimate
      graduation from high school. Other research has tried to directly measure the effect of
      medication for ADHD on the ability to perform particular academic tasks. Typically, the
      ability to efficiently and correctly solve a series of arithmetical problems - first, with no
      treatment, and then while taking stimulant medication, has been measured (8,9). These studies
      have demonstrated that both methylphenidate-based and amphetamine-based stimulant drugs
      enable greater speed, efficiency and accuracy.

      Studying arithmetical speed and accuracy to determine a medication's helpfulness in the
      school setting may be insufficient, however, since mathematics is not relevant to most of the
      academic material and skills that children are required to learn. To the investigator's
      knowledge no prior studies have evaluated the impact of medications for ADHD on
      language-based tasks such as reading or reading comprehension. Yet competency in reading,
      reading comprehension, auditory comprehension and writing is arguably more important than
      competency in arithmetic during grammar school, and becomes even more essential during middle
      school and high school. Moreover, even in apparently "arithmetical" subjects such as
      mathematics and science, word problems are often utilized, so that arithmetical ability alone
      is insufficient. Finally, it should also be noted that the most common forms of SLD are
      language-based disabilities that manifest as a weakness in reading, comprehension, or writing
      skill, but not arithmetical skill (10). For all these reasons, we should not assume that
      testing arithmetical performance is adequate to demonstrate the effectiveness of medication
      for ADHD, whether or not a coexisting SLD is present.

      Study Protocol

      This will be a single-arm study in which the language-based academic skills of children
      diagnosed with ADHD will be assessed prior to, and then during treatment with
      sustained-release guanfacine (GXR). Children will be diagnosed with ADHD using standard
      rating instruments (see below). Children meeting inclusion and exclusion criteria will
      undergo testing of language-based academic skills with the Woodcock-Johnson III test prior
      initiating treatment with GXR. The daily dose of GXR will then be initiated at 1 mg and
      titrated by 1 mg in weekly intervals, based on significant improvement in ADHD rating scales,
      the to a maximum dose of 4 mg. Once significant improvement in ADHD manifestations is
      recorded using rating scales, upward titration will stop and the dose will be maintained.
      After five weeks repeat testing using the WJIII will be done. Results of pre- and
      post-medication testing will be compared for the group using appropriate statistical methods.

      Study Population:

      We will attempt to recruit 20 or more children with ADHD in the setting of a well-established
      suburban pediatric neurology office practice.

      Primary efficacy endpoint:

      Statistically significant (p<0.05 level) improvement in Woodcock-Johnson test scores during
      treatment with GXR compared to pre-treatment.

      Inclusion and exclusion criteria:

      Children between the ages of 6 to 12 years with newly diagnosed ADHD-inattentive type or
      ADHD-combined type will be identified. The diagnosis of ADHD will be established using the
      Diagnostic and Statistical Manual of Mental and Related Disorder, version IV, Text Revision
      (DSM-IV TR, 2000) criteria and the ADHD Rating Scale IV (ADHD-RS; DuPaul et al., 1998).

      Patients with any of the following are excluded:

        -  Intelligence (IQ) below 85 as determined by formal testing (see below).

        -  Identified or suspected genetic syndromes.

        -  Autism or other pervasive developmental disorders.

        -  Psychiatric disorders other than ADHD and oppositional defiant disorder.

        -  Heart, liver or renal disease.

        -  Cancer.

        -  Epilepsy or non-febrile seizure history.

        -  Cardiac arrhythmia, bradycardia, or syncope.

        -  Any other condition considered to be potentially exacerbated or endangered by treatment
           with an alpha-2 agonist drug.

             -  Prior treatment with medication for ADHD will not be an exclusion criterion.

      Screening and initiation of study:

      Children between the ages of 6 to 12 years with newly diagnosed ADHD-inattentive type or
      -combined type will be identified. The diagnosis of ADHD will be made by means of the DSM-IV
      -TR criteria and the ADHD-RS.

      Appropriate informed consent to participate in the study will be obtained from the child's
      parent(s).

      Patients will be screened for medical conditions excluding them from the study. Vital signs
      will be checked; patients with values below the 2nd and above the 98th percentile will be
      also excluded. A comprehensive physical examination will be performed. Intelligence testing
      using the Wechsler Intelligence Scale for Children, 4th ed. (WISC; Wechsler, 2003) will be
      performed. Children with a full-scale IQ below 85 will be excluded.

      There will then be a one-week period which will serve as a washout for any currently taken
      medication for ADHD.

      Treatment with medication and testing of learning parameters:

      Children qualifying for the study will be administered selected portions of the
      Woodcock-Johnson Test III (WJ-III; Woodcock et al., 2006). We will utilize sections of this
      test evaluating phonetics, reading fluency, reading comprehension and listening
      comprehension. Writing ability will not be assessed because of the confounding influence of
      fine motor development on writing speed. Mathematical ability will also not be tested.

      This test includes an "A" and a "B" form. Only the A form will be used initially so as to
      minimize practice effect when the test is later repeated.

      Treatment with GXR will be initiated immediately after testing, and titrated over a 5-week
      period. The initial dosage will be 1 mg daily and will be titrated in weekly intervals to a
      maximum dose of 4 mg. Clinical improvement measures at follow-up visits will include the
      ADHD-RS and the Clinical Global Impression- Improvement Scale (Guy, 1976). Once a change in
      the CGI-I score of < 2 or a decrease in the ADHD-RS score of 30% or greater is noted, we will
      not further increase the daily dosage.

      Patients will return for 5 weekly visits. Vital signs, cardiac auscultation, and a routine
      follow-up physical examination will be performed at each visit.

      Patients experiencing adverse effects that are judged by the investigator to be clinically
      significant, as well as non-serious but bothersome adverse effects that do not respond to
      dose adjustment will be taken off SRG. Events judged to be serious will be reported to the
      IRB, FDA, and Shire.

      After 5 visits, subjects assessed as having had a significant improvement in the ADHD-RS or
      CGI-I will take the WJ-III "B" form (see above) beginning 2 hours after taking their current
      dose.

      Data analysis:

      The subjects' scores on the WJ-III, obtained initially and then during treatment with GXR,
      will be compared using a one-tailed t-test.

      Continuation:

      Patients who have benefited from the study drug will be given the option of continuing the
      medication, prescribed by the same physician, supplied commercially. If they elect not to
      continue, the study drug will be tapered off by 1 mg (daily dosage) per week.
    

Intervention name(s): Guanfacine (sustained release)
Intervention type(s): Drug
Intervention description(s): Treated with study drug once screening and initial testing is completed (see protocol above)
Intervention MeSH terms: Guanfacine
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Attention-deficit/hyperactivity disorder, primarily inattentive or combined type.