Neurobiological Basis of Response to Guanfacine Extended Release in Children and Adolescents With ADHD

Study Overview
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Brief Summary
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This study proposes to evaluate the effects of guanfacine extended release on brain activation during fMRI in children and adolescents with ADHD between the ages 8-15 and ADHD subjects randomized to placebo treatment. This study also proposes to collect DNA on study participants, to examine the genetic underpinning of the observed fMRI activation profiles at baseline and in response to treatment. The purpose is to examine polymorphisms of the adrenergic 2A gene (and other related targets) for genetic biomarkers in association with the fMRI findings of this study.

Detailed Description
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This study proposes to evaluate the effects of guanfacine on brain activation during fMRI in 12 children and adolescents ages 8 - 15 with ADHD treated with once-daily INTUNIV(TM) (guanfacine; GXR) extended release tablets and 12 ADHD subjects randomized to placebo treatment. Children will be comprehensively assessed using a variety of clinical and neuropsychological measures. They will be scanned at baseline while performing both the go/no-go task (a well validated task for measuring inhibitory control (Durston et al., 2002, 2003)) and the Stay Alert task - a new task designed to measure the arousal component of attention, which was used successfully in a recent fMRI study of guanfacine in healthy adults (Clerkin et al., 2009). They will then be treated with GXR or placebo for 6 - 8 weeks in accordance with titration and dosing strategies used in recent Phase III dose optimization trials (e.g., up to 4 mg/day), and re-scanned while performing the same two tasks. The fMRI scans will be conducted using a dedicated research 3.0 T Siemens scanner.

Official Title
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Neurobiological Basis of Response to Guanfacine Extended Release in Children and Adolescents With Attention-deficit/Hyperactivity Disorder (ADHD): an Functional Magnetic Resonance Imaging(fMRI) Study of Brain Activation Pre and Post Treatment

Conditions
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ADHD, Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Drug: Guanfacine Hydrochloride XR
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of any subtype of ADHD Normal findings on physical exam, laboratory studies, vital signs, and ECG Weight = 60 kgs or less Able to complete study procedures and swallow capsules; Willing to commit to the entire visit schedule Off treatment or have been discontinued from their previous medication for two weeks. Exclusion Criteria: Psychiatric comorbidity except Oppositional Defiant Disorder [ODD], Simple Phobia, and dysthymia (unless ongoing medication treatment is required); Currently a suicide risk, has previously made a suicide attempt or has a prior history of suicidal behavior; Has failed treatment with an adequate trial of an alpha-2 adrenergic agonist; Known or suspected allergy, hypersensitivity, or clinically significant intolerance to guanfacine hydrochloride. Children may not: be treated with systemic medication for a medical or psychiatric illness that have CNS effects or affect cognitive function; have a known history or presence of structural cardiac abnormalities, exercise-related cardiac events, or clinically significant bradycardia; have orthostatic hypotension or a known history of hypertension; have an abnormal ECG that is deemed clinically significant; have a history of alcohol or other substance abuse or dependence within the last 6 months; use any medications that affect BP or heart rate (excluding the subject's current ADHD medication at screening); use another investigational medicinal product or participation in a clinical study within 30 days prior to the baseline visit; be significantly overweight based on Center for Disease Control and Prevention Body Mass Index (BMI)-for-age gender specific charts; have body weight of less than 25kg; have a clinically important abnormality on urine drug and alcohol screen (excluding the subject's current ADHD stimulant, if applicable); be female and currently pregnant or lactating; have symptoms indicative of a primary sleep disorder. have braces or other metal permanently placed within their body. be too anxious to tolerate the fMRI procedure, or be claustrophobic.

Ages Eligible for Study
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Minimum Age: 8 Years
Maximum Age: 15 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: guanfacine hydrochloride XR<br>Flexible dose titration of guanfacine extended release (Intuniv; active medication). The medication is titrated in doses from 1 - 4 mg once daily | Drug: Guanfacine Hydrochloride XR<br>* Weekly adjustments based on parent ratings of symptoms, side effects, and health status per vital signs up to 4mg maximum dose<br>* Other names: GXR;|
| Placebo Comparator: Placebo Group<br>Flexible dose titration of placebo | Drug: Placebo<br>* Weekly adjustments based on parent ratings of symptoms, side effects, and health status per vital signs up to 4mg maximum dose<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Go/No-go Task Performance Correct Inhibitions | Measures of go/no-go task performance during functional magnetic resonance imaging. Performance on a go-nogo task inside the scanner. | Baseline and 8 weeks | 
| Go/No-go Task Reaction Time | Measures of go/no-go task performance during functional magnetic resonance imaging. Performance on a go-nogo task inside the scanner. | Baseline and 8 weeks | 
| Go/No-go Task Performance Correct Responses | Measures of go/no-go task performance during functional magnetic resonance imaging. Performance on a go-nogo task inside the scanner. | Baseline and 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impressions (CGI-I) | Clinical response was the Clinical Global Impression-Improvement scale (CGI-I). Lower CGI-I scores indicate greater improvement (1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6= much worse; 7=very much worse.) | up to 8 weeks | 
| Percentage Change in Atomoxetine Stimulant Side Effects Rating Scale (ASSERS) | Side effects rating scale. Assesses side effects known to occur in prior research using stimulant and non stimulant medications for treatment of ADHD. Scores range from 0 (not present) to 9 (severe side effects) and have been reported in aggregate as sum of severity responses on highest dose. This number is the sum of ASSERS, meaning it is the number and severity of side effects experienced. The percentage change in score from baseline. | up to 8 weeks | 
| Finger Windows | Neuropsychological assessment: Finger Windows - a measure of spatial working memory. The participant shows memory of a demonstrated visual pattern. The examiner models a given sequence of windows and ask the participant to imitate the sequence by placing their finger through the same windows in the correct order. The total number of correct sequences achieved determines the level of performance. | Baseline | 
| Digit Span | Neuropsychological assessment - Digit Span. The Digit Span test is either conducted verbally or using a computer program. A sequence of numbers is shown or read out to the participant. The participant is then told to repeat the numbers that were shown or read to them. This process continues until the participant can no longer remember either the full sequence of numbers or the correct order. This sequence is also continued until the participant makes an error. The Digit Span test is scored by the amount of numbers the participant was able to remember in each test. The scorer must add the total number of correct sequences, backwards and forwards. This test is also scored differently for a range of ages. | Baseline | 
| Attention Deficit Hyperactivity Disorder Rating Scale IV (ADHDRS IV) | Norm referenced parent interview to assess severity and frequency of ADHD symptoms. Scores are reported as sums 0 (no symptoms) to 54 (severe). | baseline and 8 weeks | 
| Continuous Performance Test - Commissions | Neuropsychological assessment - Continuous Performance Test - Commissions. CPT is a task-oriented computerized assessment of attention-related problems. Scores are compared with the normative scores for the age, group and gender of the person being tested. A t-score of 50 is equal to the mean, with higher values indicating more problematic behaviors and lower scores indicating less problematic behaviors. | Baseline | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Intuniv, Attention Deficit Hyperactivity Disorder, fMRI