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

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.

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.