ADHD, Attention Deficit Hyperactivity Disorder
Conditions
Keywords
Intuniv, Attention Deficit Hyperactivity Disorder, fMRI
Brief summary
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
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.
Interventions
DRUGGuanfacine Hydrochloride XR
Weekly adjustments based on parent ratings of symptoms, side effects, and health status per vital signs up to 4mg maximum dose
DRUGPlacebo
Weekly adjustments based on parent ratings of symptoms, side effects, and health status per vital signs up to 4mg maximum dose
Sponsors
Icahn School of Medicine at Mount Sinai
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 15 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Go/No-go Task Performance Correct Inhibitions | Baseline and 8 weeks | Measures of go/no-go task performance during functional magnetic resonance imaging. Performance on a go-nogo task inside the scanner. |
| Go/No-go Task Reaction Time | Baseline and 8 weeks | Measures of go/no-go task performance during functional magnetic resonance imaging. Performance on a go-nogo task inside the scanner. |
| Go/No-go Task Performance Correct Responses | Baseline and 8 weeks | Measures of go/no-go task performance during functional magnetic resonance imaging. Performance on a go-nogo task inside the scanner. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Digit Span | Baseline | 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. |
| Clinical Global Impressions (CGI-I) | up to 8 weeks | 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.) |
| Continuous Performance Test - Commissions | Baseline | 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. |
| Attention Deficit Hyperactivity Disorder Rating Scale IV (ADHDRS IV) | baseline and 8 weeks | Norm referenced parent interview to assess severity and frequency of ADHD symptoms. Scores are reported as sums 0 (no symptoms) to 54 (severe). |
| Percentage Change in Atomoxetine Stimulant Side Effects Rating Scale (ASSERS) | up to 8 weeks | 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. |
| Finger Windows | Baseline | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Guanfacine Hydrochloride XR Flexible dose titration of guanfacine extended release - titrated in doses from 1 - 4 mg once daily | 12 |
| Placebo Group Flexible dose titration of placebo | 13 |
| Total | 25 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | Guanfacine Hydrochloride XR | Placebo Group | Total |
|---|---|---|---|
| Age, Continuous | 10.6 years STANDARD_DEVIATION 1.7 | 11.5 years STANDARD_DEVIATION 2.5 | 11.1 years STANDARD_DEVIATION 2.2 |
| Attention-Deficit/Hyperactivity Disorder (ADHD) subtype Combined | 8 Participants | 9 Participants | 17 Participants |
| Attention-Deficit/Hyperactivity Disorder (ADHD) subtype Inattentive | 4 Participants | 4 Participants | 8 Participants |
| Clinical Global Impressions - Severity scale (CGI-S) | 4.9 units on a scale STANDARD_DEVIATION 1 | 5.4 units on a scale STANDARD_DEVIATION 0.9 | 5.2 units on a scale STANDARD_DEVIATION 0.9 |
| Comorbid Oppositional Defiant Disorder (ODD) | 7 Participants | 4 Participants | 11 Participants |
| Full Scale IQ | 110.0 units on a scale STANDARD_DEVIATION 21.6 | 101.8 units on a scale STANDARD_DEVIATION 13.1 | 105.7 units on a scale STANDARD_DEVIATION 17.75 |
| Prior stimulant treatment | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Female | 3 Participants | 4 Participants | 7 Participants |
| Sex: Female, Male Male | 9 Participants | 9 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 12 | 0 / 13 |
| other Total, other adverse events | 4 / 12 | 3 / 13 |
| serious Total, serious adverse events | 0 / 12 | 0 / 13 |
Outcome results
Primary
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.
Time frame: Baseline and 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Guanfacine Hydrochloride XR | Go/No-go Task Performance Correct Inhibitions | 8 Weeks Correct inhibitions | 94 percentage correct inhibitions | Standard Deviation 6 |
| Guanfacine Hydrochloride XR | Go/No-go Task Performance Correct Inhibitions | Baseline Correct inhibitions | 91 percentage correct inhibitions | Standard Deviation 8 |
| Placebo Group | Go/No-go Task Performance Correct Inhibitions | Baseline Correct inhibitions | 89 percentage correct inhibitions | Standard Deviation 10 |
| Placebo Group | Go/No-go Task Performance Correct Inhibitions | 8 Weeks Correct inhibitions | 92 percentage correct inhibitions | Standard Deviation 7 |
Primary
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.
Time frame: Baseline and 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Guanfacine Hydrochloride XR | Go/No-go Task Performance Correct Responses | Baseline Correct responses | 76 percentage correct responses | Standard Deviation 18 |
| Guanfacine Hydrochloride XR | Go/No-go Task Performance Correct Responses | 8 Weeks Correct responses | 79 percentage correct responses | Standard Deviation 15 |
| Placebo Group | Go/No-go Task Performance Correct Responses | Baseline Correct responses | 75 percentage correct responses | Standard Deviation 14 |
| Placebo Group | Go/No-go Task Performance Correct Responses | 8 Weeks Correct responses | 74 percentage correct responses | Standard Deviation 15 |
Primary
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.
Time frame: Baseline and 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Guanfacine Hydrochloride XR | Go/No-go Task Reaction Time | Baseline Reaction time (RT) | 572 ms | Standard Deviation 144 |
| Guanfacine Hydrochloride XR | Go/No-go Task Reaction Time | Baseline Reaction time standard deviation (RTSD) | 187 ms | Standard Deviation 109 |
| Guanfacine Hydrochloride XR | Go/No-go Task Reaction Time | 8 weeks Reaction time (RT) | 562 ms | Standard Deviation 106 |
| Guanfacine Hydrochloride XR | Go/No-go Task Reaction Time | 8 weeks Reaction time standard deviation (RTSD) | 184 ms | Standard Deviation 93 |
| Placebo Group | Go/No-go Task Reaction Time | 8 weeks Reaction time standard deviation (RTSD) | 166 ms | Standard Deviation 73 |
| Placebo Group | Go/No-go Task Reaction Time | Baseline Reaction time (RT) | 543 ms | Standard Deviation 99 |
| Placebo Group | Go/No-go Task Reaction Time | 8 weeks Reaction time (RT) | 550 ms | Standard Deviation 107 |
| Placebo Group | Go/No-go Task Reaction Time | Baseline Reaction time standard deviation (RTSD) | 165 ms | Standard Deviation 76 |
Secondary
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).
Time frame: baseline and 8 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Guanfacine Hydrochloride XR | Attention Deficit Hyperactivity Disorder Rating Scale IV (ADHDRS IV) | Baseline | 36.67 units on a scale | Standard Deviation 9.01 |
| Guanfacine Hydrochloride XR | Attention Deficit Hyperactivity Disorder Rating Scale IV (ADHDRS IV) | End of treatment at 8 weeks | 9.42 units on a scale | Standard Deviation 6.96 |
| Placebo Group | Attention Deficit Hyperactivity Disorder Rating Scale IV (ADHDRS IV) | Baseline | 39.15 units on a scale | Standard Deviation 9.08 |
| Placebo Group | Attention Deficit Hyperactivity Disorder Rating Scale IV (ADHDRS IV) | End of treatment at 8 weeks | 22.69 units on a scale | Standard Deviation 11.9 |
Secondary
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.)
Time frame: up to 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine Hydrochloride XR | Clinical Global Impressions (CGI-I) | 2.0 units on a scale | Standard Deviation 0.7 |
| Placebo Group | Clinical Global Impressions (CGI-I) | 2.9 units on a scale | Standard Deviation 1.1 |
Secondary
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.
Time frame: Baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Guanfacine Hydrochloride XR | Continuous Performance Test - Commissions | 48.62 t-scores | Standard Deviation 3.81 |
| Placebo Group | Continuous Performance Test - Commissions | 46.99 t-scores | Standard Deviation 2.99 |
Secondary
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.
Time frame: Baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Guanfacine Hydrochloride XR | Digit Span | Digit Span - F | 6.92 correct sequences | Standard Deviation 1.73 |
| Guanfacine Hydrochloride XR | Digit Span | Digit Span - B | 48.62 correct sequences | Standard Deviation 8.76 |
| Placebo Group | Digit Span | Digit Span - F | 7.54 correct sequences | Standard Deviation 2.54 |
| Placebo Group | Digit Span | Digit Span - B | 48.62 correct sequences | Standard Deviation 8.76 |
Secondary
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.
Time frame: Baseline
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Guanfacine Hydrochloride XR | Finger Windows | Finger Windows - F | 12.5 correct sequences | Standard Deviation 6.52 |
| Guanfacine Hydrochloride XR | Finger Windows | Finger Windows -B | 11.35 correct sequences | Standard Deviation 5.45 |
| Placebo Group | Finger Windows | Finger Windows - F | 10.75 correct sequences | Standard Deviation 4.63 |
| Placebo Group | Finger Windows | Finger Windows -B | 8.00 correct sequences | Standard Deviation 5.14 |
Secondary
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.
Time frame: up to 8 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Guanfacine Hydrochloride XR | Percentage Change in Atomoxetine Stimulant Side Effects Rating Scale (ASSERS) | 78 percentage of mean effects improvement |
| Placebo Group | Percentage Change in Atomoxetine Stimulant Side Effects Rating Scale (ASSERS) | 65.18 percentage of mean effects improvement |