Attention Deficit Disorder With Hyperactivity
Conditions
Brief summary
The purpose of this study is to determine the effects of SPD503 compared to placebo on tasks of sustained attention in children and adolescents aged 6-17 diagnosed with ADHD.
Interventions
DRUGSPD503 (Guanfacine HCl)
DRUGPlacebo
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
6 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with a primary diagnosis of ADHD * Minimum baseline visit ADHD-RS-IV score of 24 and a baseline CGI-S score =\>4 * Male or non-pregnant female subject who agrees to comply with any applicable contraceptive requirements * Subject weighs \> 55 lbs and is not morbidly overweight
Exclusion criteria
* Subject has a comorbid psychiatric diagnosis (except ODD) with significant symptoms such as any severe comorbid Axis II disorders or severe Axis I disorders * Subject has a history of seizure disorder * Subject has any specific cardiac condition or family history of significant cardiac condition * Subject is pregnant, lactating or within six month post-partum
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Choice Reaction Time (CRT) at 6 Weeks | Baseline and 6 weeks | Choice reaction time (CRT) is a computerized assessment that trains the subject in holding down a press-pad and releasing the press-pad in response to stimuli presented on the screen. The task requires the subject to react as soon as a yellow dot appears in one of five locations, and the subject must respond by lifting their hand from the press-pad. This is the reaction time (RT) and ranges from 100 to 5000 msec. Lower scores indicate better performance. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in DSST/Coding Scores at 6 Weeks in Age Category 6-7 Years | Baseline and 6 weeks | The Digital Symbol Substitution Task/Coding Test (DSST/Coding) assesses relative contributions of speed, memory, and visual scanning. Subjects are required to copy symbols that are paired with simple geometric shapes or numbers within a specific time. Scores range from 0-65 in age category 6-7 years and 0-199 in age category 8-17 years. Higher scores indicate better performance. |
| Change From Baseline in Spatial Working Memory (SWM) Scores at 6 Weeks | Baseline and 6 weeks | The Spatial Working Memory (SWM) Test is a computerized assessment of working memory and strategy performance. The subject is required to find blue tokens in various displayed boxes and use the tokens to fill a column on the right side of the screen. Subjects can only find tokens in new boxes, therefore they must remember where previous tokens were found. SWM scores including number of between errors, number of within errors, and number of double errors range 0-800 and SWM strategy scores range 8-56. Lower scores indicate better performance. |
| Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Total Score at 6 Weeks | Baseline and 6 weeks | Change in the Attention Deficit Hyperactivity Disorder Rating Scale-fourth edition (ADHD-RS-IV) total score from baseline. The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54. |
| Change From Baseline in Digital Symbol Substitution Task/Coding Test (DSST/Coding) Scores at 6 Weeks in Age Category 8-17 Years | Baseline and 6 weeks | The Digital Symbol Substitution Task/Coding Test (DSST/Coding) assesses relative contributions of speed, memory, and visual scanning. Subjects are required to copy symbols that are paired with simple geometric shapes or numbers within a specific time. Scores range from 0-65 in age category 6-7 years and 0-199 in age category 8-17 years. Higher scores indicate better performance. |
| Change From Baseline in Pediatric Daytime Sleepiness Scale (PDSS) Scores at 6 Weeks | Baseline and 6 weeks | The Pediatric Daytime Sleepiness Scale (PDSS) is an 8 question questionnaire scored on a scale from 0 (never) to 4 (always). Total scores range from 0 to 32, with increasing score reflecting greater sleepiness. |
| Change From Baseline in Pictorial Sleepiness Scale (PSS) Scores at 6 Weeks | Baseline and 6 weeks | The Pictorial Sleepiness Scale (PSS) scores range from 1 (far left wide awake face) to 5 (far right very sleepy face). Increasing score reflects greater sleepiness. |
| Number of Participants With Improvement in Clinical Global Impression-Improvement (CGI-I) at 6 Weeks | 6 weeks | Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale. |
Participant flow
Pre-assignment details
A total of 182 subjects were enrolled. Four (4) subjects were terminated prior to receiving study medication. Thus, 178 were randomized and received study medication.
Participants by arm
| Arm | Count |
|---|---|
| SPD503 Subjects received either 1, 2, or 3 mg once-daily of SPD503 (Guanfacine hydrochloride) for 6 weeks. | 121 |
| Placebo | 57 |
| Total | 178 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Non-compliance | 1 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 2 |
Baseline characteristics
| Characteristic | Placebo | SPD503 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 57 Participants | 121 Participants | 178 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 12.8 years STANDARD_DEVIATION 2.77 | 12.6 years STANDARD_DEVIATION 2.83 | 12.6 years STANDARD_DEVIATION 2.81 |
| Region of Enrollment United States | 57 Participants | 121 Participants | 178 Participants |
| Sex: Female, Male Female | 13 Participants | 41 Participants | 54 Participants |
| Sex: Female, Male Male | 44 Participants | 80 Participants | 124 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 96 / 121 | 32 / 57 |
| serious Total, serious adverse events | 2 / 121 | 0 / 57 |
Outcome results
Primary
Change From Baseline in Choice Reaction Time (CRT) at 6 Weeks
Choice reaction time (CRT) is a computerized assessment that trains the subject in holding down a press-pad and releasing the press-pad in response to stimuli presented on the screen. The task requires the subject to react as soon as a yellow dot appears in one of five locations, and the subject must respond by lifting their hand from the press-pad. This is the reaction time (RT) and ranges from 100 to 5000 msec. Lower scores indicate better performance.
Time frame: Baseline and 6 weeks
Population: Per protocol (PP) defined as all subjects who completed the study and were deemed to be protocol-compliant.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in Choice Reaction Time (CRT) at 6 Weeks | 20.7 msec | Standard Deviation 63.11 |
| Placebo | Change From Baseline in Choice Reaction Time (CRT) at 6 Weeks | 21.9 msec | Standard Deviation 64.04 |
p-value: 0.844ANCOVA
Secondary
Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Total Score at 6 Weeks
Change in the Attention Deficit Hyperactivity Disorder Rating Scale-fourth edition (ADHD-RS-IV) total score from baseline. The ADHD-RS-IV consists of 18 items scored on a 4-point scale ranging from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54.
Time frame: Baseline and 6 weeks
Population: Full Analysis Set (FAS) defined as all subjects who received at least one dose of investigational product.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Total Score at 6 Weeks | -8.8 Units on a Scale | Standard Deviation 5.98 |
| Placebo | Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Total Score at 6 Weeks | -5.5 Units on a Scale | Standard Deviation 7.23 |
p-value: 0.001ANCOVA
Secondary
Change From Baseline in Digital Symbol Substitution Task/Coding Test (DSST/Coding) Scores at 6 Weeks in Age Category 8-17 Years
The Digital Symbol Substitution Task/Coding Test (DSST/Coding) assesses relative contributions of speed, memory, and visual scanning. Subjects are required to copy symbols that are paired with simple geometric shapes or numbers within a specific time. Scores range from 0-65 in age category 6-7 years and 0-199 in age category 8-17 years. Higher scores indicate better performance.
Time frame: Baseline and 6 weeks
Population: PP
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in Digital Symbol Substitution Task/Coding Test (DSST/Coding) Scores at 6 Weeks in Age Category 8-17 Years | 18.3 Units on a scale | Standard Deviation 14.03 |
| Placebo | Change From Baseline in Digital Symbol Substitution Task/Coding Test (DSST/Coding) Scores at 6 Weeks in Age Category 8-17 Years | 20.7 Units on a scale | Standard Deviation 17.18 |
p-value: 0.274ANCOVA
Secondary
Change From Baseline in DSST/Coding Scores at 6 Weeks in Age Category 6-7 Years
The Digital Symbol Substitution Task/Coding Test (DSST/Coding) assesses relative contributions of speed, memory, and visual scanning. Subjects are required to copy symbols that are paired with simple geometric shapes or numbers within a specific time. Scores range from 0-65 in age category 6-7 years and 0-199 in age category 8-17 years. Higher scores indicate better performance.
Time frame: Baseline and 6 weeks
Population: PP
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in DSST/Coding Scores at 6 Weeks in Age Category 6-7 Years | 1.9 Units on a scale | Standard Deviation 1.95 |
| Placebo | Change From Baseline in DSST/Coding Scores at 6 Weeks in Age Category 6-7 Years | 9.7 Units on a scale | Standard Deviation 0 |
Secondary
Change From Baseline in Pediatric Daytime Sleepiness Scale (PDSS) Scores at 6 Weeks
The Pediatric Daytime Sleepiness Scale (PDSS) is an 8 question questionnaire scored on a scale from 0 (never) to 4 (always). Total scores range from 0 to 32, with increasing score reflecting greater sleepiness.
Time frame: Baseline and 6 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in Pediatric Daytime Sleepiness Scale (PDSS) Scores at 6 Weeks | -1.3 Units on a Scale | Standard Deviation 5.36 |
| Placebo | Change From Baseline in Pediatric Daytime Sleepiness Scale (PDSS) Scores at 6 Weeks | 0.9 Units on a Scale | Standard Deviation 5.31 |
p-value: 0.02ANCOVA
Secondary
Change From Baseline in Pictorial Sleepiness Scale (PSS) Scores at 6 Weeks
The Pictorial Sleepiness Scale (PSS) scores range from 1 (far left wide awake face) to 5 (far right very sleepy face). Increasing score reflects greater sleepiness.
Time frame: Baseline and 6 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in Pictorial Sleepiness Scale (PSS) Scores at 6 Weeks | 0.0 Units on a Scale | Standard Deviation 0.61 |
| Placebo | Change From Baseline in Pictorial Sleepiness Scale (PSS) Scores at 6 Weeks | 0.1 Units on a Scale | Standard Deviation 0.63 |
p-value: 0.231ANCOVA
Secondary
Change From Baseline in Spatial Working Memory (SWM) Scores at 6 Weeks
The Spatial Working Memory (SWM) Test is a computerized assessment of working memory and strategy performance. The subject is required to find blue tokens in various displayed boxes and use the tokens to fill a column on the right side of the screen. Subjects can only find tokens in new boxes, therefore they must remember where previous tokens were found. SWM scores including number of between errors, number of within errors, and number of double errors range 0-800 and SWM strategy scores range 8-56. Lower scores indicate better performance.
Time frame: Baseline and 6 weeks
Population: PP
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SPD503 | Change From Baseline in Spatial Working Memory (SWM) Scores at 6 Weeks | Between errors | -4.4 Units on a scale | Standard Deviation 7.42 |
| SPD503 | Change From Baseline in Spatial Working Memory (SWM) Scores at 6 Weeks | Within errors | 0.0 Units on a scale | Standard Deviation 1.11 |
| SPD503 | Change From Baseline in Spatial Working Memory (SWM) Scores at 6 Weeks | Double errors | -0.0 Units on a scale | Standard Deviation 0.69 |
| SPD503 | Change From Baseline in Spatial Working Memory (SWM) Scores at 6 Weeks | Strategy | -0.9 Units on a scale | Standard Deviation 2.74 |
| Placebo | Change From Baseline in Spatial Working Memory (SWM) Scores at 6 Weeks | Strategy | -0.1 Units on a scale | Standard Deviation 2.56 |
| Placebo | Change From Baseline in Spatial Working Memory (SWM) Scores at 6 Weeks | Between errors | -3.2 Units on a scale | Standard Deviation 6.75 |
| Placebo | Change From Baseline in Spatial Working Memory (SWM) Scores at 6 Weeks | Double errors | 0.1 Units on a scale | Standard Deviation 0.53 |
| Placebo | Change From Baseline in Spatial Working Memory (SWM) Scores at 6 Weeks | Within errors | -0.1 Units on a scale | Standard Deviation 0.73 |
Comparison: Between errorsp-value: 0.307ANCOVA
Comparison: Within errorsp-value: 0.552ANCOVA
Comparison: Double errorsp-value: 0.917ANCOVA
Comparison: Strategyp-value: 0.068ANCOVA
Secondary
Number of Participants With Improvement in Clinical Global Impression-Improvement (CGI-I) at 6 Weeks
Clinical Global Impression-Improvement (CGI-I) consists of a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Improvement is defined as a score of 1 (very much improved) or 2 (much improved) on the scale.
Time frame: 6 weeks
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SPD503 | Number of Participants With Improvement in Clinical Global Impression-Improvement (CGI-I) at 6 Weeks | 67 Participants |
| Placebo | Number of Participants With Improvement in Clinical Global Impression-Improvement (CGI-I) at 6 Weeks | 20 Participants |
p-value: 0.007Cochran-Mantel-Haenszel