ADHD
Conditions
Brief summary
To assess efficacy and safety of SPD503(guanfacine hydrochloride) in subjects with ADHD and oppositional symptoms.
Interventions
DRUGSPD503 (Guanfacine hydrochloride)
Subjects will start at 1mg tablet each morning and will subsequently be titrated (in 1 mg weekly increments) to optimal dose based upon tolerance and response to investigational product (not to exceed 4 mg/day).
DRUGPlacebo
Placebo
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
6 Years to 12 Years
Healthy volunteers
No
Inclusion criteria
* Healthy subjects with ADHD and oppositional symptoms * ADHD-RS\>=24 * CGI \>=4 * T-score of Opp subscale CPRS-R:L \>=65 * Normal ECG and BP * \>= 55 lbs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Oppositional Subscale of the Conners' Parent Rating Scale-Revised Long Form (CPRS-R:L) Score at Up to 8 Weeks | Baseline and up to 8 weeks | The oppositional subscale of the CPRS-R:L contains 10 items designed to reflect criteria for oppositional defiance disorder (ODD). Each item is scored on a range from 0 (not true at all) to 3 (very much true) with total scores ranging from 0 to 30. Higher scores are reflective of more severe symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | up to 8 weeks | CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill) |
| Number of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) | up to 8 weeks | 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. |
| Change From Baseline in the 40-Item Conduct Problem Scale of the New York Parent's Rating Scale-School-aged (NYPRS-S) Score at Up to 8 Weeks | Baseline and up to 8 weeks | Each item on the NYPRS-S is scored from a range of 0 (not at all) to 3 (very much) with total scores ranging from 0 to 120. Higher scores are reflective of increased disease severity. |
| Change From Baseline in the Parent Stress Index-Short Form (PSI/SF) Score at Up to 8 Weeks | Baseline and up to 8 weeks | The response to each of the 36 items on the PSI/SF is converted to a five-point scale from 1 (strongly agree) to 5 (strongly disagree) with total scores ranging from 36 to 180. A higher score is reflective of less stress for the parents. |
| Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Total Score at Up to 8 Weeks | Baseline and up to 8 weeks | 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 Electrocardiogram Results (QTcF Interval) at Up to 8 Weeks | Baseline and up to 8 weeks | QTcF is the QT interval using Fridericia's correction formula. QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). The QT interval has to be corrected in order to aid interpretation. |
| Change From Baseline in Pulse Rate at Up to 8 Weeks | Baseline and up to 8 weeks | — |
| Change From Baseline in Systolic Blood Pressure at Up to 8 Weeks | Baseline and up to 8 weeks | — |
| Change From Baseline in Diastolic Blood Pressure at Up to 8 Weeks | Baseline and up to 8 weeks | — |
| Number of Participants With Overall Satisfaction on the Medication Satisfaction Survey (MSS) | up to 8 weeks | The Medication Satisfaction Survey (MSS) consists of 11 questions each being answered with one of six responses (strongly agree, agree, somewhat agree, somewhat disagree, disagree, strongly disagree). Overall satisfaction with their child taking the study medication, Question #11, with a response of strongly agree or agree. |
Countries
United States
Participant flow
Pre-assignment details
217 subjects were randomized (138 to SPD503 and 79 to placebo). However, only 214 subjects received at least one dose of study medication (136 for SPD503 and 78 for placebo). Therefore, 214 subjects constitute the safety population.
Participants by arm
| Arm | Count |
|---|---|
| SPD503 Subjects will receive either 1, 2, 3, or 4 mg/day oral doses of SPD503 (Guanfacine hydrochloride) | 138 |
| Placebo | 79 |
| Total | 217 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 14 | 1 |
| Overall Study | Did not respond to calls | 1 | 0 |
| Overall Study | History of lead poisoning | 0 | 1 |
| Overall Study | Lack of Efficacy | 3 | 12 |
| Overall Study | Lost to Follow-up | 1 | 4 |
| Overall Study | Protocol Violation | 1 | 7 |
| Overall Study | refused blood collection | 1 | 0 |
| Overall Study | Subject in juvenile detention center | 1 | 0 |
| Overall Study | Withdrawal by Subject | 7 | 6 |
Baseline characteristics
| Characteristic | Placebo | SPD503 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 79 Participants | 138 Participants | 217 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 | 9.3 years STANDARD_DEVIATION 2.04 | 9.4 years STANDARD_DEVIATION 1.73 | 9.4 years STANDARD_DEVIATION 1.84 |
| Region of Enrollment United States | 79 Participants | 138 Participants | 217 Participants |
| Sex: Female, Male Female | 19 Participants | 50 Participants | 69 Participants |
| Sex: Female, Male Male | 60 Participants | 88 Participants | 148 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 115 / 136 | 47 / 78 |
| serious Total, serious adverse events | 0 / 136 | 0 / 78 |
Outcome results
Primary
Change From Baseline in the Oppositional Subscale of the Conners' Parent Rating Scale-Revised Long Form (CPRS-R:L) Score at Up to 8 Weeks
The oppositional subscale of the CPRS-R:L contains 10 items designed to reflect criteria for oppositional defiance disorder (ODD). Each item is scored on a range from 0 (not true at all) to 3 (very much true) with total scores ranging from 0 to 30. Higher scores are reflective of more severe symptoms.
Time frame: Baseline and up to 8 weeks
Population: Full Analysis Set (FAS) defined as all randomized subjects who received at least one dose of any investigational product during this study and with a baseline and at least one post-baseline efficacy measurement.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in the Oppositional Subscale of the Conners' Parent Rating Scale-Revised Long Form (CPRS-R:L) Score at Up to 8 Weeks | -10.8 Units on a scale | Standard Deviation 7.23 |
| Placebo | Change From Baseline in the Oppositional Subscale of the Conners' Parent Rating Scale-Revised Long Form (CPRS-R:L) Score at Up to 8 Weeks | -7.0 Units on a scale | Standard Deviation 7.63 |
p-value: <0.001ANCOVA
Secondary
Assessment of Clinical Global Impression-Severity of Illness (CGI-S)
CGI-S assesses the severity of the subject's condition on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill)
Time frame: up to 8 weeks
Population: FAS
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SPD503 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 3 (Mildly ill) | 29 Participants |
| SPD503 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 5 (Markedly ill) | 13 Participants |
| SPD503 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 2 (Borderline mentally ill) | 33 Participants |
| SPD503 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 6 (Severely ill) | 4 Participants |
| SPD503 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 4 (Moderately ill) | 26 Participants |
| SPD503 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 7 (Among the most extremely ill) | 0 Participants |
| SPD503 | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 1 (Normal, not at all ill) | 25 Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 7 (Among the most extremely ill) | 0 Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 1 (Normal, not at all ill) | 3 Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 2 (Borderline mentally ill) | 6 Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 3 (Mildly ill) | 15 Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 4 (Moderately ill) | 24 Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 5 (Markedly ill) | 22 Participants |
| Placebo | Assessment of Clinical Global Impression-Severity of Illness (CGI-S) | 6 (Severely ill) | 5 Participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Total Score at Up to 8 Weeks
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 up to 8 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Total Score at Up to 8 Weeks | -23.8 Units on a scale | Standard Deviation 14.43 |
| Placebo | Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Total Score at Up to 8 Weeks | -11.4 Units on a scale | Standard Deviation 12.65 |
p-value: <0.001ANCOVA
Secondary
Change From Baseline in Diastolic Blood Pressure at Up to 8 Weeks
Time frame: Baseline and up to 8 weeks
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in Diastolic Blood Pressure at Up to 8 Weeks | -1.3 mmHg | Standard Deviation 8.48 |
| Placebo | Change From Baseline in Diastolic Blood Pressure at Up to 8 Weeks | 0.9 mmHg | Standard Deviation 7.38 |
Secondary
Change From Baseline in Electrocardiogram Results (QTcF Interval) at Up to 8 Weeks
QTcF is the QT interval using Fridericia's correction formula. QT interval is a measure of time between the start of the Q wave and the end of the T wave and is dependent on the heart rate (e.g., the faster the heart rate, the shorter the QT interval). The QT interval has to be corrected in order to aid interpretation.
Time frame: Baseline and up to 8 weeks
Population: Safety population defined as all randomized subjects who received at least one dose of any investigational product during this study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in Electrocardiogram Results (QTcF Interval) at Up to 8 Weeks | 5.2 msec | Standard Deviation 15.74 |
| Placebo | Change From Baseline in Electrocardiogram Results (QTcF Interval) at Up to 8 Weeks | 2.1 msec | Standard Deviation 17.41 |
Secondary
Change From Baseline in Pulse Rate at Up to 8 Weeks
Time frame: Baseline and up to 8 weeks
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in Pulse Rate at Up to 8 Weeks | -4.3 beats/min | Standard Deviation 11.89 |
| Placebo | Change From Baseline in Pulse Rate at Up to 8 Weeks | 0.7 beats/min | Standard Deviation 11.44 |
Secondary
Change From Baseline in Systolic Blood Pressure at Up to 8 Weeks
Time frame: Baseline and up to 8 weeks
Population: Safety population
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in Systolic Blood Pressure at Up to 8 Weeks | -2.6 mmHg | Standard Deviation 10.27 |
| Placebo | Change From Baseline in Systolic Blood Pressure at Up to 8 Weeks | 0.7 mmHg | Standard Deviation 8.18 |
Secondary
Change From Baseline in the 40-Item Conduct Problem Scale of the New York Parent's Rating Scale-School-aged (NYPRS-S) Score at Up to 8 Weeks
Each item on the NYPRS-S is scored from a range of 0 (not at all) to 3 (very much) with total scores ranging from 0 to 120. Higher scores are reflective of increased disease severity.
Time frame: Baseline and up to 8 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in the 40-Item Conduct Problem Scale of the New York Parent's Rating Scale-School-aged (NYPRS-S) Score at Up to 8 Weeks | -15.6 units on a scale | Standard Deviation 12.86 |
| Placebo | Change From Baseline in the 40-Item Conduct Problem Scale of the New York Parent's Rating Scale-School-aged (NYPRS-S) Score at Up to 8 Weeks | -10.3 units on a scale | Standard Deviation 13.25 |
p-value: <0.001ANCOVA
Secondary
Change From Baseline in the Parent Stress Index-Short Form (PSI/SF) Score at Up to 8 Weeks
The response to each of the 36 items on the PSI/SF is converted to a five-point scale from 1 (strongly agree) to 5 (strongly disagree) with total scores ranging from 36 to 180. A higher score is reflective of less stress for the parents.
Time frame: Baseline and up to 8 weeks
Population: FAS
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| SPD503 | Change From Baseline in the Parent Stress Index-Short Form (PSI/SF) Score at Up to 8 Weeks | 17.3 Units on a scale | Standard Deviation 19.76 |
| Placebo | Change From Baseline in the Parent Stress Index-Short Form (PSI/SF) Score at Up to 8 Weeks | 7.2 Units on a scale | Standard Deviation 18.29 |
p-value: 0.002ANCOVA
Secondary
Number of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I)
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: up to 8 weeks
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SPD503 | Number of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) | 93 Participants |
| Placebo | Number of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) | 24 Participants |
p-value: <0.001Cochran-Mantel-Haenszel
Secondary
Number of Participants With Overall Satisfaction on the Medication Satisfaction Survey (MSS)
The Medication Satisfaction Survey (MSS) consists of 11 questions each being answered with one of six responses (strongly agree, agree, somewhat agree, somewhat disagree, disagree, strongly disagree). Overall satisfaction with their child taking the study medication, Question #11, with a response of strongly agree or agree.
Time frame: up to 8 weeks
Population: FAS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SPD503 | Number of Participants With Overall Satisfaction on the Medication Satisfaction Survey (MSS) | 84 Participants |
| Placebo | Number of Participants With Overall Satisfaction on the Medication Satisfaction Survey (MSS) | 21 Participants |
p-value: <0.001ANOVA