Attention-Deficit/Hyperactivity Disorder (ADHD)
Conditions
Brief summary
This was a randomized, double-blind, placebo-controlled, multicenter, 5-arm, parallel-group, dose-ranging study to assess the efficacy and safety of SPN-812 (Viloxazine Extended-release Capsule) in children 6-12 years of age with ADHD.
Detailed description
This study is a randomized, double-blind, placebo-controlled, multicenter, 5-arm, parallel-group, dose-ranging study to assess the efficacy, safety, and tolerability of SPN-812 (Viloxazine Extended-release Capsule) as monotherapy in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children (6-12 years of age). Subjects are randomized in a 1:2:2:2:2 ratio to receive placebo or one of four active treatments (100 mg, 200 mg, 300 mg, or 400 mg SPN-812). The primary objective is to assess the efficacy of SPN-812 in reducing ADHD symptoms as measured by the Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV).
Interventions
DRUGPlacebo
Placebo was administered once daily
DRUG100mg SPN-812
100mg SPN-812 was administered once daily and compared to placebo
DRUG200mg SPN-812
200mg SPN-812 was administered once daily and compared to placebo
DRUG300mg SPN-812
300mg SPN-812 was administered once daily and compared to placebo
DRUG400mg SPN-812
400mg SPN-812 was administered once daily and compared to placebo
Sponsors
Supernus Pharmaceuticals, Inc.
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
1. Healthy male or female subjects, 6-12 years of age, inclusive, with a diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM IV), confirmed with the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID). 2. ADHD-RS-IV-Parent Version: Investigator Administered and Scored score of at least 26. 3. CGI-S score of at least 4 4. Weight of at least 20 kg. 5. Free of medication for the treatment of ADHD or any psychosis for at least one week prior to enrollment.
Exclusion criteria
1. Current or lifetime diagnosis of major depressive disorder, bipolar disorder, personality disorder, Tourette's disorder, or psychosis not otherwise specified. 2. Currently meeting DSM-IV criteria for pervasive developmental disorder, obsessive compulsive disorder, post-traumatic stress disorder, or any other anxiety disorder as primary diagnosis. 3. Significant systemic disease. 4. Evidence of suicidality within the six months before Screening or at Screening. 5. BMI greater than 95th percentile for the appropriate age and gender. 6. Pregnancy or refusal to practice abstinence during the study for female subjects of childbearing potential (FOCP). 7. Substance or alcohol use during the last three months. 8. Positive urine screen for cotinine, alcohol, or drugs of abuse at Screening.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Efficacy of SPN-812 on the Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) | Baseline to Week 8 (End of Study) | The Primary Endpoint was the change from baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) Total score at Week 8 (End of Study). The ADHD-RS-IV is an ADHD-specific rating scale designed and validated to assess current ADHD symptomatology. The scale consists of 18 items that directly correspond to the 18 Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) symptoms of ADHD. Each item is rated on a 4-point Likert-type scale from 0 (never or rarely) to 3 (very often). A Total score is calculated by adding the responses of all 18 items (range: 0-54; the higher the score, the more severe the ADHD symptoms). Lower change from baseline scores (\<0) represent a better outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of SPN-812 on Clinical Global Impression - Improvement (CGI-I) Scale | Week 8 (End of Study) | The first additional secondary endpoint was the Clinical Global Impression-Improvement (CGI-I) Scale score at Week 8 (End of Study). The CGI-I scale is a single item assessment of how much the patient's illness has improved or worsened relative to a baseline state prior to the beginning of treatment. The CGI-I is rated on a 7-point Likert scale from 1 to 7, where 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. Successful therapy is indicated by a lower score (\<4) in subsequent testing. |
| Effect of SPN-812 on the Clinical Global Impression - Severity (CGI-S) Scale | Baseline to Week 8 (End of Study) | The second additional secondary endpoint was the change from baseline in the Clinical Global Impression-Severity (CGI-S) Scale score at Week 8 (End of Study). The CGI-S scale is a single item clinician/investigator rating of the clinician's assessment of the severity of the ADHD symptoms in relation to the clinician's total experience with patients with ADHD. The CGI-S was rated on a 7-point Likert scale, where 1 = Normal, not at all ill, 2 = Borderline Ill, 3 = Mildly Ill, 4 = Moderately Ill, 5 = Markedly Ill, 6 = Severely Ill, and 7 = Extremely Ill. Successful therapy is indicated by a lower CGI-S score in subsequent testing. A lower change from baseline score (\<0) represents a better outcome. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Treatment A: Placebo was administered once daily | 24 |
| 100mg SPN-812 Treatment B: 100mg SPN-812 was administered once daily and compared to placebo | 45 |
| 200mg SPN-812 Treatment C: 200mg SPN-812 was administered once daily and compared to placebo | 46 |
| 300mg SPN-812 Treatment D: 300mg SPN-812 was administered once daily and compared to placebo | 47 |
| 400mg SPN-812 Treatment E: 400mg SPN-812 was administered once daily and compared to placebo | 44 |
| Total | 206 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Administrative reason | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Adverse Event | 0 | 4 | 3 | 1 | 5 |
| Overall Study | Failed to meet eligibility | 0 | 1 | 1 | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 2 | 5 | 5 | 4 |
| Overall Study | Multiple reasons | 1 | 0 | 2 | 2 | 1 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Protocol Violation | 0 | 1 | 1 | 1 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 5 | 4 | 4 |
Baseline characteristics
| Characteristic | Placebo | Total | 400mg SPN-812 | 300mg SPN-812 | 200mg SPN-812 | 100mg SPN-812 |
|---|---|---|---|---|---|---|
| ADHD RS-IV Hyperactivity/ Impulsivity Subscale Score | 20.5 scores on a scale STANDARD_DEVIATION 4.4 | 20.3 scores on a scale STANDARD_DEVIATION 5.14 | 19.7 scores on a scale STANDARD_DEVIATION 4.43 | 19.4 scores on a scale STANDARD_DEVIATION 5.99 | 21.7 scores on a scale STANDARD_DEVIATION 5.1 | 20.3 scores on a scale STANDARD_DEVIATION 5.15 |
| ADHD RS-IV Inattention Subscale Score | 21.9 scores on a scale STANDARD_DEVIATION 4.72 | 21.8 scores on a scale STANDARD_DEVIATION 4.06 | 21.0 scores on a scale STANDARD_DEVIATION 4.71 | 21.8 scores on a scale STANDARD_DEVIATION 3.75 | 22.2 scores on a scale STANDARD_DEVIATION 3.57 | 22.1 scores on a scale STANDARD_DEVIATION 3.86 |
| ADHD RS-IV Total Score | 42.4 scores on a scale STANDARD_DEVIATION 7.76 | 42.1 scores on a scale STANDARD_DEVIATION 7.57 | 40.8 scores on a scale STANDARD_DEVIATION 7.87 | 41.3 scores on a scale STANDARD_DEVIATION 7.94 | 43.9 scores on a scale STANDARD_DEVIATION 7.45 | 42.4 scores on a scale STANDARD_DEVIATION 6.82 |
| Age, Continuous | 8.4 years STANDARD_DEVIATION 1.89 | 8.8 years STANDARD_DEVIATION 1.97 | 9.0 years STANDARD_DEVIATION 2.18 | 8.9 years STANDARD_DEVIATION 1.95 | 9.1 years STANDARD_DEVIATION 1.95 | 8.2 years STANDARD_DEVIATION 1.78 |
| Age, Customized 10 to 12 years | 8 Participants | 71 Participants | 17 Participants | 17 Participants | 20 Participants | 9 Participants |
| Age, Customized 6 to 9 years | 16 Participants | 135 Participants | 27 Participants | 30 Participants | 26 Participants | 36 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 7 Participants | 79 Participants | 15 Participants | 22 Participants | 16 Participants | 19 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 6 Participants | 1 Participants | 0 Participants | 1 Participants | 4 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 17 Participants | 117 Participants | 28 Participants | 24 Participants | 26 Participants | 22 Participants |
| Region of Enrollment United States | 24 participants | 206 participants | 44 participants | 47 participants | 46 participants | 45 participants |
| Sex: Female, Male Female | 13 Participants | 68 Participants | 13 Participants | 11 Participants | 13 Participants | 18 Participants |
| Sex: Female, Male Male | 11 Participants | 138 Participants | 31 Participants | 36 Participants | 33 Participants | 27 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 48 | 0 / 48 | 0 / 48 | 0 / 49 |
| other Total, other adverse events | 3 / 24 | 23 / 48 | 22 / 48 | 30 / 48 | 30 / 49 |
| serious Total, serious adverse events | 0 / 24 | 0 / 48 | 0 / 48 | 0 / 48 | 0 / 49 |
Outcome results
Primary
The Efficacy of SPN-812 on the Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV)
The Primary Endpoint was the change from baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) Total score at Week 8 (End of Study). The ADHD-RS-IV is an ADHD-specific rating scale designed and validated to assess current ADHD symptomatology. The scale consists of 18 items that directly correspond to the 18 Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) symptoms of ADHD. Each item is rated on a 4-point Likert-type scale from 0 (never or rarely) to 3 (very often). A Total score is calculated by adding the responses of all 18 items (range: 0-54; the higher the score, the more severe the ADHD symptoms). Lower change from baseline scores (\<0) represent a better outcome.
Time frame: Baseline to Week 8 (End of Study)
Population: Intent-to-Treat (ITT) Population: The ITT population includes subjects who were randomized, took at least one dose of study medication, have a baseline Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) assessment and have at least one post-baseline ADHD-RS-IV assessment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | The Efficacy of SPN-812 on the Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) | -10.5 units on a scale | Standard Deviation 11.82 |
| 100mg SPN-812 | The Efficacy of SPN-812 on the Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) | -16.7 units on a scale | Standard Deviation 14.57 |
| 200mg SPN-812 | The Efficacy of SPN-812 on the Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) | -18.4 units on a scale | Standard Deviation 15.61 |
| 300mg SPN-812 | The Efficacy of SPN-812 on the Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) | -18.6 units on a scale | Standard Deviation 14.38 |
| 400mg SPN-812 | The Efficacy of SPN-812 on the Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) | -19.0 units on a scale | Standard Deviation 14.51 |
p-value: 0.026895% CI: [-15.3, -0.9]ANOVA
p-value: 0.020995% CI: [-15.8, -1.3]ANOVA
p-value: 0.089995% CI: [-13.4, 1]ANOVA
p-value: 0.03195% CI: [-15.1, -0.7]ANOVA
Secondary
Effect of SPN-812 on Clinical Global Impression - Improvement (CGI-I) Scale
The first additional secondary endpoint was the Clinical Global Impression-Improvement (CGI-I) Scale score at Week 8 (End of Study). The CGI-I scale is a single item assessment of how much the patient's illness has improved or worsened relative to a baseline state prior to the beginning of treatment. The CGI-I is rated on a 7-point Likert scale from 1 to 7, where 1 = Very much improved, 2 = Much improved, 3 = Minimally improved, 4 = No change, 5 = Minimally worse, 6 = Much worse, and 7 = Very much worse. Successful therapy is indicated by a lower score (\<4) in subsequent testing.
Time frame: Week 8 (End of Study)
Population: Intent-to-Treat (ITT) Population: The ITT population includes subjects who were randomized, took at least one dose of study medication, have a baseline Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) assessment and have at least one post-baseline ADHD-RS-IV assessment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Effect of SPN-812 on Clinical Global Impression - Improvement (CGI-I) Scale | 3.0 units on a scale | Standard Deviation 0.88 |
| 100mg SPN-812 | Effect of SPN-812 on Clinical Global Impression - Improvement (CGI-I) Scale | 2.6 units on a scale | Standard Deviation 1.1 |
| 200mg SPN-812 | Effect of SPN-812 on Clinical Global Impression - Improvement (CGI-I) Scale | 2.6 units on a scale | Standard Deviation 1.26 |
| 300mg SPN-812 | Effect of SPN-812 on Clinical Global Impression - Improvement (CGI-I) Scale | 2.2 units on a scale | Standard Deviation 1.25 |
| 400mg SPN-812 | Effect of SPN-812 on Clinical Global Impression - Improvement (CGI-I) Scale | 2.4 units on a scale | Standard Deviation 1.13 |
p-value: 0.130595% CI: [-1, 0.1]ANOVA
p-value: 0.137695% CI: [-1, 0.1]ANOVA
p-value: 0.00995% CI: [-1.3, -0.2]ANOVA
p-value: 0.054695% CI: [-1.1, 0]ANOVA
Secondary
Effect of SPN-812 on the Clinical Global Impression - Severity (CGI-S) Scale
The second additional secondary endpoint was the change from baseline in the Clinical Global Impression-Severity (CGI-S) Scale score at Week 8 (End of Study). The CGI-S scale is a single item clinician/investigator rating of the clinician's assessment of the severity of the ADHD symptoms in relation to the clinician's total experience with patients with ADHD. The CGI-S was rated on a 7-point Likert scale, where 1 = Normal, not at all ill, 2 = Borderline Ill, 3 = Mildly Ill, 4 = Moderately Ill, 5 = Markedly Ill, 6 = Severely Ill, and 7 = Extremely Ill. Successful therapy is indicated by a lower CGI-S score in subsequent testing. A lower change from baseline score (\<0) represents a better outcome.
Time frame: Baseline to Week 8 (End of Study)
Population: Intent-to-Treat (ITT) Population: The ITT population includes subjects who were randomized, took at least one dose of study medication, have a baseline Attention-Deficit/Hyperactivity Disorder Rating Scale, 4th Edition (ADHD-RS-IV) assessment and have at least one post-baseline ADHD-RS-IV assessment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Effect of SPN-812 on the Clinical Global Impression - Severity (CGI-S) Scale | -0.8 units on a scale | Standard Deviation 0.98 |
| 100mg SPN-812 | Effect of SPN-812 on the Clinical Global Impression - Severity (CGI-S) Scale | -1.4 units on a scale | Standard Deviation 1.44 |
| 200mg SPN-812 | Effect of SPN-812 on the Clinical Global Impression - Severity (CGI-S) Scale | -1.5 units on a scale | Standard Deviation 1.44 |
| 300mg SPN-812 | Effect of SPN-812 on the Clinical Global Impression - Severity (CGI-S) Scale | -1.6 units on a scale | Standard Deviation 1.37 |
| 400mg SPN-812 | Effect of SPN-812 on the Clinical Global Impression - Severity (CGI-S) Scale | -1.7 units on a scale | Standard Deviation 1.41 |
p-value: 0.070895% CI: [-1.3, 0.1]ANCOVA
p-value: 0.030995% CI: [-1.4, -0.1]ANCOVA
p-value: 0.014895% CI: [-1.5, -0.2]ANCOVA
p-value: 0.013695% CI: [-1.6, -0.2]ANCOVA