Attention-deficit/Hyperactivity Disorder
Conditions
Keywords
ADHD
Brief summary
The purpose of this study is to determine effectiveness of Vyvanse compared to Concerta in adolescents with Attention-deficit/Hyperactivity Disorder (ADHD).
Interventions
DRUGLisdexamfetamine dimesylate
Daily oral dosing in the AM ranging from 30- 70 mg. 4 week forced dose titration, 2 week dose maintenance
DRUGMethylphenidate Hydrochloride
Daily oral dosing in the AM ranging from 18-72 mg. 4 week force dose titration, 2 week dose maintenance
DRUGPlacebo
Daily oral dosing in the AM for 6 weeks
Sponsors
Shire
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
13 Years to 17 Years
Healthy volunteers
No
Inclusion criteria
* Subject must be 13-17 years of age, inclusive, at the time of consent. * Subject must weigh more than 79.5lb. * The parent/LAR must be available at approximately 7:00AM (±2 hours) to dispense the dose of investigational product for the study duration. * Subject, who is a female, must have a negative serum beta human chorionic gonadotropin (β-HCG) pregnancy test and a negative urine pregnancy test and agree to comply with any applicable contraceptive requirements of the protocol. * Subject has an ADHD-RS-IV total score ≥28. * Subject is able to swallow a capsule. * Subject does not have hypertension and has a resting sitting blood pressure less than or equal to 135/85mmHg.
Exclusion criteria
* Subject has a current, controlled (with medications prohibited in this study) or uncontrolled, comorbid psychiatric diagnosis with significant symptoms such as any significant comorbid Axis II disorder or significant Axis I disorder (such as post traumatic stress disorder, psychosis, bipolar illness, pervasive developmental disorder, severe obsessive compulsive disorder, depressive or anxiety disorder. * Diagnosis of conduct disorder. Oppositional defiant disorder is not exclusionary. * Subject is considered a suicide risk, has previously made a suicide attempt, or is currently demonstrating active suicidal ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded. * Subject is underweight or overweight. * Subject has a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process requiring antibiotics), disability, or other condition. Mild, stable asthma is not exclusionary. * Subject has a history of seizures (other than infantile febrile seizures), a chronic or current tic disorder, or a current diagnosis and/or a known family history of Tourette's Disorder. * Subject has a known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems that may place him/her at increased vulnerability to the sympathomimetic effects of a stimulant medication. * Subject has a known family history of sudden cardiac death or ventricular arrhythmia. * Subject has any clinically significant ECG or clinically significant laboratory abnormality. * Subject has current abnormal thyroid function, defined as abnormal thyroid stimulating hormone (TSH) and thyroxine (T4). Treatment with a stable dose of thyroid medication for at least 3 months is permitted. * Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in the investigational product. * Subject has a documented allergy, hypersensitivity, or intolerance to MPH or to any excipients in the reference product. * Subject has failed to fully respond to an adequate course(s) (dose and duration) of MPH or amphetamine therapy. * Subject has a history of suspected substance abuse or dependence disorder (excluding nicotine). Subjects with a lifetime history of amphetamine, cocaine, or other stimulant abuse and/or dependence will be excluded. * Subject has a positive urine drug result. * Subject has previously participated in this study or another clinical study involving SPD489/NRP104. * Subject has glaucoma. * Subject is required to take or anticipates the need to take medications that have CNS effects or affect performance, such as sedating antihistamines and decongestant sympathomimetics, or are monoamine oxidase inhibitors. Stable use of bronchodilator inhalers is not exclusionary. * Subject is female and is pregnant or lactating. * Subject is well controlled on his/her current ADHD medication. * Subject has a pre-existing severe gastrointestinal tract narrowing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6 | Baseline, Week 6 | The ADHD-RS-IV was developed to measure the behaviors of children with ADHD and is commonly used in clinical studies of ADHD. The ADHD-RS-IV consisted of 18 items designed to reflect current symptomatology of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision (DSM-IV-TR) criteria. Each item was scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54, Higher score = more severe symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With an Improvement on Clinical Global Impression - Global Improvement (CGI-I) at Week 6 | Week 6 | The Clinical Global Impressions Scale permits a global evaluation of the participant's severity of illness and improvement over time. The scale included a severity of illness item and a global improvement item. The investigator performed the CGI-I to rate the improvement of a participant's ADHD symptoms based on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse.). Percentage of participants with an improved measurement (response of very much improved and much improved) is reported. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Baseline up to 3 days after last dose (last dose at Week 6) | An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were events between first dose of double-blind investigational product and up to 3 days after last dose that were absent before treatment or that worsened relative to pretreatment state. |
| Change From Baseline in Blood Pressure at Week 6 | Baseline, Week 6 | — |
| Change From Baseline in Pulse Rate at Week 6 | Baseline, Week 6 | — |
Countries
Canada, Germany, Hungary, Sweden, United States
Participant flow
Recruitment details
The study was conducted at 77 sites in the United States, Canada, and Europe.
Pre-assignment details
Of the 778 screened participants, 229 were screen failures and 549 were randomized to treatment. A total of 547 participants were treated and the reasons for 2 'randomized but not treated' participants included withdrawal by 1 participant in the Methylphenidate group and 1 participant with a protocol violation in the Lisdexamfetamine group.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 2 placebo over encapsulated capsules once daily orally for 6 weeks. | 110 |
| Lisdexamfetamine Dimesylate Lisdexamfetamine dimesylate (LDX, Vyvanse®, SPD489) 30 to 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 4 weeks (forced dose titration), followed by LDX 70 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule for 2 weeks (dose maintenance). | 218 |
| Methylphenidate Methylphenidate (Concerta, OROS-MPH) 18 to 72 mg over encapsulated capsule once daily orally along with placebo over encapsulated capsule (no placebo administered when methylphenidate 72 mg \[2\*36 mg capsules\] was administered) for 4 weeks (forced dose titration), followed by methylphenidate 72 mg (2\*36 mg capsules) over encapsulated capsule once daily orally for 2 weeks (dose maintenance). | 219 |
| Total | 547 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 15 | 14 |
| Overall Study | Lack of Efficacy | 4 | 3 | 1 |
| Overall Study | Lost to Follow-up | 1 | 3 | 6 |
| Overall Study | Other | 3 | 4 | 3 |
| Overall Study | Protocol Violation | 3 | 3 | 3 |
| Overall Study | Withdrawal by Subject | 1 | 9 | 6 |
Baseline characteristics
| Characteristic | Placebo | Lisdexamfetamine Dimesylate | Methylphenidate | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 110 Participants | 218 Participants | 219 Participants | 547 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 14.7 years STANDARD_DEVIATION 1.37 | 14.6 years STANDARD_DEVIATION 1.38 | 14.7 years STANDARD_DEVIATION 1.42 | 14.7 years STANDARD_DEVIATION 1.4 |
| Attention-deficit/Hyperactivity Disorder (ADHD) Subtype Combined Subtype | 68 Participants | 146 Participants | 144 Participants | 358 Participants |
| Attention-deficit/Hyperactivity Disorder (ADHD) Subtype Predominantly Hyperactive/Impulsive | 2 Participants | 2 Participants | 4 Participants | 8 Participants |
| Attention-deficit/Hyperactivity Disorder (ADHD) Subtype Predominantly Inattentive | 40 Participants | 70 Participants | 71 Participants | 181 Participants |
| Attention-deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Total Score | 36.1 units on a scale STANDARD_DEVIATION 5.91 | 37.2 units on a scale STANDARD_DEVIATION 6.46 | 36.9 units on a scale STANDARD_DEVIATION 6.42 | 36.9 units on a scale STANDARD_DEVIATION 6.34 |
| Clinical Global Impressions - Severity of Illness (CGI-S) Borderline mentally ill | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Clinical Global Impressions - Severity of Illness (CGI-S) Markedly ill | 41 Participants | 106 Participants | 90 Participants | 237 Participants |
| Clinical Global Impressions - Severity of Illness (CGI-S) Mildly ill | 2 Participants | 4 Participants | 1 Participants | 7 Participants |
| Clinical Global Impressions - Severity of Illness (CGI-S) Moderately ill | 60 Participants | 93 Participants | 115 Participants | 268 Participants |
| Clinical Global Impressions - Severity of Illness (CGI-S) Severely ill | 6 Participants | 15 Participants | 13 Participants | 34 Participants |
| Sex: Female, Male Female | 34 Participants | 83 Participants | 69 Participants | 186 Participants |
| Sex: Female, Male Male | 76 Participants | 135 Participants | 150 Participants | 361 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 32 / 110 | 113 / 218 | 99 / 219 |
| serious Total, serious adverse events | 1 / 110 | 1 / 218 | 1 / 219 |
Outcome results
Primary
Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6
The ADHD-RS-IV was developed to measure the behaviors of children with ADHD and is commonly used in clinical studies of ADHD. The ADHD-RS-IV consisted of 18 items designed to reflect current symptomatology of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, 4th Edition-Text Revision (DSM-IV-TR) criteria. Each item was scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54, Higher score = more severe symptoms.
Time frame: Baseline, Week 6
Population: Full Analysis Set (FAS) was defined as all participants in the Safety set who had at least 1 post-baseline measurement of the ADHD-RS-IV. Not all FAS participants were evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6 | -17 units on a scale | Standard Error 1.03 |
| Lisdexamfetamine Dimesylate | Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6 | -25.4 units on a scale | Standard Error 0.74 |
| Methylphenidate | Change From Baseline in Attention-Deficit/Hyperactivity Disorder Rating Scale, Fourth Edition (ADHD-RS-IV) Total Score at Week 6 | -22.1 units on a scale | Standard Error 0.73 |
Comparison: The least squares mean (LSM), the difference in LSM and its 95% confidence interval (CI), and the p-value were from a mixed effects model for repeated measures that included treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on Restricted maximum likelihood (REML) method of estimation and utilized an unstructured covariance.p-value: =0.001395% CI: [-5.4, -1.3]Mixed Models Analysis
Comparison: The LSM, the difference in LSM and its 95% CI, and the p-value were from a mixed effects model for repeated measures that included treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on REML method of estimation and utilized an unstructured covariance.p-value: <0.000195% CI: [-11, -6]Mixed Models Analysis
Comparison: The LSM, the difference in LSM and its 95% CI, and the p-value were from a mixed effects model for repeated measures that includes treatment group, visit, interaction of the treatment group with the visit as factors, baseline score as a covariate, and an adjustment for the interaction of the baseline score with the visit. The model was based on REML method of estimation and utilized an unstructured covariance.p-value: <0.000195% CI: [-7.6, -2.6]Mixed Models Analysis
Secondary
Percentage of Participants With an Improvement on Clinical Global Impression - Global Improvement (CGI-I) at Week 6
The Clinical Global Impressions Scale permits a global evaluation of the participant's severity of illness and improvement over time. The scale included a severity of illness item and a global improvement item. The investigator performed the CGI-I to rate the improvement of a participant's ADHD symptoms based on a 7-point scale (1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; or 7=very much worse.). Percentage of participants with an improved measurement (response of very much improved and much improved) is reported.
Time frame: Week 6
Population: FAS.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Percentage of Participants With an Improvement on Clinical Global Impression - Global Improvement (CGI-I) at Week 6 | 50 percentage of participants |
| Lisdexamfetamine Dimesylate | Percentage of Participants With an Improvement on Clinical Global Impression - Global Improvement (CGI-I) at Week 6 | 81.4 percentage of participants |
| Methylphenidate | Percentage of Participants With an Improvement on Clinical Global Impression - Global Improvement (CGI-I) at Week 6 | 71.3 percentage of participants |
Other Pre-specified
Change From Baseline in Blood Pressure at Week 6
Time frame: Baseline, Week 6
Population: Safety set. Not all Safety set participants were evaluable for this outcome measure.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Change From Baseline in Blood Pressure at Week 6 | Systolic blood pressure | -1 millimeter of mercury (mmHg) | Standard Deviation 9.88 |
| Placebo | Change From Baseline in Blood Pressure at Week 6 | Diastolic blood pressure | -0.1 millimeter of mercury (mmHg) | Standard Deviation 8.1 |
| Lisdexamfetamine Dimesylate | Change From Baseline in Blood Pressure at Week 6 | Systolic blood pressure | 1.5 millimeter of mercury (mmHg) | Standard Deviation 9.56 |
| Lisdexamfetamine Dimesylate | Change From Baseline in Blood Pressure at Week 6 | Diastolic blood pressure | 3.4 millimeter of mercury (mmHg) | Standard Deviation 8.15 |
| Methylphenidate | Change From Baseline in Blood Pressure at Week 6 | Systolic blood pressure | 2.4 millimeter of mercury (mmHg) | Standard Deviation 9.97 |
| Methylphenidate | Change From Baseline in Blood Pressure at Week 6 | Diastolic blood pressure | 3.5 millimeter of mercury (mmHg) | Standard Deviation 8.59 |
Other Pre-specified
Change From Baseline in Pulse Rate at Week 6
Time frame: Baseline, Week 6
Population: Safety set. Not all Safety set participants were evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Pulse Rate at Week 6 | 2.4 Beats per minute | Standard Deviation 10.81 |
| Lisdexamfetamine Dimesylate | Change From Baseline in Pulse Rate at Week 6 | 6.7 Beats per minute | Standard Deviation 12.46 |
| Methylphenidate | Change From Baseline in Pulse Rate at Week 6 | 8.2 Beats per minute | Standard Deviation 12.7 |
Other Pre-specified
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
An adverse event (AE) was defined as any untoward medical occurrence in a clinical investigation participant administered as a pharmaceutical product that did not necessarily have a causal relationship with this treatment. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. TEAEs were events between first dose of double-blind investigational product and up to 3 days after last dose that were absent before treatment or that worsened relative to pretreatment state.
Time frame: Baseline up to 3 days after last dose (last dose at Week 6)
Population: Safety set.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 49 participants |
| Placebo | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with serious TEAEs | 1 participants |
| Lisdexamfetamine Dimesylate | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 145 participants |
| Lisdexamfetamine Dimesylate | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with serious TEAEs | 1 participants |
| Methylphenidate | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 129 participants |
| Methylphenidate | Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with serious TEAEs | 1 participants |