Comparing the Effectiveness of New Versus Older Treatments for Attention Deficit Hyperactivity Disorder (The NOTA Study)

Study Overview
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Brief Summary
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This study will determine whether two new psychostimulant medications are more effective, tolerable, and acceptable than two older medications for treating attention deficit hyperactivity disorder.

Detailed Description
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Attention deficit hyperactivity disorder (ADHD) is characterized by impulsiveness, hyperactivity, and inattention. It is seen primarily in children and adolescents and is often treated with psychostimulant medications. Osmotic-release oral system (OROS) methylphenidate, brand name Concerta, and mixed amphetamine salts extended release, brand name Adderall XR, are psychostimulant medications that have shown both efficacy (that they can have therapeutic benefits) and effectiveness (that they typically have therapeutic benefits in practice). Two newer psychostimulant medications-lisdexamfetamine dimesylate, brand name Vyvanse, and methylphenidate transdermal system, brand name Daytrana-have shown efficacy but have not been tested for effectiveness, nor have they been tested head-to-head against the older psychostimulants. This study will test the effectiveness, tolerability (lack of side effects), and acceptability (ease of use for patients) of the two newer psychostimulant medications and compare them to each other and to the two older psychostimulants. Participation in this study will last 6 weeks, although some treatments may continue past the end of the study. At enrollment, participants will undergo a series of baseline evaluations. These will include interviews and assessments of ADHD symptoms, concurrent psychiatric disorders, medical and psychiatric history, family history of mental illness, risk and protective factors, other treatments, treatment expectancy of both the youth and parent, and vital signs. In consultation with their doctors, participants will be allowed to exclude zero, one, or two of the study medications; if they choose to exclude both of the new ADHD medications, they will not able to participate in the study. Participants will then be randomly assigned to one of the treatments they choose to include. They will receive a prescription for the medication and instructions for how to use it from their doctors; the study protocol does not specify a particular treatment regimen. Participants will undergo a second set of evaluations after 6 weeks of treatment or before, if the treatment ends earlier. This will include interviews and assessments similar to those administered at baseline as well as evaluation of any medication side effects.

Official Title
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A Randomized Controlled Trial of Methylphenidate Transdermal System (Daytrana), Lisdexamfetamine Dimesylate (Vyvanse), OROS MPH (Concerta), and Mixed Amphetamine Salts Extended Release (Adderall XR) in Children and Adolescents With ADHD

Conditions
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Attention Deficit Disorder With Hyperactivity

Intervention / Treatment
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* Drug: Methylphenidate transdermal system
* Drug: Lisdexamfetamine dimesylate
* Drug: Osmotic-release oral system methylphenidate (OROS MPH)
* Drug: Mixed amphetamine salts extended release


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Meets DSM-IV diagnostic criteria for ADHD combined, hyperactive/impulsive, or inattentive subtype Outpatient at study entry Speaks English Willing to be randomly assigned to one of the study treatment options as outlined in the protocol No known significant history of cardiovascular disorders, including pre-existing congenital heart disease, structural heart disease, known clinically significant electrocardiogram (ECG) abnormality, or other clinically significant cardiac disorder Willing to initiate study medication for ADHD within 7 days of the study baseline visit May be receiving stable treatment with other drug for a comorbid disorder, defined as no changes in dose or form of drug treatment for at least 2 weeks prior to the study enrollment visit May be receiving psychosocial interventions for ADHD or a comorbid disorder, defined as no changes in form of psychosocial treatment for at least 4 weeks prior to the study enrollment visit Exclusion Criteria: Hypersensitivity to study medication Inpatient status at study entry Currently taking another medication for ADHD, including another psychostimulant, atomoxetine, or bupropion Receiving treatment with a tricyclic antidepressant at study enrollment, with the exception of low-dose imipramine for enuresis or amitriptyline for chronic pain Received treatment with a monoamine oxidase inhibitor (MAOI) within the past 30 days Psychostimulant drug dependence, bipolar disorder, or schizophrenia Presence of psychosis Severe mental retardation Autism or Asperger's syndrome Active suicidal ideation Unable or unwilling to comply with the protocol Demonstrates a lack of benefit from, an intolerance to, or contraindication to psychostimulant medicine Presence of other clinically significant medical conditions, including hyperthyroidism, epilepsy or other seizure disorder, any condition for which an increase in blood pressure or heart rate would be problematic, glaucoma or other significant eye disease for which a psychostimulant would be problematic, or pre-existing gastrointestinal obstruction with gastrointestinal narrowing Pregnant or positive result of pregnancy test

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 1<br>Participants will receive methylphenidate transdermal system. | Drug: Methylphenidate transdermal system<br>* Not specified in protocol; determined by local standard of care.<br>* Other names: Daytrana;|
| Active Comparator: 2<br>Participants will receive lisdexamfetamine dimesylate. | Drug: Lisdexamfetamine dimesylate<br>* Not specified in protocol; determined by local standard of care.<br>* Other names: Vyvanse;|
| Active Comparator: 3<br>Participants will receive osmotic-release oral system methylphenidate (OROS MPH). | Drug: Osmotic-release oral system methylphenidate (OROS MPH)<br>* Not specified in protocol; determined by local standard of care.<br>* Other names: Concerta;|
| Active Comparator: 4<br>Participants will receive mixed amphetamine salts extended release. | Drug: Mixed amphetamine salts extended release<br>* Not specified in protocol; determined by local standard of care.<br>* Other names: Adderall XR;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dichotomized Clinical Global Impression-Effectiveness (CGI-E) Scale | The CGI-E is the value at which the participant's Therapeutic Benefit and Adverse Impact to the study drug intersect. This number is determined by combining each participant's scores for the degree of Therapeutic Benefit versus the degree to which problems with Tolerability and/or Acceptability adversely impact the subject. Participants are then determined to be Responders or Non-responders to the study medication. For example, a subject who is very much improved (CGI-I=1) or much improved (CGI-I=2) therapeutically and whose adverse impact rating is none (score 1,5) or mild (score 2,6) will be categorized as a Responder. All others whose adverse impact rating is moderate (score 3,7,11,15)or outweighs therapeutic effect (score 4,8,12,16) will be categorized as Non-responders to study medication. The CGI scores are totaled for each participant and a mean score is calculated. A median total score was calculated for each treatment group. | Measured at each participant's last visit, which can occur at or before Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impressions-Improvement (CGI-I) Scale | The CGI-I score at the subject's last study visit at or before Week 6, is one of the 3 secondary endpoints that contribute to the primary endpoint (CGI-E). The CGI-I scale will be used to rate improvement in the subject's condition (benefits) since baseline using the following 7-point scale: 1=very much improved, 2=much improved, 3=minimally improved, 4=not changed, 5=minimally worse, 6=much worse; 7=very much worse. | Measured at each participant's last visit, which can occur at or before Week 6 | 
| Clinical Global Improvements-Acceptability (CGI-A) Scale | The CGI-A score at the subject's last study visit at or before Week 6 is one of the 3 secondary endpoints that contribute to the primary endpoint (CGI-E). The CGI-A will be used to assess the acceptability of the study medication with respect to the subject's experience with the formulation of medication. The 7-point rating for the CGI-A will be: 1=very high acceptability, 2=high acceptability, 3=above average acceptability, 4=average acceptability, 5=low acceptability, 6=very low acceptability, 7=extremely low acceptability | Measured at each participant's last visit, which can occur at or before Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ADHD, Methylphenidate, Amphetamine