Safety and Efficacy of SPD489 on Executive Function Behaviors in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD)

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the efficacy of SPD489 compared to placebo on executive function (self-regulation) behaviors in adults with ADHD who report clinically significant impairment of executive function behavior in their everyday environment, as measured by the self-report Behavior Rating Inventory of Executive Function - Adult Version (BRIEF-A) Global Executive Composite (GEC) T-score.

Official Title
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A Phase 4, Randomized, Double-Blind, Multicenter, Placebo-controlled, Parallel Group Study Evaluating the Safety and Efficacy of SPD489 on Executive Function (Self-Regulation) Behaviors in Adults With Attention-Deficit/Hyperactivity Disorder (ADHD) Reporting Clinically Significant Impairment of Real-World Executive Function Behavior.

Conditions
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ADHD Specifically With Executive Function Impairment

Intervention / Treatment
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* Drug: SPD489
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject must be 18-55 years of age, inclusive at the time of consent. Subject has an established close relationship of at least 6-months duration before screening (Visit -1) with an informant who will be able to observe and be willing to report on the subject's behavior and symptoms in multiple social settings during the course of the study. Informant is defined as a person who has a domicile relationship with the subject. When applicable, the informant should be the subject's spouse/significant other. Additionally, the informant cannot participate as a subject in the study and can only serve as the informant for a single subject. Subject has a lifestyle that in the opinion of the Investigator will enable the subject to complete all study testing and requirements defined in the protocol. Female subjects must have a negative serum beta human chorionic gonadotropin (HCG) pregnancy test at screening (Visit -1) and a negative urine pregnancy test at baseline (Visit 0) and agree to comply with any applicable contraceptive requirements of the protocol. Subject meets the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD (diagnostic code 314.00 and 314.01) established by a comprehensive psychiatric evaluation that reviews DSM-IV-TR criteria with at least 6 of the 9 subtype criteria met. The Adult ADHD Clinical Diagnostic Scale version 1.2 (ACDS v1.2) will be utilized as the diagnostic tool. Subject has a total score of ≥65 on BRIEF-A GEC T-score by self-report at baseline (Visit 0). Subject has a total score of ≥28 using the Adult ADHD-RS with prompts at baseline (Visit 0). Subject must have a minimum level of intellectual functioning as determined by the Investigator at screening (Visit -1). Subject is able to swallow a capsule. Subject is willing and able to comply with all the testing and requirements defined in this protocol. Subject and informant must be able to provide written, personally signed and dated informed consent to participate in the study in accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines and applicable regulations before completing any study related procedures. Exclusion Criteria Subject has a current comorbid psychiatric disorder that is either controlled with medications prohibited in this study or is uncontrolled and associated with significant symptoms. Prohibited disorders include those associated with diagnoses including but not limited to any severe comorbid Axis II disorder or severe Axis I disorder (such as Post Traumatic Stress Disorder [PTSD], psychosis, bipolar illness, pervasive developmental disorder, severe obsessive compulsive disorder, severe depressive or severe anxiety disorder). Other symptomatic manifestations (such as agitated states) that contraindicate treatment with SPD489 or confound efficacy or safety assessments in the opinion of the examining physician are also prohibited. Comorbid psychiatric diagnoses will be established by the psychiatric evaluation that includes the Structured Clinical Interview for DSM-IV-TR disorders (SCID-I). Subjects who are currently considered a suicide risk, any subject who has previously made a suicide attempt or those who are currently demonstrating active suicidal ideation. The subject has a body mass index (BMI) of <18.5 or ≥40. Subject has a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process requiring antibiotics), disability, or other condition that might confound the results of safety assessments administered in the study or that might increase risk to the subject. Similarly, the subject will be excluded if he or she has any additional condition(s) that in the Investigator's opinion would prohibit the subject from completing the study or would not be in the best interest of the subject. This would include any significant illness or unstable medical condition that could lead to difficulty complying with the protocol. Mild, stable asthma is not exclusionary. Subject has a history of seizures (other than infantile febrile seizures), any tic disorder, a current diagnosis and/or a known family history of Tourette's Disorder. Subject has known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, transient ischemic attack or stroke or other serious cardiac problems that may place them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Subject has a known family history of sudden cardiac death or ventricular arrhythmia. Subject has any clinically significant ECG or clinically significant laboratory abnormality at screening (Visit -1). Subject has current abnormal thyroid function, defined as abnormal screening 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 history of moderate to severe hypertension or has a resting sitting systolic blood pressure >139mmHg or diastolic blood pressure >89mmHg. Subjects with well-controlled mild or moderate hypertension on a single antihypertensive agent are allowed. Combination antihypertensive medications are not allowed. Subject is taking any medication that is excluded. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamines. Subject has a documented allergy, hypersensitivity, or intolerance to any excipients in the investigational medicinal product. Subject has failed to respond to one or more adequate courses (dose and duration) of amphetamine therapy. Subject has a recent history (within the past 6 months) of suspected substance abuse or dependence disorder (excluding nicotine) in accordance with DSM-IV-TR criteria. Subject has a positive urine drug result at screening (Visit -1) (with the exception of subject's current stimulant therapy, if any). Subject has taken an investigational drug or taken part in a clinical trial, including an SPD489 clinical trial, within 30 days prior to screening (Visit -1). Subject has glaucoma. Subject is taking other medications that have central nervous system (CNS) effects or affect performance, such as sedating antihistamines and decongestant sympathomimetics, or are monoamine oxidase inhibitors (during or within 7 days of investigational medicinal product administration). Stable use of bronchodilator inhalers is not exclusionary. Subject is female and pregnant or lactating. Subjects who have previously been randomized into this study and subsequently withdrawn. Subject is well controlled on their current ADHD medication with acceptable tolerability.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: SPD489<br> | Drug: SPD489<br>* 1 capsule per day (30, 50 or 70 mg), daily throughout the double-blind treatment period (10 weeks)<br>* Other names: Vyvanse;|
| Placebo Comparator: Placebo<br> | Other: Placebo<br>* 1 capsule per day, daily throughout the double-blind treatment period (10 weeks)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Subject-reported Behavior Rating Inventory of Executive Function - Adult Version Global Executive Composite T-score (BRIEF-A GEC T) at up to 10 Weeks | BRIEF-A Global Executive Composite assesses behavioral aspects of executive function. Items are rated 1 (never), 2 (sometimes), and 3 (often). There is no range for a total score. Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline and up to 10 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Adult ADHD Impact Module (AIM-A) Multi-Item Scales Total Score at up to 10 Weeks | The AIM-A was developed to assess impact of core ADHD symptoms on daily functioning and quality of life. For multi-item scales, subjects respond to items using a Likert scale with responses ranging from 1 (strongly agree) to 5 (strongly disagree). Scores were computed by deriving the mean of the item sets and transforming the scale score on a continuum from 0 to 100 using a standard formula. Higher scores indicate a better quality of life. | Baseline and up to 10 weeks | 
| Change From Baseline in Informant-reported BRIEF-A T-scores at up to 10 Weeks | BRIEF-A is a validated 75-item questionnaire composed of three indexes (Global Executive Composite, Behavioral Recognition Index, and Metacognition Index). Items are rated 1 (never), 2 (sometimes), and 3 (often). Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline and up to10 weeks | 
| Change From Baseline in Subject-reported BRIEF-A T-scores at up to 10 Weeks | BRIEF-A is a validated 75-item questionnaire composed of three indexes (Global Executive Composite, Behavioral Recognition Index, and Metacognition Index). Global Executive Composite was reported as the Primary Outcome. Items are rated 1 (never), 2 (sometimes), and 3 (often). There is no range for a total score. Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline and up to 10 weeks | 
| Change From Baseline in Subject-reported BRIEF-A Clinical Subscales T-scores at up to 10 Weeks | BRIEF-A clinical subscales items are rated 1 (never), 2 (sometimes), and 3 (often). There is no range for a total score. Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline and up to 10 weeks | 
| Change From Baseline in Informant-reported BRIEF-A Clinical Subscales T-scores at up to 10 Weeks | BRIEF-A clinical subscales items are rated 1 (never), 2 (sometimes), and 3 (often). There is no range for a total score. Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline and up to 10 weeks | 
| Change From Baseline in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS) With Adult Prompts Total Score at up to 10 Weeks | The ADHD-RS 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. Lower scores indicate reduction in symptoms. | Baseline and up to 10 weeks | 
| Percent of Participants With Clinical Global Impression - Severity of Illness (CGI-S) at Baseline | 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) | Baseline | 
| Percent of Participants With Clinical Global Impression - Severity of Illness (CGI-S) at up to 10 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) | Up to 10 weeks post-dose | 
| Percent of Participants With Improvement on Clinical Global Impression - Global Improvement (CGI-I) at up to 10 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. | Up to 10 weeks post-dose | 
| Change From Baseline in AIM-A Multi-Item Scales of Living With ADHD and General Well-being Score at up to 10 Weeks | The AIM-A was developed to assess impact of core ADHD symptoms on daily functioning and quality of life. For multi-item scales, subjects respond to items using a Likert scale with responses ranging from 1 (strongly agree) to 5 (strongly disagree). Scores were computed by deriving the mean of the item sets and transforming the scale score on a continuum from 0 to 100 using a standard formula. Higher scores indicate a better quality of life. | Baseline and up to 10 weeks | 
| Change From Baseline in AIM-A Quality of Life Questions 1 and 4 Scores at up to 10 Weeks | Question 1: 'On a scale of 1 to 10, how would you rate the overall quality of life right now?' It is rated on a scale of 1 (worst) to 10 (best). Higher scores representing a more positive rating. Question 4: 'How much do you agree with this statement: Over the past few weeks, I've had more good days than bad days?' This is rated on a scale of 1 (strongly agree) to 5 (strongly disagree). Lower scores represent better quality of life. | Baseline and up to 10 weeks | 
| Change From Baseline in Conner's Adult ADHD Rating Scale-Observer: Short Version (CAARS-O:S) ADHD Index T-score at up to 10 Weeks | The CAARS-O:S is an assessment tool with prompts provided to an observer who describes ADHD-related symptoms in an adult subject. The 26-item scale is scored on a 4-point scale from 0 (not at all) to 3 (very much, very frequently). There is no range for a total score. Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline and up to 10 weeks | 
| Change From Baseline in CAARS-O:S Factor-derived Subscale T-scores at up to 10 Weeks | The CAARS-O:S is an assessment tool with prompts provided to an observer who describes ADHD-related symptoms in an adult subject. The 26-item scale is scored on a 4-point scale from 0 (not at all) to 3 (very much, very frequently). There is no range for a total score. Raw scale scores are used to generate T-scores. A reduction in score indicates less impairment. | Baseline and up to 10 weeks | 
| Change From Baseline in Adult ADHD Quality of Life (AAQoL) Scale Total Score at up to 10 Weeks | AAQoL is a validated 29-item scale consisting of 4 subscales. The AAQoL yields a total score and 4 subscale scores. Subjects rate each item on a 5-point Likert scale ranging from 1 (not at all/never) to 5 (extremely/very often). These scores are then transformed to a 0-100 point scale with higher scores indicating better quality of life. | Baseline and up to 10 weeks |