Double-blind, Placebo-controlled, Randomised Withdrawal, Extension, Safety and Efficacy Study of LDX in Children and Adolescents Aged 6-17

Study Overview
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Brief Summary
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The main aim of this study is to evaluate the long-term maintenance of efficacy of LDX after administered to children and adolescents aged 6-17 with ADHD for at least 6 months

Official Title
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A Phase III, Double-blind, Placebo-controlled, Randomised Withdrawal, Multicentre, Extension, Safety and Efficacy Study of Lisdexamfetamine Dimesylate (LDX) in Children and Adolescents Aged 6-17 With Attention- Deficit/Hyperactivity Disorder (ADHD)

Conditions
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ADHD

Intervention / Treatment
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* Drug: Lisdexamfetamine dimesylate (LDX)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject's parent or legally authorised representative(LAR) must provide signature of informed consent, and there must be documentation of assent (if applicable) by the subject indicating that the subject is aware of the investigational nature of the study and the required procedures and restrictions in accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 and applicable regulations before completing any study-related procedures. Subject and parent/LAR are willing and able to comply with all the testing and requirements defined in this protocol, including oversight of morning dosing. Specifically, the parent/LAR must be available upon awakening, at approximately 7:00AM, to dispense the dose of test product for the duration of the study. Subject is a male or female aged 6-17 years inclusive at the time of consent for the antecedent study (SPD489-325). Subject satisfied all entry criteria for the antecedent study (SPD489-325), and completed a minimum of 4 weeks of double-blind treatment, reached Visit 4 and completed the 1-week post-treatment washout in the antecedent study (SPD489-325), without experiencing any clinically significant AEs that would preclude exposure to LDX. Subject must have a satisfactory medical assessment with no clinically significant or relevant abnormalities as determined by medical history, physical examination findings and clinical laboratory test results. Subject has blood pressure measurements within the 95th percentile for age, gender, and height. Exclusion Criteria: Subject was terminated from SPD489-325 for non-compliance and/or experienced an SAE or AE resulting in termination from the antecedent study. Subject has a current, controlled (requiring a restricted medication) or uncontrolled, comorbid psychiatric diagnosis with significant symptoms such as any severe comorbid Axis II disorder or severe Axis I disorder (such as Post Traumatic Stress Disorder, psychosis, bipolar illness, pervasive developmental disorder, severe obsessive compulsive disorder, severe depressive or severe anxiety disorder) or other symptomatic manifestations, such as agitated states, marked anxiety, or tension that, in the opinion of the examining clinician, will contraindicate treatment with LDX or confound efficacy or safety assessments. Comorbid psychiatric diagnoses will be established at the Screening Visit (Visit -1)of the antecedent study (SPD489-325)with the Screening interview of the Kiddie-SADS-Present and Lifetime-Diagnostic Interview (K-SADS-PL)and additional modules if warranted by the results of the initial interview. Participation in behavioural therapy is permitted provided the subject was receiving the therapy for at least 1 month at the time of the Baseline Visit (Visit 0) of the antecedent study (SPD489-325). Subject has a conduct disorder. Oppositional defiant disorder is not exclusionary. Subject has any concurrent chronic or acute illness or unstable medical condition that could confound the results of safety assessments, increase risk to the subject or lead to difficulty complying with the protocol. Subject is currently considered a suicide risk, has previously made a suicide attempt or has a prior history of, or is currently, demonstrating active suicidal ideation. Subject is female and is pregnant or lactating. Subject has glaucoma. Subject has any clinically significant ECG at Visit 8 of the antecedent study (SPD489-325) or clinically significant laboratory abnormalities at Visit 7 of the antecedent study (SPD489-325). Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine. Subject has a recent history (within the past 6 months) of suspected substance abuse or dependence disorder (excluding nicotine)in accordance with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM-IV-TR)criteria. Subject has a history of seizures (other than infantile febrile seizures), a tic disorder, 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 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 is taking any medication that is excluded. Subject is taking other medications that have central nervous system (CNS) effects, affect performance, such as sedating antihistamines and decongestant sympathomimetics, or are monoamine oxidase inhibitors (during or within 14 days of investigational medicinal product administration). Stable use of bronchodilator inhalers is not exclusionary. Subject has a documented allergy, hypersensitivity, or intolerance to any excipients in the investigational medicinal product(s).

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lisdexamfetamine dimesylate (LDX)<br>Open-label 30, 50, or 70mg | Drug: Lisdexamfetamine dimesylate (LDX)<br>* LDX 30, 50, or 70mg capsule once per day (open-label and double-blind periods)<br>* Other names: Vyvanse, SPD489;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Placebo capsule once per day (double-blind period)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent of Participants With Treatment Failures at End of The Randomized Withdrawal Period | Treatment failure defined as 50% increase (worsening) in Attention Deficit Hyperactivity Disorder Rating Scale (ADHD-RS-IV) total score and >= 2 point increase (worsening) in the Clinical Global Impression-Severity of Illness (CGI-S) score observed at any visit during the randomized withdrawal period compared to the respective scores at baseline of randomized withdrawal period. Subjects without an endpoint value were classed as treatment failures. | Baseline of the randomized withdrawal period and its relevant endpoint (Up to 6 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Open-Label Baseline in The Attention Deficit Hyperactivity Disorder Rating Scale-Fourth Edition (ADHD-RS-IV) Total Score at Endpoint (Week-26) of The Open-label Period | ADHD-RS-IV consists of 18 items scored on a 4-point scale from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54. A decrease in score indicates an improvement in ADHD symptomology. | Open-label baseline and Endpoint (Week-26) | 
| Change From Randomized Withdrawal Baseline in The ADHD-RS-IV Total Score at Endpoint of The Randomized Withdrawal Period | ADHD-RS-IV consists of 18 items scored on a 4-point scale from 0 (no symptoms) to 3 (severe symptoms) with total score ranging from 0 to 54. A decrease in score indicates an improvement in ADHD symptomology. | Baseline of the randomized withdrawal period and its relevant endpoint (Up to 6 weeks) | 
| Percent of Participants With Clinical Global Impression - Severity of Illness (CGI-S) at Endpoint (Week-26) of The Open-label Period | 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) | At Week 26 | 
| Percent of Participants With CGI-S at Endpoint of The Randomized Withdrawal Period, Last Observation Carried Forward (LOCF) | 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) | At endpoint of the randomized withdrawal period (Up to 6 weeks) | 
| Percent of Participants With Improvement on Clinical Global Impression - Improvement (CGI-I) at Endpoint (Week-26) of The Open-label Period | 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. Improvement includes CGI-I categories of very much improved and much improved. No improvement includes all other assessed categories. | At Week 26 | 
| Change From Open-label Baseline in The Health Utilities Index-2 (HUI-2) Scores at Endpoint (Week-26) of The Open-label Period, LOCF | HUI is used to describe health status and to obtain utility scores by collecting data using one or more questionnaires in formats selected to match the specific study design criteria. Scoring ranges from 0.00 (dead) to 1.00 (perfect health). Higher scores represent better health status. | At open-label baseline and endpoint (Week-26) of the open-label period | 
| Change From Randomized Withdrawal Baseline in The HUI-2 Scores at Endpoint of The Randomized Withdrawal Period | HUI is used to describe health status and to obtain utility scores by collecting data using one or more questionnaires in formats selected to match the specific study design criteria. Scoring ranges from 0.00 (dead) to 1.00 (perfect health). Higher scores represent better health status. | Baseline of the randomized withdrawal period and its relevant endpoint (Up to 6 weeks) | 
| Change From Open-label Baseline in The Child Health and Illness Profile, Child Edition: Parent Report Form (CHIP-CE:PRF) Global T-score at Endpoint (Week-26) of The Open-label Period | The CHIP-CE:PRF evaluates health-related quality of life. It is composed of 5 domains (satisfaction, comfort, resilience, avoidance, and achievement) consisting of a total of 76 items. The global score is an average of the scores for the 5 domains. The majority of items assess frequency of events using a 5-point response format. There is no range for a total score. Raw scale scores are used to generate T-scores. Higher scores indicate better health. | At open-label baseline and endpoint (Week-26) of the open-label period | 
| Change From Randomized Withdrawal Baseline in The CHIP-CE:PRF Global T-score at Endpoint of The Randomized Withdrawal Period | The CHIP-CE:PRF evaluates health-related quality of life. It is composed of 5 domains (satisfaction, comfort, resilience, avoidance, and achievement) consisting of a total of 76 items. The global score is an average of the scores for the 5 domains. The majority of items assess frequency of events using a 5-point response format. There is no range for a total score. Raw scale scores are used to generate T-scores. Higher scores indicate better health. | Baseline of the randomized withdrawal period and its relevant endpoint (Up to 6 weeks) | 
| Change From Open-Label Baseline in The Weiss Functional Impairment Rating Scale - Parent Report (WFIRS-P) Global Score at Endpoint (Week-26) of The Open-label Period | The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. | At open-label baseline and endpoint (Week-26) of the open-label period | 
| Change From Randomized Withdrawal Baseline in The WFIRS-P Global Score at Endpoint of The Randomized Withdrawal Period | The WFIRS-P is a 50-item scale with each item scored from 0 (never/not at all) to 3 (very often/very much). Mean scores range from 0 to 3. Higher scores indicate greater functional impairment. | Baseline of the randomized withdrawal period and its relevant endpoint (Up to 6 weeks) | 
| Change From Open-Label Baseline in The Brief Psychiatric Rating Scale for Children (BPRS-C) Total Score at Endpoint (Week-26) of The Open-label Period | The BPRS-C characterizes psychopathology. A total of 21 items are rated on a scale from 0 (not present) to 6 (extremely severe) with a total score ranging from 0 to 126. A decrease in score indicates a reduction in psychopathology. | At open-label baseline and endpoint (Week-26) of the open-label period | 
| Change From Randomized Withdrawal Baseline in BPRS-C Total Score at Endpoint of The Randomized Withdrawal Period | The BPRS-C characterizes psychopathology. A total of 21 items are rated on a scale from 0 (not present) to 6 (extremely severe) with a total score ranging from 0 to 126. A decrease in score indicates a reduction in psychopathology. | Baseline of the randomized withdrawal period and its relevant endpoint (Up to 6 weeks) |