Lisdexamfetamine Dimesylate 2-year Safety Study in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD)

Study Overview
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Brief Summary
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While the Lisdexamfetamine Dimesylate (SPD489) clinical program has studied the efficacy, safety, and tolerability of SPD489 in treating core symptoms of ADHD in children and adolescents aged 6-17 years and adults aged 18-55 years, the majority of these studies have been of short duration - up to 8 weeks. A number of long-term studies have been undertaken (up to 1 year) and these have confirmed the safety and ongoing efficacy in this patient population. In order to run a study with investigational medication within Poland the study changed to a Phase 3 rather than a Phase 4 study in that country. Please note that the study number remains as SPD489-404. Study SPD489-404 has been designed to further evaluate the long-term effects of SPD489 in children and adolescents over a 2-year treatment period.

Official Title
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A Phase 4, Open-Label, Multicentre, Safety Study of Lisdexamfetamine Dimesylate in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder (ADHD)

Conditions
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Attention Deficit Hyperactivity Disorder (ADHD)

Intervention / Treatment
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* Drug: Lisdexamfetamine dimesylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For subjects who participated in another SPD489 study (SPD489-317, SPD489-325, or SPD489 326): Subject is a male or female aged 6-17 years. Subject participated in SPD489-317, completed 9 weeks of treatment, and completed the 1 week post-treatment safety follow-up visit. For subjects who have not participated in another SPD489 study: Subject is a male or female aged 6-17 years. Subject must meet DSM-IV-TR criteria for a primary diagnosis of ADHD based on a detailed psychiatric evaluation. For all subjects: Subject has a Baseline ADHD-RS-IV total score greater than or equal to 28. Subject, who is female of childbearing potential (FOCP), must have a negative serum beta Human Chorionic Gonadotropin (HCG) pregnancy test, and a negative urine pregnancy test at Baseline, be non-lactating and agree to comply with any applicable contraceptive requirements of the protocol. Subject and parent/LAR are willing and able to comply with all the testing and requirements defined, including oversight of morning dosing. Specifically, the parent/LAR must be available upon awakening, at approximately 7:00 AM, to dispense the dose of Investigational Product for the duration of the study. Subject aged greater than or equal to 18 years has a systolic blood pressure less than or equal to 139 mmHg and a diastolic blood pressure less than or equal to 89 mmHg. Subject is able to swallow a capsule. Exclusion Criteria: For subjects who participated in another SPD489 study (SPD489-317, SPD489-325, or SPD489 326): Subject was terminated from a previous SPD489 study (SPD489-325 or SPD489 326) for protocol non-adherence and/or subject non-compliance and/or experienced a medication-related SAE or AE resulting in termination from the previous study. Subject experienced any clinically significant AEs in a prior SPD489 study (SPD489 317, SPD489-325, or SPD489-326) that, in the opinion of the Investigator, would preclude further exposure to SPD489. For all subjects: Subject's symptoms are well-controlled on their currently prescribed ADHD medication with acceptable tolerability. Subject has a positive urine drug result at Screening. 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. Subject has taken another Investigational Product or taken part in a clinical study with the exception of a prior SPD489 study (SPD489-317, SPD489 325, or SPD489 326) within 30 days prior to Screening. Subject weighs less than 22.7 kg (50 lbs). Subject is significantly overweight. Subject has a conduct disorder. Oppositional defiant disorder is not exclusionary. 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 conducted in the study or that might increase risk to the subject. Subject is currently considered a suicide risk in the opinion of the Investigator, has previously made a suicide attempt, or has a prior history of, or is currently demonstrating active suicidal ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator Subject has glaucoma. 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 any clinically significant ECG abnormality. Subject has any clinically significant laboratory abnormalities. Subject has a documented allergy, hypersensitivity, or intolerance to any active ingredient or excipients in SPD489. 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 history of seizures (other than infantile febrile seizures), a chronic or current tic disorder, a current diagnosis of Tourette's Disorder, or a known family history of Tourette's Disorder. Subject has a history of tics that is judged by the Investigator to be exclusionary. Subject has a known history of symptomatic cardiovascular or cerebrovascular 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 has a medical condition, other than ADHD, that requires treatment with medications that have central nervous system effects and/or affect performance. Stable use of anticholinergic or theophylline bronchodilators is not exclusionary.

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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lisdexamfetamine Dimesylate<br> | Drug: Lisdexamfetamine dimesylate<br>* Optimized dose of either 30, 50 or 70 mg capsule administered once daily for 2 years<br>* Other names: Vyvanse, SPD489, LDX;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With All Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. It included both serious and non-serious adverse event. 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. AEs were defined as treatment-emergent if they started or worsened during the period between the day of a participant's first dose of investigational product in this study and the 3 days following cessation of treatment. | Baseline up to 3 days after the last dose of study treatment (up to 2 years) | 
| Change From Baseline in Pulse Rate at Last On-treatment Assessment (LOTA) |  | Baseline (Week 0), LOTA (Week 104) | 
| Change From Baseline in Sitting Diastolic Blood Pressure (DBP) at Last On-treatment Assessment (LOTA) |  | Baseline (Week 0), LOTA (Week 104) | 
| Change From Baseline in Sitting Systolic Blood Pressure (SBP) at Last On-treatment Assessment (LOTA) |  | Baseline (Week 0), LOTA (Week 104) | 
| Change From Baseline in Body Weight at Last On-treatment Assessment (LOTA) |  | Baseline (Week 0), LOTA (Week 104) | 
| Change From Baseline in Height at Last On-treatment Assessment (LOTA) |  | Baseline (Week 0), LOTA (Week 104) | 
| Change From Baseline in Body Mass Index (BMI) at Last On-treatment Assessment (LOTA) | BMI was calculated as (weight [kilogram] per height [square meter]). | Baseline (Week 0), LOTA (Week 104) | 
| Change From Baseline in Heart Rate at Last On-treatment Assessment (LOTA) |  | Baseline (Week 0), LOTA (Week 104) | 
| Change From Baseline in QT Interval at Last On-treatment Assessment (LOTA) |  | Baseline (Week 0), LOTA (Week 104) | 
| Change From Baseline in QT Interval Corrected Using Fridericia's Formula (QTcF) at Last On-treatment Assessment (LOTA) |  | Baseline (Week 0), LOTA (Week 104) | 
| Change From Baseline in Brief Psychiatric Rating Scale for Children (BPRSC) Total Scores at Last On-treatment Assessment (LOTA) | The BPRS-C that was designed to provide a characterization of the child and adolescent psychopathology, was used to monitor participant's safety. The BPRS-C assessed 7 independent factors (3 items each), for a total of 21 items that represented behavioural disorders, depression, thinking disturbance, psychomotor excitation, withdrawal retardation, anxiety, and organicity. Each item was rated using a 7-point scale including 0 (not present), 1 (very mild), 2 (mild), 3 (moderate), 4 (moderately severe), 5 (severe), and 6 (extremely severe). Total score is the sum of each item score; range from 0 to 126. Higher score indicated worse psychology. | Baseline (Week 0), LOTA (Week 104) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Total Score at Last On-treatment Assessment (LOTA) | ADHD-RS-IV consisted of 18 items designed to reflect current symptomatology of ADHD based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition - Text Revision (DSM-IV-TR) criteria, completed by the Investigator. Each item was scored from a range of 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54. The 18 items were grouped into 2 sub-scales: hyperactivity/impulsivity (even number items 2-18 with score range of 0 to 27) and inattention (odd number items 1-17 with score range of 0 to 27). Higher scores depicted worse symptoms. | Baseline (Week 0), LOTA (Week 104) | 
| Number of Participants With Clinical Global Impression-Global Improvement (CGI-I) at Last On-treatment Assessment (LOTA) | The Clinical Global Impressions (CGI) Scale permits a global evaluation of the participants' severity and improvement over time. This assessment will help guide the clinician on dosing adjustments. The CGI has been used extensively in clinical studies of ADHD. CGI-I was a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), evaluated by the Investigator. | LOTA (Week 104) | 
| Number of Participants With Clinical Global Impression-Severity of Illness (CGI-S) at Last On-treatment Assessment (LOTA) | The Clinical Global Impressions (CGI) Scale permits a global evaluation of the participants' severity and improvement over time. This assessment will help guide the clinician on dosing adjustments. The CGI has been used extensively in clinical studies of ADHD. CGI-S was a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill participants), evaluated by the Investigator. | LOTA (Week 104) | 

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