Safety, Tolerability, Pharmacokinetic, and Efficacy Study of SPD489 in Preschool Children With Attention-deficit/Hyperactivity Disorder

Study Overview
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Brief Summary
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The purpose of this study is to gain initial safety, tolerability, pharmacokinetic, and efficacy information on SPD489 in preschool children 4-5 years old who are diagnosed with ADHD. Generating such data will provide data on the use of SPD489 in the preschool ADHD population.

Official Title
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A Phase 2, Open-label, Multicenter, Exploratory Safety, Tolerability, Pharmacokinetic, and Efficacy Study of SPD489 in Preschool Children Aged 4-5 Years With Attention-deficit/Hyperactivity Disorder

Conditions
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Attention Deficit Hyperactivity Disorder (ADHD)

Intervention / Treatment
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* Drug: SPD489


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is a male or female aged 4-5 years inclusive at the time of consent. Only recruiting male subjects as of December 2015 Subject's parent or LAR must provide signature of informed consent, and there must be documentation of assent (if applicable) by the subject in accordance with the ICH GCP Guideline E6 (1996) and applicable regulations, before completing any study-related procedures. Subject and parent/LAR are willing and able to comply with all of the testing and requirements defined in the protocol, including oversight of morning dosing. Specifically, the same parent/LAR should be available daily to dispense the dose of investigational product for the study duration. Subject must meet DSM-IV-TR criteria for a primary diagnosis of ADHD (all subtypes) based on a detailed psychiatric evaluation conducted by a sponsor-approved clinician Subject has an ADHD-RS-IV Preschool Version total score ≥93rd percentile at the Baseline Visit (Visit 0). For boys, this is a score of ≥32. For girls, this is a score of ≥24. Subject has a CGI-S score ≥4 at the Baseline Visit (Visit 0). Subject has a Peabody Picture Vocabulary Test, Fourth Edition standard score of ≥70 at the Screening Visit (Visit -1). Subject has undergone an adequate course of non-pharmacological treatment based on investigator judgment or the subject has a severe enough condition to consider enrollment without undergoing prior non-pharmacological treatment based on investigator judgment. Subject has, in the opinion of the investigator, participated in a structured group activity (e.g., preschool, sports, Sunday school) so as to assess symptoms and impairment in a setting outside the home. Subject has lived with the same parent/LAR for ≥6 months. Exclusion Criteria: Subject is required to or anticipates the need to take medications that have CNS effects or affect performance, such as sedating antihistamines and decongestant sympathomimetics, or are taking monoamine oxidase inhibitors. Stable use of bronchodilator inhalers is not exclusionary. Subject has taken another investigational product or has taken part in a clinical study within 30 days prior to the Screening Visit (Visit -1). Subject is well controlled on his/her current ADHD medication with acceptable tolerability. 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. 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. The additional conditions 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 failed to fully respond, based on investigator judgment, to a previously administered adequate course of amphetamine therapy. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in the investigational product. Subject has a known family history of sudden cardiac death or ventricular arrhythmia. Subject has a blood pressure measurement ≥95th percentile for age, sex, and height at the Screening Visit (Visit -1) or the Baseline Visit (Visit 0). 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 placing them at increased vulnerability to the sympathomimetic effects of a stimulant drug. Subject has any clinically significant electrocardiogram at the Screening Visit (Visit -1) or the Baseline Visit (Visit 0) or clinically significant laboratory abnormalities at the Screening Visit (Visit -1) based on investigator judgment. Subject has current abnormal thyroid function, defined as abnormal thyroid stimulating hormone and thyroxine at the Screening Visit (Visit -1). Treatment with a stable dose of thyroid medication for at least 3 months is permitted. Subject has a current diagnosis of adjustment disorder, autism, psychosis, or bipolar disorder. Subject is currently considered at risk for suicide in the opinion of the investigator, has previously made a suicide attempt, 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 a height ≤5th percentile for age and sex at the Screening Visit (Visit -1). Subject has a weight ≤5th percentile for age and sex at the Screening Visit (Visit -1). Subject has a history of seizures (other than infantile febrile seizures) or a current diagnosis of Tourette's disorder. Subject has a chronic or current tic disorder that is judged by the investigator to be exclusionary. Subject is taking any medication that is excluded.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 5 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>There are 4 periods in this study: 1)screening and washout; 2) Dose Optimization; 3) Dose Maintenance; 4) Safety Follow-up. SPD489 will be used to treat all subjects. | Drug: SPD489<br>* All subjects will begin with 5mg of SPD489 daily and will be titrated until optimal dose is reached (5, 10, 15, 20, and 30mg)<br>* Other names: Lisdexmfetamine dimesylate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) at the Specified Dose Level | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An AE was considered treatment-emergent if it had a start date on or after, or had a start date before but increased in severity after the first dose of investigational product. | From start of study treatment up to safety follow-up (Week 9) | 
| Change in Sleep Patterns Assessed by Children's Sleep Habits Questionnaire at Week 8 / End of Treatment (ET) | Children's Sleep Habits Questionnaire is a tool designed to screen the most common sleep problems in children, and consists of 33 items for scoring. The instrument evaluates the child's sleep based on behavior within 8 different subscales: bedtime resistance, sleep-onset delay, sleep duration, sleep anxiety, night walkings, parasomnias, sleep-disordered breathing, and daytime sleepiness. Each item receives a score from 1 (problem occurs rarely) to 3 (problem usually occurs); therefore, a higher score is the worse outcome. Scale ranges are as follows: bedtime resistance: 6 to 18, sleep onset delay: 1 to 3, sleep duration: 3 to 9, sleep anxiety: 4 to 12, night walkings: 3 to 9, parasomnias: 7 to 21, sleep-disordered breathing: 3 to 9, daytime sleepiness: 8 to 24, and total disturbance (items from all scales): 33 to 99. | Baseline, Week 8/ET | 
| Number of Participants With Suicide Related Behavior Assessed by Columbia-Suicide Severity Rating Scale Questionnaire (C-SSRS) | The C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviors. The interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behaviour occurred. The interview was initiated with 5 (yes/no) questions, presented in ascending order of severity, about suicidal ideation. The most severe type of ideation was rated for frequency, duration, controllability, deterrents, and reason. If the answer to the first 2 ideation questions was yes, the clinician asked questions 3-5. Active suicidal ideation included any participant who answered yes to questions 2-5. If the answers to ideation questions 1 and 2 were No, then the clinician proceeded to 5 (yes/no) questions that addressed suicidal behavior, which was categorized as actual attempt, interrupted attempt, aborted attempt, preparatory acts or behaviors, and completed suicide. | Baseline, Week 8/ET | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Attention Deficit/Hyperactivity Disorder Rating Scale (ADHD-RS-IV) Preschool Version Total Score at FoTA (Final on Treatment Assessment) | The ADHD-RS-IV Preschool Version is an 18-item questionnaire that requires the respondent to rate the frequency of occurrence of ADHD symptoms as defined by Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition (DSM-IV-TR) criteria. Each item is scored on a 4-point scale ranging from 0 (never or rarely) to 3 (very often) with total scores ranging from 0-54. The 18 items may be grouped into 2 subscales: hyperactivity/impulsivity (even numbered items 2-18) and inattentiveness (odd numbered items 1-17). Data presented here was analysed at Final on-Treatment Assessment (FoTA). | Baseline, FoTA | 
| Number of Participants With Improvement on Clinical Global Impression-Improvement (CGI-I) | CGI-I was performed to rate the severity of a participant's condition 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). Data presented here was analysed at Final on-Treatment Assessment (FoTA). Improved is defined as a score of very much improved or much improved. | FoTA | 
| Area Under the Concentration-Time Curve From Time Zero to Time of the Last Quantifiable Concentration (AUC 0-last) of SPD489 in Plasma | AUC 0-last is the area under the concentration-time curve from time zero to the time of the last quantifiable concentration of SPD489 in plasma. Pharmacokinetic (PK) parameters were compared against the study NRP104-201 (NCT00557011) to observe and compare the effects of SPD489. | Visit 7 [Dose Maintenance Phase] at pre-dose, and 1, 2, 3, 4, 6, and 8 h post-dose |