Safety and Efficacy Study in Preschool Children Aged 4-5 Years With Attention-deficit/Hyperactivity Disorder (ADHD)

Study Overview
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Brief Summary
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The purpose of this study is to determine if an investigational treatment is effective in improving the total score on the ADHD-RS-IV Preschool Version in children 4-5 years old diagnosed with ADHD.

Official Title
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A Phase 3, Randomized, Double-blind, Multicenter, Parallel-group, Placebo-controlled, Fixed-Dose Safety and Efficacy Study of SPD489 Compared With Placebo 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: Placebo
* Drug: SPD489 (Lisdexamfetamine dimesylate)
* Drug: SPD489


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant is a male or female aged 4-5 years inclusive at the time of consent Participant's parent(s) or legally authorized representative (LAR) must provide signature of informed consent, and there must be documentation of assent (if applicable) by the participant before completing any study related procedures. Participant and parent(s)/LAR are willing and able to comply with all of the testing and requirements defined in the protocol, including oversight of morning dosing. Participant must meet DSM-IV-TR criteria for a primary diagnosis of ADHD (any sub-type). Participant has an ADHD-RS-IV Preschool Version Total Score at the baseline visit (Visit 0) greater than or equal to 28 for boys, and greater than or equal to 24 for girls. Participant has a Clinical Global Impressions - Severity of Illness (CGI-S) score greater than or equal to 4 at the baseline visit (Visit 0). Participant has a Peabody Picture Vocabulary Test standard score of greater than or equal to 70 at the screening visit (Visit -1). Participant has undergone an adequate course of non-pharmacological treatment or has a severe enough condition to consider enrollment without undergoing prior non-pharmacological treatment. Participant has 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. Participant has lived with the same parent(s) or guardian for greater than or equal to 6 months. Exclusion Criteria: Participant is required to or anticipates the need to take any prohibited medications or medications that have central nervous system (CNS) effects or have an effect on performance. Stable use of bronchodilator inhalers is not exclusionary. Participant has taken another investigational product or has taken part in a clinical study within 30 days prior to the screening visit (Visit -1). Participant is well-controlled on his/her current ADHD medication with acceptable tolerability. Participant has a concurrent chronic or acute illness, disability, or other condition that might confound the results of safety assessments or may increase risk to the participant.. Participant has glaucoma. Participant has failed to fully respond to an adequate course of amphetamine therapy. Participant has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in the investigational product. Participant has a known family history of sudden cardiac death or ventricular arrhythmia. Participant has a blood pressure measurement greater than or equal to 95th percentile for age, sex, and height at the screening visit (Visit -1) or the baseline visit (Visit 0) or history of moderate or severe hypertension. Participant has a known history of symptomatic cardiovascular disease, unexplained syncope, exertional chest pain,advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious cardiac problems. Participant has any clinically significant clinical laboratory abnormalities at the screening visit (Visit -1) or electrocardiogram (ECG) at screening visit (Visit-1) or baseline visit (Visit 0) based on investigator judgment. Participant has current abnormal thyroid function, defined as abnormal thyroid stimulating hormone (TSH) and thyroxine (T4) at the screening visit (Visit -1). Treatment with a stable dose of thyroid medication for at least 3 months is permitted. Participant has a current, controlled (requiring medication or therapy) or uncontrolled, co-morbid psychiatric disorder including but not limited to any of the below co-morbid Axis I disorders and Axis II disorders: i. post-traumatic stress disorder or adjustment disorder ii. bipolar illness, psychosis, or a family history of these disorders iii. pervasive developmental disorder iv. obsessive-compulsive disorder (OCD) v. psychosis/schizophrenia vi. a serious tic disorder, or a family history of Tourette's disorder vii. Participant 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. viii. a history of physical, sexual, or emotional abuse ix. any other disorder or agitated state that in the opinion of the investigator, contraindicates SPD489 or lisdexamfetamine dimesylate treatment or confound efficacy or safety assessments. Participant has initiated behavioral therapy within 1 month of the baseline visit (Visit 0). Participant may not initiate behavioral therapy during the study. Participant has a height less than equal to (<=) 5th percentile for age and sex at the screening visit (Visit -1). Participant has a weight <= 5th percentile for age and sex at the screening visit (Visit -1). Participant lives with anyone who currently abuses stimulants or cocaine. Participant has a history of seizures (other than infantile febrile seizures). Participant is taking any medication that is excluded per the protocol.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participant will receive placebo matching to SPD489 (Lisdexamfetamine dimesylate) capsule for 6 weeks. | Drug: Placebo<br>* Placebo matching to SPD489 (Lisdexamfetamine dimesylate) capsule for 6 weeks.<br>|
| Experimental: SPD489 (Lisdexamfetamine dimesylate)<br>Participants will be randomized to receive SPD489 capsule in a 5:5:5:5:6 ratio to SPD489 5, 10, 20, 30 milligram (mg) orally once daily for 6 weeks. Dosing will begin with the lowest strength of SPD489 (5 mg), and will be titrated until the randomly assigned fixed-dose is reached. | Drug: SPD489 (Lisdexamfetamine dimesylate)<br>* SPD489 capsule in a 5:5:5:5:6 ratio to 5, 10, 20, 30 mg orally once daily for 6 weeks.<br>Drug: SPD489<br>* SPD489<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Clinician-Administered Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Preschool Version Total Score at Week 6 | ADHD-RS-IV Preschool Version was adapted from the ADHD Rating Scale-IV and provided examples appropriate for the developmental level of preschool children. The ADHD-RS-IV Preschool Version was an 18-item questionnaire that required the respondent to rate the frequency of occurrence of ADHD symptoms as defined by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria. Each item was 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 were grouped into 2 subscales: hyperactivity/impulsivity (even numbered items 2-18) and inattentiveness (odd numbered items 1-17). Full analysis set (FAS) consisted of all participants in the safety analysis set who had at least 1 post-dose ADHD RS IV preschool version total score assessment. | Baseline, Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinical Global Impressions Global Improvement (CGI-I) at Week 6 | CGI-I was an overall assessment of global symptom improvement by evaluation of the participant's condition severity and improvement over time. Scoring was done based on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse), where higher score reported worse condition. The scoring was elaborated as: 1=very much improved; 2=much improved; 3=minimally improved; 4=no change; 5=minimally worse; 6=much worse; 7=very much worse. FAS consisted of all participants in the safety analysis set who had at least 1 post-dose ADHD RS IV preschool version total score assessment. | Week 6 | 
| Dose Response Relationship for Change From Baseline in ADHD-RS-IV Preschool Version Total Score in Preschool Children at Week 6 | Dose response relationship was evaluated by using the ADHD-RS Preschool Version Total Score. ADHD-RS-IV Preschool Version was adapted from the ADHD Rating Scale-IV and provided examples appropriate for the developmental level of preschool children. The ADHD-RS-IV Preschool Version was 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 Disorders, Fourth Edition-Text Revision (DSM-IV-TR) criteria. Each item was 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 were grouped into 2 subscales: hyperactivity/impulsivity (even numbered items 2-18) and inattentiveness (odd numbered items 1-17). Dose response analysis set consisted of all participants in the safety analysis set who had at least 1 valid primary efficacy measurement on the randomized target dose level of the investigational product. | Baseline, Week 6 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a investigational product (IP) and that does not necessarily had a causal relationship with this treatment. TEAEs were defined as AEs that start or deteriorate on or after the date of the first dose of IP and no later than 3 days following the last dose of IP. | From start of study drug administration up to follow-up (Week 7) | 
| Number of Participants With Potentially Clinically Significant Changes in Vital Signs | Vital sign assessments included blood pressure (systolic and diastolic), average pulse rate. Number of participants with potentially clinically significant changes in vital signs were reported. mmHg represents millimetre of mercury in the outcome measure data. | Week 6 | 
| Change From Baseline in Height at Week 6 | Height was measured in inche without shoes, with the participant stood on a flat surface and with chin parallel to the floor. | Baseline, Week 6 | 
| Change From Baseline in Body Weight at Week 6 | Body weight was measured in percentile without shoes. Body weight percentile was normalized by sex and age using the Centers for Disease Control and Prevention (CDC) growth charts. Body weight percentiles were categorized as lesser than (<) 5th, 5th to < 95th, and greater than or equal to (>=) 95th percentiles. Change from baseline in body weight at Week 6 was reported. | Baseline, Week 6 | 
| Change From Baseline in Body Mass Index (BMI) at Week 6 | BMI was derived from height and weight. BMI percentile was normalized by sex and age using the CDC growth charts. BMI percentiles were categorized as: Underweight (BMI < 5th percentile); Healthy weight (BMI 5th percentile up to < 85th percentile); Overweight (BMI 85th percentile < 95th percentile); Obese (BMI >= 95th percentile). Change from baseline in body mass index at Week 6 was reported. | Baseline, Week 6 | 
| Number of Participants With Potentially Clinically Significant Changes in Clinical Laboratory Values | Clinical laboratory evaluations included biochemistry and endocrinology, hematology, and urinalysis. Number of participants with potentially clinically significant changes in clinical laboratory values were reported. ULN in measure data represents upper limit of normal, mcmol/L represents to Micromoles Per Litre, > = represents greater than or equal to. | Week 6 | 
| Number of Participants With Potentially Clinically Significant Changes in Electrocardiogram (ECG) Parameters | Number of participants with potentially clinically significant changes in ECG parameters were reported. QTcF interval represents QT Fridericia's Correction Formula interval, QTcB interval represents QTc corrected by Bazett's in measure data. | Week 6 | 
| Children's Sleep Habits Questionnaire (CSHQ) at Week 6 | Children's Sleep Habits Questionnaire was a tool designed to screen the most common sleep problems in children, and consisted of 33 items for scoring. The instrument evaluated 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. | Week 6 | 
| Number of Participants With a Positive Response Using Columbia Suicide Severity Rating Scale (C-SSRS) | C-SSRS was semi-structured interview that captured the occurrence, severity, and frequency of suicide-related thoughts and behaviors during the assessment period. The interview included definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behavior occurred. The C-SSRS contained 2 required items pertaining to suicidal ideation, 4 required items pertaining to suicidal behavior, and 1 required item pertaining to non-suicidal but self-injurious behavior. In situations where there was a positive response to the screening questions, there were 8 additional suicidal ideation items and 4 additional suicidal behavior items which were completed. Thus, there was a maximum of 19 items to be completed. Here number of participants responded as yes to suicidal ideation or behaviour were reported. | Up to Week 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SPD489, Lisdexamfetamine dimesylate, ADHD, hyperactivity, Neurobehavioral disorder