Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect and safety of Lisdexamfetamine dimesylate (Vyvanse®) in the treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents with ADHD and comorbid Autism Spectrum Disorder (ASD). This would be a novel study as there is no known safety or efficacy data for amphetamine based medications in this population. In addition, although health related quality of life and executive function are known to improve with the treatment of lisdexamfetamine dimesylate in the ADHD population (Banaschewski 2013; Findling 2009; Turgay 2010), it has not been shown in the co-morbid ADHD and ASD population. ADHD is the most common pediatric neurobiological condition affecting approximately five percent of the pediatric population (Feldman 2009). ASD is being increasingly recognized as affecting a substantial amount of the pediatric population, with recent prevalence data showing 1 in 68 affected (Baio, 2014). Prior to the introduction of DSM-5 (APA, 2013), exclusion criteria precluded the diagnosis of ADHD when ASD was present. Studies have shown that 41%-71% of children with ASD also meet criteria for ADHD (Goldstein 2004, Sturm 2004,Yoshida 2004, Gadow 2006). This means that up to 1% of the population may have co-morbid ADHD and ASD. With the official recognition of this comorbidity, treatment of comorbid ADHD when ASD is also present has been increasingly recognized as an important strategy in improving executive functioning and quality of life in those affected. Studies have indicated that some of the medications commonly used to treat ADHD, are effective and safe when used in comorbid ADHD and ASD. At this time, there have been well designed studies demonstrating safety and efficacy for methylphenidate (Ghuman et al. 2009; Handen et al. 2000; Quintana et al. 1995; RUPP 2005), guanfacine XR (Posey 2004; Scahill 2015), and atomoxetine (Arnold 2006; Harfterkamp 2012).

Detailed Description
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ADHD is the most common pediatric neurobiological condition affecting approximately five percent of the pediatric population (Faraone, Stephen V., Sergeant, J. et al. 2003; Feldman & Belanger 2009). ASD is being increasingly recognized as affecting a substantial amount of the pediatric population, with recent prevalence data showing 1 in 68 affected (U.S. Department of Health and Human Services 2010). Prior to the introduction of DSM-5, exclusion criteria precluded the diagnosis for ADHD when ASD was present (American Psychiatric Association 2013). Studies have shown that 41%-71% of children with ASD also meet criteria for ADHD, meaning up to 1% of the population may have comorbid ADHD and ASD (Goldstein & Schewbach 2004). With the official recognition of comorbidity, treatment of comorbid ADHD when ASD is also present has been increasingly recognized as an important strategy in decreasing ADHD symptoms, and improving executive functioning and quality of life of those affected. Studies have indicated that some of the medications (methylphenidate, guanfacine XR and atomoxetine) commonly used to treat ADHD are effective and safe when used in comorbid ADHD and ASD (Ornstein & Kollins 2012; Ghuman et al. 2009; Handen et al. 2000; Quintana et al. 1995; Posey et al. 2004; Scahill et al. 2015; M. et al. 2012). While amphetamine class compounds are amongst the first line of treatment in ADHD, the lack of studies in this population has discouraged their use in subjects with comorbid ADHD and ASD. The lack of safety and efficacy data is problematic as it limits therapeutic options for the population of subjects with ADHD and ASD. Amphetamines and methylphenidate medications are equally considered first line treatment options for ADHD (CADDRA 2011). Some subjects may preferentially respond to one group of medications over another, therefore it is important to have clear safety and efficacy data for both therapeutic options. A retrospective chart review of this population indicates that treatment is started with methylphenidate versus combined amphetamine/dextroamfetamine at a ratio of 2.78:1 (Stigler et al. 2004). Due to the availability of evidence of efficacy in this comorbid population, clinicians may choose to skip to what is considered a second line medication for ADHD symptomatology rather than using LDX (or another amphetamine-based ADHD medication such as dexedrine or Adderall XR) that may have a larger effect size for treating these symptoms. LDX has been shown to be an effective treatment for ADHD in subjects 6 and above. With long lasting effectiveness shown to last up to 14 hours, it could potentially improve ADHD symptoms and overall quality of life for children and adolescents with ADHD and ASD in home, school and after-school functioning. The purpose of this study is to evaluate the safety and efficacy of LDX in treating ADHD when ASD is co-morbid.

Official Title
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A Multi-Center, Open Label, Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With Attention Deficit Hyperactivity Disorder and Autism Spectrum Disorder

Conditions
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Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorder

Intervention / Treatment
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* Drug: Lisdexamfetamine Dimesylate


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject aged 6-12 years at the time of consent/assent. Subjects parent(s) or legally authorized representative (LAR) must provide signature of informed consent, and there must be documentation of assent (if applicable) by the subject in accordance with the International Council on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 (1996), any updates or revisions, and applicable regulations, before completing any study related procedures. Subject and parent(s)/LAR are willing and able to comply with all of the requirements defined in the protocol. Subject meets Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) criteria for a diagnosis of ADHD combined presentation, inattentive presentation or hyperactive/impulsive presentation based on history and a minimum ADHD-RS score of 32 and a minimum CGI-S of 4 at baseline. Subject meets DSM-V criteria for a diagnosis of ASD-level 1 based on history and Autism Diagnostic Observation Scale (ADOS-2). Subject has an SRS-2 total score of ≥ 70. Subject has a Clinical Global Impressions - Severity of Illness (CGI-S) score ≥ 4 at the baseline visit (visit 2) Subject has a blood pressure measurement within 95th percentile for age, and sex (Appendix 1,1.1,2 & 2.2). Subject and parent/legally authorized representative (LAR) are willing, able and likely to comply with the study procedures and restrictions within the protocol. Exclusion Criteria: Subject has any condition that, in the opinion of the investigator, represent an inappropriate risk to the subject or may confound the interpretation of the study. Subject has a known history or presence of structural cardiac abnormalities, cardiovascular or cerebrovascular disease, serious heart rhythm abnormalities, syncope, tachycardia, cardiac conduction problems (such as clinically significant heart block or QT interval prolongation), exercise-related cardiac events including syncope and pre-syncope or clinically significant bradycardia. Subject 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 placing them at increased vulnerability to sympathomimetic effects of a stimulant drug. Subject has a history of seizure disorder (other than a single childhood febrile seizure occurring before the age of 3 years). Subject has glaucoma. Subject is currently using prohibited medication. Subject has a known or suspected allergy, hypersensitivity, or clinically significant intolerance to LDX. Subject has taken another investigational product within 30 day prior to baseline. Subject has initiated behavioural therapy within 1 month of the baseline visit (visit 0). Subject may not initiate behavioural therapy during the study. Subject is female and is pregnant or currently lactating. 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 suicide ideation. Subjects with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the investigator. History of failure to respond to an adequate trial of an amphetamine based medication. Subject is currently abusing an illicit substance or lives with someone known to currently abuse stimulants or cocaine.. Subject has a known renal or hepatic insufficiency.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 12 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
Interventional Model Description: Multi-Center Open Label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Lisdexamphetamine<br>All participants will receive Lisdexamfetamine Dimesylate (LDX) at an optimized dose based on protocol | Drug: Lisdexamfetamine Dimesylate<br>* Medication to treat ADHD<br>* Other names: Vyvanse;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ADHD Symptoms | Physician rated scale ADHD IV-RS each item is scaled 1 to 3 with a total between 0 and 54 | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Health Related Quality of Life | Parent completed rating scale called Child Health and Illness Profile- Child Edition: Parent Report Form ( CHIP-CE-PRF) . This is a generic child health status questionnaire that comprehensively describes all aspects of child health that can be influenced by the health care and school systems. It includes subdomains of satisfaction, discomfort, resilience, risk avoidance, achievement, and disorders. The domains and subdomains were conceptually derived and generally supported by factor analysis. The majority of items assess frequency of behaviors or experiences. Most items use a five-point response format. When a recall period is used, it is typically the past 4 weeks. Scale scores are obtained by computing the average of the individual item responses, whether scoring the domain or subdomain (in the PRF). The scale scores are standardized with a mean of 50 and standard deviation of 10. Higher scores indicate better health. | 12 weeks | 
| Executive Function | The BRIEF-P is a 90 item parent completed questionnaire with a global executive composite score (GEC). GEC is reported as a t-score and a t-score of less than 65 is within normal limits | 12 weeks | 
| Severity of illness | The severity of illness using the Clinical Global Impression-severity of illness, a 7 point scale which is physician rated | 12 weeks | 
| Improvement of Subjects | The severity of illness using the Clinical Global Impression-improvement of illness, a 7 point scale which is physician rated To evaluate the change in functional impairment in subjects. A score of 1 indicates very much improved while a score of 7 indicates very much worse | 12 weeks | 
| Safety-Adverse events | Adverse events are recorded at every visit | 12 weeks | 
| Safety - suicidality | Using the Columbia-Suicide Severity Rating Scale the incidence of suicidal thoughts and actions are recorded. The C-SSRS (Posner et al. 2011; Posner et al. 2010) is a semi-structured interview that captures the occurrence, severity, and frequency of suicide-related thoughts and behaviours during the assessment period. The interview includes definitions and suggested questions to solicit the type of information needed to determine if a suicide-related thought or behaviour has occurred. | 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vyvanse, executive function, safety