Efficacy of GXR as Adjunctive Therapy With Psycho-stimulant on Executive Function in Children With ADHD

Study Overview
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Brief Summary
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This study looks to examine whether or not INTUNIV extended release can help children aged 6-12 years diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD) in improving Executive Function when added to their usual care stimulant therapy. Executive functions are a set of mental processes that include emotional control, planning, organization, working memory, inhibition of behaviors, and managing time and space. As children with ADHD usually have difficulties with Executive Function, and Executive function difficulties lead to more difficulties in school and behaviour, it is anticipated that adding INTUNIV extended release to usual stimulant therapy will improve Executive Function scores as rated by parents and teachers. Improvements in quality of life will also be measured.

Detailed Description
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Although stimulant medications have been shown to have positive impact on executive function (EF) (Findling et al, 2009; Hale et al. 2011), little has been documented about the effect of INTUNIV extended release on EF in children. The manifestation of clinical symptoms related to impairment in EF often leads to the search for additional treatment options and in many cases to adjunct therapies to the traditional stimulant medication treatment regimen. Demonstrating that the addition of INTUNIV extended release to usual stimulant therapy is effective for symptom control as well as in improving EF may influence clinical treatment algorithms and the need for health care resources to effectively manage patients. Since EF deficits negatively impact academic achievement and behavior at school and because children spend a large number of daytime hours at school, the concordance of any reported improvement in the school and the home environment will be examined. Overall improvement in quality of life with the addition of INTUNIV extended release will also be evaluated.

Official Title
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A Single-Center, Randomized, Double Blind, Placebo-Controlled, Crossover Evaluation of the Effect of GXR as Adjunctive Treatment With Stimulant on Executive Function and Quality of Life at Home and School in Children With ADHD

Conditions
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Attention Deficit Hyperactivity Disorder

Intervention / Treatment
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* Drug: Guanfacine extended release
* Drug: Placebo
* Drug: Stimulant therapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patient aged 6 to 12 years at the time of consent/assent and to then of study. A patient who would turn 13 before the end of the study cannot be enrolled Patient's parent or legally authorized representative (LAR) must provide signed informed consent before any study-related procedures are completed. Patient meets the diagnostic standard manual-5 criteria for a primary diagnosis of ADHD, combined sub-type, hyperactive/impulsive sub-type, or inattentive sub-type Patient is currently on a stable stimulant regimen but whose EF is suboptimal. Suboptimal EF is defined as a global executive composite t-score greater than 65 (>1.5 SD from mean) on the BRIEF-P questionnaire at screening. Patient who is currently and is expected to remain on a stable stimulant regimen throughout the study. A stable stimulant regimen is defined as: •No significant change in dose or dosing frequency within the past 30 days prior to screening and stimulant is felt to be optimized by the investigator. Patient is functioning at an age-appropriate level intellectually, as judged by the Investigator. Patient is able to swallow intact tablets. Patient has sitting blood pressure (BP) measurement within the 95th percentile for age, sex, and height (see Blood Pressure Levels for Boys and Girls by Age and Height Percentile Patient and parent/LAR understand, are willing, able, and likely to fully comply with the study procedures and restrictions defined in this protocol. Exclusion Criteria: Patient has a current, controlled (requiring a prohibited medication or behavioural modification program) or uncontrolled, co-morbid psychiatric diagnosis [except oppositional defiant disorder (ODD)], including any severe co-morbid Axis II disorders or severe Axis I disorders such as post-traumatic stress disorder (PTSD), bipolar illness, psychosis, pervasive developmental disorder, obsessive-compulsive disorder (OCD), substance abuse disorder, or other symptomatic manifestations or lifetime history of bipolar illness, psychosis or conduct disorder. Patient has any condition or illness which, in the opinion of the Investigator, represents an inappropriate risk to the patient and/or could confound the interpretation of the study. Mild stable asthma treated without the use of beta-2 agonist is not exclusionary. Patient has a known personal history, or presence, of structural cardiac abnormalities, cardiovascular or cerebrovascular disease, serious heart rhythm abnormalities, syncope, tachycardia, cardiac conduction problems (e.g., clinically significant heart block or QT interval prolongation: QTc >0.44 seconds), exercise-related cardiac events including syncope and pre-syncope, or clinically significant bradycardia. Patient has a known family history (in siblings, parents, and/or grand-parents) of sudden cardiac death, ventricular arrhythmia, or QT prolongation (QTc >0.44 seconds). Patient has a known history of hypertension (see Blood Pressure Levels for Boys and Girls by Age and Height Percentile Patient has glaucoma. Patient has a history of a seizure disorder (other than a simple childhood febrile seizure). Patient has renal or hepatic insufficiency Patient is currently using prohibited medication. Patient has taken another investigational product within 30 days prior to the Enrolment Visit. Patient has a known or suspected allergy, hypersensitivity, or clinically significant intolerance to guanfacine hydrochloride or any of its active ingredients or patient is taking other products containing guanfacine. History of adverse event or failure to respond (lack of efficacy) to an adequate trial of an alpha-agonist. Patient is female and is pregnant or currently lactating. Patient 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. Patients with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the Investigator.

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
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo first then GXR<br>patient will continue to take stable dosage of usual stimulant therapy (Ritalin, Ritalin SR, Biphentin, Concerta, Vyvanse, Adderall or Dexedrine). In the first intervention period subject took placebo and second intervention period subject took GXR. GXR dose was optimized to between 1 and 4mg. | Drug: Guanfacine extended release<br> <br> * Other names: Intuniv extended release;Drug: Placebo<br> <br> Drug: Stimulant therapy<br>* patient will continue to take stable dosage of usual stimulant therapy (Ritalin, Ritalin SR, Biphentin, Concerta, Vyvanse, Adderall or Dexedrine)<br>|
| Placebo Comparator: GXR first then Placebo<br>patient will continue to take stable dosage of usual stimulant(Ritalin, Ritalin SR, Biphentin, Concerta, Vyvanse, Adderall or Dexedrine). In the first intervention period subject took GXR and second intervention period subject took placebo. GXR dose was optimized to between 1 and 4mg. | Drug: Guanfacine extended release<br> <br> * Other names: Intuniv extended release;Drug: Placebo<br> <br> Drug: Stimulant therapy<br>* patient will continue to take stable dosage of usual stimulant therapy (Ritalin, Ritalin SR, Biphentin, Concerta, Vyvanse, Adderall or Dexedrine)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Adjunctive INTUNIV Extended Release Treatment on Executive Function as Assessed by Change From Baseline on the BRIEF-parent Questionnaires | The Behavioural Rating Inventory of Executive Function (BRIEF) was developed to assess such real-world expressions of executive function in the home (BRIEF-P) as assessed by the parent. This is an 86 item questionnaire completed by the parents. The score is converted to a t-score with a score less than 65 being considered within the normal range. Higher scores are worsening in function. | measured at baseline and end of each 12 week treament arm | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effect of Adjunctive INTUNIV Extended Release Treatment on Change in Quality of Life as Assessed by the KINDL®-Child Questionnaire. | The KINDL is a quality of life questionnaire of 24 items completed by the subject (KINDL-child). It is a generic instrument for assessing Health Related quality of life in children and adolescents aged 3 years and older. Norm values are given based on representative German data from the German National Health Interview and Examination Survey for Children and Adolescents (KiGGS) study, a broad survey realized by the German Robert-Koch Institute. The KINDL scores were converted to range between 0 and 100 with higher scores indicating better quality of life as reported by the child | Measured at baseline and end of each 12 week treatment arm | 
| Effect of Adjunct Therapy on ADHD Symptom Control as Assessed by the Change in the ADHD Rating Scale (ADHD-RS-IV) | The ADHD-RS-IV is completed by the Investigator familiar with the scale. It is an 18 item scale designed to reflect current symptomatology of ADHD based on the DSM-5 criteria. Each item is scored from a range of 0 (reflecting no symptoms) to 3 (reflecting severe symptoms) with total scores ranging from 0-54, with higher scores reflecting more severe symptoms | comparison from baseline to end of each 12 week treatment arm | 
| Subjects Experiencing Suicidal Ideation, Suicidal Behaviour and Self-injurious Behaviour Without Suicidal Intent and Incident of Serious Adverse Events in Each Treatment Arm | To compare the number of subjects experiencing suicidal ideation, suicidal behaviour and self-injurious behaviour without suicidal intent as assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) and incident of Serious Adverse Events (SAEs) in each treatment arm | Measured up to 30 weeks | 
| Evaluate the Effect of Adjunctive INTUNIV Extended Release Treatment on Change in Quality of Life as Assessed by the KINDL®-Parent Questionnaire. | The KINDL is a quality of life questionnaire of 24 items completed by the parent (KINDL-parent). It is a generic instrument for assessing Health Related quality of life in children and adolescents aged 3 years and older. Norm values are given based on representative German data from the German National Health Interview and Examination Survey for Children and Adolescents (KiGGS) study, a broad survey realized by the German Robert-Koch Institute. The KINDL scores were converted to range between 0 and 100 with higher scores indicating better quality of life as reported by the parent. | Measured at baseline and end of each 12 week treatment arm | 
| Effect of Adjunct Therapy on ADHD Symptom Control as Assessed by the Change on the Clinical Global Impression of Severity (CGI-S) Scale | The Clinical Global Impression- Severity scale is a scale of illness ranging from 1 (normal) to 7 (among the most severely ill patients). Subjects who felt normal, not at all ill or borderline mentally ill are considered improved. The outcome measure is reporting the percentage of participants showing improvement | comparison from baseline to end of each 12 week treatment arm | 
| Evaluate the Effect of Adjunct Therapy on ADHD Symptom Control as Assessed by the Change in Clinical Global Impression of Improvement (CGI-I) Scale | CGI-I is a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Subjects who felt very much improved or much improved are considered improved.The outcome measure is reporting the percentage of participants showing improvement | comparison from baseline to end of each 12 week treatment arm | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Attention Deficit Hyperactivity Disorder, Intuniv extended release, Executive Function, Quality of Life