A Phase 4, Multicenter, 2-part Study Composed of a Randomized, Double-blind, Parallel-group, Placebo-controlled, Active-comparator, Dose-optimization Evaluation followed by a Open-label Evaluation to Assess the Safety and Efficacy of Guanfacine Hydrochloride Prolonged-release (SPD503) in Children and Adolescents aged 6 to 17 Years with Attention-deficit/Hyperactivity Disorder

The primary objective of this study is to evaluate the long-term safety of **TAK-503** (formerly known as SPD503) in children and adolescents aged 6 to 17 years diagnosed with **Attention-deficit/hyperactivity disorder (ADHD)**, for whom stimulants are unsuitable, not tolerated, or ineffective. This evaluation is clinically relevant as it addresses the need for alternative treatment options in this population. The study aims to compare TAK-503 with atomoxetine after 12 months of once-daily treatment, focusing on psychomotor speed and attention, as measured by the Cambridge automated neuropsychological test battery (CANTAB) reaction time (RTI) task.

Secondary objectives include assessing various cognitive domains and physiological parameters: - Cognitive domain, sustained attention as measured by the CANTAB Rapid Visual Information Processing (RVP) task. - Cognitive domain, Spatial Working Memory (SWM), a component of executive function, as measured by CANTAB SWM task between errors. - Cognitive domain, response control/inhibition as measured by the CANTAB Stop Signal Task (SST). - Cognition domain, recognition memory as measured by the CANTAB Delayed Matching to Sample (DMS) task. - Sexual maturation as measured by Tanner stage. - Growth as measured by weight, height, and body mass index (BMI). - Incidence of treatment-emergent adverse events (TEAEs). - Vital sign and electrocardiogram (ECG) results. - Psychiatric symptoms as measured by the Brief Psychiatric Rating Scale for Children (BPRS-C) total score and factors for Depression, Anxiety, Psychomotor Excitation, Behavior Problems, Withdrawal, Thinking Disturbance, and Organicity.

The clinical trial involves a total of **219 participants** diagnosed with **Attention-deficit/hyperactivity disorder (ADHD)**. The study population comprises both male and female subjects aged 6 to 17 years, who are functioning at an age-appropriate intellectual level. Participants were selected based on their diagnosis of ADHD, specifically those for whom stimulant medications are not suitable, not tolerated, or have been ineffective. The trial includes children and adolescents who are able to swallow intact tablets and have blood pressure measurements within the 95th percentile for their age, sex, and height. The study population is considered vulnerable, and all participants are required to comply with the study's requirements, including oversight of morning dosing by a parent or legally authorized representative. The trial does not specify any particular lifestyle considerations such as diet or physical activity. Participants must meet the DSM-5 criteria for ADHD and have specific baseline scores on the ADHD-RS-5 and CGI-S scales. Female participants of childbearing potential must have negative pregnancy tests and agree to comply with contraceptive requirements. The sponsor has not provided additional information regarding lifestyle or other demographic factors.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled**, and **active-comparator** study to evaluate the safety and efficacy of **Guanfacine Hydrochloride** prolonged-release in children and adolescents aged 6 to 17 years diagnosed with **Attention-deficit/hyperactivity disorder (ADHD)**. The trial is structured in two parts: an initial dose-optimization phase followed by an open-label evaluation. The study aims to assess the long-term safety of Guanfacine Hydrochloride, particularly in patients for whom stimulant medications are unsuitable, not tolerated, or ineffective. The trial is expected to last until September 2027, with participant involvement spanning up to 141 days.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, intellectual functioning, and ADHD diagnosis according to DSM-5 criteria. The screening visit will also include assessments like the Kiddie-Schedule for Affective Disorders-Present and Lifetime Version (K-SADSPL) and blood pressure measurements. Following the screening, eligible participants will enter the dose-optimization phase, where they will be randomly assigned to receive either Guanfacine Hydrochloride, **Atomoxetine Hydrochloride**, or a placebo. The primary endpoint is the change from baseline in the Cambridge automated neuropsychological test battery (CANTAB) reaction time task, with secondary endpoints including various cognitive and behavioral assessments.

Throughout the trial, participants will attend regular follow-up visits to monitor safety and efficacy outcomes, including vital signs, electrocardiogram (ECG) results, and ADHD symptom scores. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of all collected data. Participants may be withdrawn from the study early if they experience adverse effects, fail to comply with study procedures, or if the investigator deems it necessary for their safety. The trial's rigorous design ensures that the data collected will provide valuable insights into the treatment of ADHD in this population.

The clinical trial involves the administration of **Atomoxetine Hydrochloride**, which is provided in the form of a hard capsule. The active substance, atomoxetine hydrochloride, is of chemical origin. The maximum daily dose is 100 mg, with a total maximum dose of 98,700 mg over a treatment period of 141 days. The medication is administered orally. The capsule is over-encapsulated to ensure blinding in the study. Participant compliance is monitored through regular assessments and adherence checks.

Another experimental medication used in the trial is **Guanfacine**, marketed as Intuniv, available in prolonged-release tablet form. The active substance, guanfacine, is also of chemical origin. The maximum daily dose is 7 mg, with a total maximum dose of 6,909 mg over the same treatment period of 141 days. This medication is administered orally. The prolonged-release formulation is designed to maintain stable plasma levels, and participant adherence is monitored through scheduled visits and pill counts.

The study also includes a placebo group, where participants receive a placebo identical in appearance to the active medications to maintain blinding. The placebo is administered orally, following the same dosing schedule as the active treatments. Compliance in the placebo group is monitored similarly to the active treatment groups.

The efficacy of the clinical trial will be assessed using several key endpoints. The primary efficacy endpoint is the change in the ADHD-RS-5 total score, which evaluates the severity of Attention-deficit/Hyperactivity Disorder (ADHD) symptoms. Secondary efficacy endpoints include subscale scores for hyperactivity/impulsivity and inattention domains, as well as the Clinical Global Impressions-Improvement (CGI-I) score, which is calculated from the Clinical Global Impressions-Severity (CGI-S) score. Additional secondary efficacy measures include the Child Health and Illness Profile-Child Edition: Parent Report Form (CHIP-CE:PRF) and the C3PS Total Score, along with scores for Learning Problems and Executive Functioning subscales.

The efficacy parameters will be measured at various timepoints throughout the study, including baseline and subsequent visits, to monitor changes over time. The ADHD-RS-5 and CGI scales are validated tools commonly used in clinical trials to assess symptom severity and improvement. Data collection will be conducted in a structured manner, ensuring consistency and reliability in the assessment of treatment effects. The analysis of these efficacy parameters will be performed using appropriate statistical methods to determine the significance and clinical relevance of the findings.