A Study of TAK-503 in Children and Teenagers With Attention Deficit Hyperactivity Disorder (ADHD)

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 1-Year 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 main aim of this study is learn more about long-term TAK-503 treatment in children and teenagers with ADHD for whom earlier stimulant treatment did not work.

The study has two parts (A and B). In Part A, participants will take tablets of TAK-503, atomoxetine or placebo and in Part B TAK-503 tablets.

This study will be conducted in two parts Part A and Part B. Part A is a double-blinded, double-dummy, placebo-controlled study with an atomoxetine arm as an active reference to TAK-503. Eligible participants with ADHD will be randomized in a 1:1:1 ratio among TAK-503, atomoxetine, and placebo treatment arms up to 49 weeks of double-blinded treatment. Upon completion of Part A, participants will roll over to Part B directly as per the study protocol directions for an additional 52 weeks of open-label TAK-503 treatment.

Inclusion Criteria:

Study Part A:

• Participant is a male or female aged 6 to 17 years inclusive at the time of consent/assent.
• Participant must meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a primary diagnosis of ADHD based on a detailed psychiatric evaluation using the Kiddie-Schedule for Affective Disorders-Present and Lifetime Version (K-SADS-PL) by a trained child and adolescent psychiatrist at screening (Visit 1A).
• Participant for whom prior stimulant therapy is not suitable, not tolerated, or shown to be ineffective as determined by investigator clinical assessment and review of the Prior Stimulant Medication Questionnaire (PSMQ) administered during screening (Visit 1A).
• Participant has an ADHD-RS-5 total score greater than or equal to (> =) 28 at baseline (Visit 2A).
• Participant has a baseline (Visit 2A) CGI-S score > = 4.
• Participant who is a female of childbearing potential (FOCP) and postmenarchal must have a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test at screening (Visit 1A) and a negative urine pregnancy test at baseline (Visit 2A), be nonlactating, and agree to comply with any applicable contraceptive requirements described in the protocol. Female of child bearing potential is defined as any female participant who is at least aged 9 years or younger than 9 years and postmenarchal.
• Participants parent or legally authorized representative (LAR) must provide signature of informed consent. Documentation of assent (if applicable) must be provided by the participant indicating that the participant is aware of the investigational nature of the study and the required procedures and restrictions in accordance with the International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6[R2] and applicable regulations, before completing any study-related procedures.
• Participant and parent/LAR are willing and able to comply with all the testing and requirements defined in this protocol, including oversight of morning dosing. Specifically, the parent/LAR must be available for the duration of the study to administer the investigational medicinal product (IMP) dose each morning when the participant awakens.
• Participant has supine and standing blood pressure (BP) measurements less than the 95th percentile for age, sex, and height at both screening (Visit 1A) and baseline (Visit 2A).
• Participant is functioning at an age-appropriate level intellectually, as judged by the investigator.
• Participant is able to swallow intact tablets and capsules.

Study Part B:

• Female participants of child-bearing potential must have a negative serum β-hCG pregnancy test if a screening visit is conducted and/or a negative urine pregnancy test at baseline and agree to comply with any applicable contraceptive requirements of the protocol. An FOCP is defined as any female participant who is at least aged 9 years or younger than 9 years and postmenarchal.
• Participant has a supine and standing BP measurement less than the 95th percentile for age, sex, and height.

Exclusion Criteria:

Study Part A:

• Participant has a current, controlled (requiring medication or therapy) or uncontrolled, comorbid psychiatric disorder (except oppositional defiant disorder), including but not limited to any of the following comorbid Axis I and Axis II disorders (the K-SADS-PL should be reviewed to confirm diagnosis, if necessary):

  1. Post-traumatic stress disorder (PTSD)
  2. Bipolar illness, psychosis, or family history in either biological parent
  3. Pervasive developmental disorder
  4. Obsessive-compulsive disorder (OCD)
  5. Psychosis/schizophrenia
  6. Serious tic disorder or a family history of Tourette's disorder

• Participant is currently considered to be a suicide risk by the investigator; has made a previous suicide attempt; has a history of, or currently demonstrating, active suicidal ideation.

• Participant has a substance abuse disorder as defined by DSM-5 criteria or has been suspected of a substance abuse or dependence disorder (except nicotine) within the past 6 months.

• Participant has a clinically important abnormality on the urine drug and alcohol screen (except for the participants current ADHD stimulant, if applicable) at screening (Visit 1A).

• Participant has been physically, sexually, and/or emotionally abused.

• Participant has any other disorder that as judged by the investigator could contraindicate TAK-503 or confound the results of the safety and efficacy assessments.

• Participant has any condition or illness including any clinically significant abnormal laboratory value at screening (Visit 1A) or, if the laboratory test was repeated, at baseline (Visit 2A) that, as judged by the investigator, would be an inappropriate risk to the participant and/or could confound the interpretation of study results.

• Participant has current abnormal thyroid function, defined as abnormal thyroid-stimulating hormone and thyroxine at screening (Visit 1A). Treatment with a stable dose of thyroid medication for > = 3 months before screening will be permitted.

• Participant has a known history or presence of: malignancy (except nonmelanoma skin cancer), pregnancy, and/or a developmental delay or abnormality associated with growth or sexual maturation delays that are not related to ADHD.

• Children aged 6 to 12 years with a body weight less than (<) 25.0 kg or adolescents aged > = 13 years with a body weight < 34.0 kg at screening (Visit 1A) or baseline (Visit 2A).

• Participant is significantly overweight based on the Centers for Disease Control (CDC) BMI-for-age sex-specific charts at screening (Visit 1A) or baseline (Visit 2A). For this study, significantly overweight will be defined as a BMI that is greater than the 95th percentile.

• Participant has a known history or presence of: structural cardiac abnormalities, serious heart rhythm abnormalities, syncope, cardiac conduction problems (e.g. clinically significant heart block or QT interval prolongation), bradycardia, or exercise-related cardiac events including syncope and presyncope.

• Participant has clinically significant electrocardiogram (ECG) findings, as judged by the investigator, at baseline (Visit 2A).

• Participant has orthostatic hypotension* or a known history of hypertension. (*Orthostatic hypotension is defined as a sustained reduction of systolic blood pressure of at least 20 millimeter of mercury (mm Hg) or diastolic blood pressure of 10 mm Hg within 3 minutes of standing from supine.)

• Participant has a known family history of sudden cardiac death or ventricular arrhythmia.

• Participant is currently using any medication that violates protocol-specified washout criteria at baseline (Visit 2A), including any ADHD medication or other prohibited medications such as herbal supplements, medications that affect BP or heart rate (HR) or medications that have central nervous system (CNS) effects or affect cognitive performance, such as sedating antihistamines and decongestant sympathomimetics (inhaled bronchodilators are permitted) or a history of chronic use of sedating medications (i.e., antihistamines).

• Participant has a medical condition except ADHD that requires treatment with any medication that affects the CNS.

• Participant is female and pregnant or currently lactating.

• Participant has taken another investigational product or participated in a clinical study within 30 days before screening (Visit 1A).

• Participant does not tolerate or has a known or suspected allergy, hypersensitivity, or clinically significant intolerance to guanfacine hydrochloride, atomoxetine, or any TAK-503 or atomoxetine drug product component.

• Participant has a history of a seizure disorder (except for a single childhood febrile seizure episode that occurred before the age of 3 years)

• Participant is well-controlled on his/her current ADHD medication with acceptable tolerability, and the parent/treating physician does not object to the current medication.

• Participant has alanine transaminase (ALT) greater than (>) 2*upper limit of normal (ULN) or aspartate aminotransferase (AST) >2*ULN or bilirubin >1.5*ULN at screening.

Study Part B:

• Participant failed screening, voluntarily withdrew, or was discontinued from Study Part A for protocol nonadherence, participant noncompliance, or TEAE or SAE.
• Participant had any clinically significant TEAE during Study Part A that, as judged by the investigator, would preclude exposure to TAK-503.
• Participant has a history of alcohol or other substance abuse or dependence, as defined by DSM-5 (with the exception of nicotine) within the last 6 months.
• Participant currently uses any of the prohibited medication or other medications, including herbal supplements, that affect BP or HR or that have CNS effects or affect cognitive performance, such as sedating antihistamines and decongestant sympathomimetics (inhaled bronchodilators are permitted) or a history of chronic use of sedating medications (i.e. antihistamines) in violation of the protocol-specified washout criteria at baseline.
• Participant has a known or suspected allergy, hypersensitivity, or clinically significant intolerance to guanfacine hydrochloride, or any components found in TAK-503.
• Participant has taken any IMP except placebo in Study Part A within the 30 days before baseline of Study Part B (Visit 2B).
• Participant is significantly overweight based on the CDC BMI-for-age sex-specific charts at screening. Significantly overweight is defined as a BMI > 95th percentile.
• Participant is a child aged 6 to 12 years with a body weight of < 25.0 kg or an adolescent aged > = 13 years with a body weight of < 34.0 kg at screening (Visit 1B)
• Participant has any condition or illness including clinically significant abnormal laboratory values at screening which as judged by the investigator would represent an inappropriate risk to the participant and/or confound the interpretation of study results.
• Participant is currently considered a suicide risk as judged by the investigator, has previously made a suicide attempt, has a history of, or is currently demonstrating active suicidal ideation. Participants with intermittent passive suicidal ideation are not necessarily excluded based on the assessment of the investigator.
• Participant has clinically significant ECG findings, as judged by the investigator, at baseline (Visit 2B).
• Participant has a known history or presence of structural cardiac abnormalities, serious heart rhythm abnormalities, syncope, cardiac conduction problems (e.g. clinically significant heart block), exercise-related cardiac events including syncope and presyncope, or clinically significant bradycardia.
• Participant has orthostatic hypotension or a known history of hypertension. (*Orthostatic hypotension is defined as a sustained reduction of systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of 10 mm Hg within 3 minutes of standing from supine).
• Participant has a history of a seizure disorder (except for a single childhood febrile seizure episode that occurred before the age of 3 years) or the presence of a serious tic disorder including Tourette's syndrome.
• Participant has a medical condition except ADHD, which requires treatment with any medication that affects the CNS.
• Participant has ALT >2*ULN or AST >2*ULN or bilirubin >1.5*ULN at screening.