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

Inclusion Criteria:

Study Part A:

• Participant is a male or female aged 6 to 17 years inclusive at the time ofconsent/assent.

• Participant must meet Diagnostic and Statistical Manual of Mental Disorders, FifthEdition (DSM-5) criteria for a primary diagnosis of ADHD based on a detailedpsychiatric evaluation using the Kiddie-Schedule for Affective Disorders-Present andLifetime Version (K-SADS-PL) by a trained child and adolescent psychiatrist atscreening (Visit 1A).

• Participant for whom prior stimulant therapy is not suitable, not tolerated, orshown to be ineffective as determined by investigator clinical assessment and reviewof 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 atbaseline (Visit 2A).

• Participant has a baseline (Visit 2A) CGI-S score > = 4.

• Participant who is a female of childbearing potential (FOCP) and postmenarchal musthave a negative serum beta-human chorionic gonadotropin (β-hCG) pregnancy test atscreening (Visit 1A) and a negative urine pregnancy test at baseline (Visit 2A), benonlactating, and agree to comply with any applicable contraceptive requirementsdescribed in the protocol. Female of child bearing potential is defined as anyfemale participant who is at least aged 9 years or younger than 9 years andpostmenarchal.

• Participants parent or legally authorized representative (LAR) must providesignature of informed consent. Documentation of assent (if applicable) must beprovided by the participant indicating that the participant is aware of theinvestigational nature of the study and the required procedures and restrictions inaccordance with the International Council for Harmonisation (ICH) Good ClinicalPractice (GCP) Guideline E6[R2] and applicable regulations, before completing anystudy-related procedures.

• Participant and parent/LAR are willing and able to comply with all the testing andrequirements defined in this protocol, including oversight of morning dosing.Specifically, the parent/LAR must be available for the duration of the study toadminister the investigational medicinal product (IMP) dose each morning when theparticipant 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 bythe 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-hCGpregnancy test if a screening visit is conducted and/or a negative urine pregnancytest at baseline and agree to comply with any applicable contraceptive requirementsof the protocol. An FOCP is defined as any female participant who is at least aged 9years or younger than 9 years and postmenarchal.

• Participant has a supine and standing BP measurement less than the 95th percentilefor age, sex, and height.

Exclusion Criteria:

Study Part A:

• Participant has a current, controlled (requiring medication or therapy) oruncontrolled, comorbid psychiatric disorder (except oppositional defiant disorder),including but not limited to any of the following comorbid Axis I and Axis IIdisorders (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; hasmade 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 beensuspected of a substance abuse or dependence disorder (except nicotine) within thepast 6 months.

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

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

• Participant has any other disorder that as judged by the investigator couldcontraindicate TAK-503 or confound the results of the safety and efficacyassessments.

• Participant has any condition or illness including any clinically significantabnormal laboratory value at screening (Visit 1A) or, if the laboratory test wasrepeated, at baseline (Visit 2A) that, as judged by the investigator, would be aninappropriate risk to the participant and/or could confound the interpretation ofstudy results.

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

• Participant has a known history or presence of: malignancy (except nonmelanoma skincancer), pregnancy, and/or a developmental delay or abnormality associated withgrowth 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 adolescentsaged > = 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 isgreater 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, orexercise-related cardiac events including syncope and presyncope.

• Participant has clinically significant electrocardiogram (ECG) findings, as judgedby 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 bloodpressure 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 ventriculararrhythmia.

• Participant is currently using any medication that violates protocol-specifiedwashout criteria at baseline (Visit 2A), including any ADHD medication or otherprohibited medications such as herbal supplements, medications that affect BP orheart rate (HR) or medications that have central nervous system (CNS) effects oraffect cognitive performance, such as sedating antihistamines and decongestantsympathomimetics (inhaled bronchodilators are permitted) or a history of chronic useof sedating medications (i.e., antihistamines).

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

• Participant is female and pregnant or currently lactating.

• Participant has taken another investigational product or participated in a clinicalstudy 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, orany TAK-503 or atomoxetine drug product component.

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

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

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

Study Part B:

• Participant failed screening, voluntarily withdrew, or was discontinued from StudyPart A for protocol nonadherence, participant noncompliance, or TEAE or SAE.

• Participant had any clinically significant TEAE during Study Part A that, as judgedby the investigator, would preclude exposure to TAK-503.

• Participant has a history of alcohol or other substance abuse or dependence, asdefined 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 oraffect cognitive performance, such as sedating antihistamines and decongestantsympathomimetics (inhaled bronchodilators are permitted) or a history of chronic useof sedating medications (i.e. antihistamines) in violation of the protocol-specifiedwashout criteria at baseline.

• Participant has a known or suspected allergy, hypersensitivity, or clinicallysignificant intolerance to guanfacine hydrochloride, or any components found inTAK-503.

• Participant has taken any IMP except placebo in Study Part A within the 30 daysbefore baseline of Study Part B (Visit 2B).

• Participant is significantly overweight based on the CDC BMI-for-age sex-specificcharts 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 anadolescent aged > = 13 years with a body weight of < 34.0 kg at screening (Visit 1B)

• Participant has any condition or illness including clinically significant abnormallaboratory values at screening which as judged by the investigator would representan inappropriate risk to the participant and/or confound the interpretation of studyresults.

• Participant is currently considered a suicide risk as judged by the investigator,has previously made a suicide attempt, has a history of, or is currentlydemonstrating active suicidal ideation. Participants with intermittent passivesuicidal ideation are not necessarily excluded based on the assessment of theinvestigator.

• 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 includingsyncope 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 bloodpressure of at least 20 mm Hg or diastolic blood pressure of 10 mm Hg within 3minutes of standing from supine).

• Participant has a history of a seizure disorder (except for a single childhoodfebrile seizure episode that occurred before the age of 3 years) or the presence ofa serious tic disorder including Tourette's syndrome.

• Participant has a medical condition except ADHD, which requires treatment with anymedication that affects the CNS.

• Participant has ALT >2ULN or AST >2ULN or bilirubin >1.5*ULN at screening.