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

Shire396 enrolled

Overview

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Enrollment

396

Conditions

Attention Deficit Hyperactivity Disorder

Interventions

Guanfacine hydrochloride (TAK-503)DRUG

Participants aged 6 to 12 years will receive a dose of 1 to 4 mg and aged 13 to 17 years will receive a dose of 5 to 7 mg TAK-503 oral tablets once daily for 18 weeks in Part A or 52 weeks in Part B.

Atomoxetine hydrochlorideDRUG

Participants will receive Atomoxetine hydrochloride oral capsule once daily for 18 weeks in Part A.

PlaceboOTHER

Participants aged 6 to 12 years will receive a dose of 1 to 4 mg and aged 13 to 17 years will receive a dose of 5 to 7 mg placebo matched to TAK 503 oral tablets once daily for 18 weeks and placebo matched to atomoxetine hydrochloride oral capsules at once daily for 18 weeks in Part A.

Eligibility

Sex: ALLMin age: 6 YearsMax age: 17 Years

Medical Language ↔ Plain English

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.

Locations (50)

Outcomes

Primary Outcomes

Part A: Change From Baseline in the Cambridge Neuropsychological Test Automated Battery (CANTAB) Reaction Time (RTI) Task at Week 18

The neurocognitive function effects of TAK-503 on adolescents and children were evaluated using CANTAB assessments. The RTI task of CANTAB measured motor, mental response speeds and assessed movement time, reaction time, response accuracy and impulsivity. In CANTAB RTI task, a yellow dot appeared in one of circles (five circles for five-choice variant) and participant must react as soon as possible, releasing the button at bottom of screen and selecting the circle in which the dot appeared. Time taken from yellow dot appearing, to the participants releasing press-pad was defined as reaction time. Movement time was defined as time taken from the participant releasing the press-pad to touching the screen. Times for this assessment were calculated for correct trials and measured in milliseconds (msec) ranging from 100 to 5100, with a higher time indicating worse performance of the task. Negative change from baseline indicates improvement in reaction speed.

Time frame: At Baseline, Week 18

Part A: Change From Baseline in the CANTAB RTI Task at Week 49

The neurocognitive function effects of TAK-503 on adolescents and children were evaluated using CANTAB assessments. The RTI task of CANTAB measured motor, mental response speeds and assessed movement time, reaction time, response accuracy and impulsivity. In CANTAB RTI task, a yellow dot appeared in one of circles (five circle for five-choice variant) and participant must react as soon as possible, releasing the button at bottom of screen and selecting the circle in which the dot appeared. Time taken from yellow dot appearing, to the participants releasing press-pad was defined as reaction time. Movement time was defined as time taken from the participant releasing the press-pad to touching the screen. Times for this assessment were calculated for correct trials and measured in msec ranging from 100 to 5100, with a higher time indicating worse performance of the task. Negative change from baseline indicates improvement in reaction speed.

Time frame: At Baseline, Week 49

Part B: Change From Baseline in the CANTAB RTI Task at Week 49

The neurocognitive function effects of TAK-503 on adolescents and children were evaluated using CANTAB assessments. The RTI task of CANTAB measured motor, mental response speeds and assessed movement time, reaction time, response accuracy and impulsivity. In CANTAB RTI task, a yellow dot appeared in one of circles (five circle for five-choice variant) and participant must react as soon as possible, releasing the button at bottom of screen and selecting the circle in which the dot appeared. Time taken from yellow dot appearing, to the participants releasing press-pad was defined as reaction time. Movement time was defined as time taken from the participant releasing the press-pad to touching the screen. Times for this assessment were calculated for correct trials and measured in msec ranging from 100 to 5100, with a higher time indicating worse performance of the task. Negative change from baseline indicates improvement in reaction speed.

Data from ClinicalTrials.gov

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Secondary Outcomes

Part A: Change From Baseline in the Rapid Visual Information Processing (RVP) Task of the CANTAB: Mean Response Latency

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. RVP measured the ability to sustain attention over time and was a sensitive measure of frontal-parietal function. In this task, single digits appear in a pseudo-random order at a rate of 100 digits per minute in a box at the center of the screen. Participants were to detect a 3-digit target sequence (e.g. 2-4-6) and respond by pressing a button at the bottom of the screen when the final number of the sequence appears on the screen. Mean Response Latency was defined as the mean response time on trials where participants responded correctly. Higher time indicated worse performance.

Time frame: Baseline, Weeks 18 and 49

Part B: Change From Baseline in the RVP Task of the CANTAB: Mean Response Latency

Time frame: Baseline, Week 49

Part A: Change From Baseline in the RVP Task of the CANTAB: A'

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. RVP measured the ability to sustain attention over time and was a sensitive measure of frontal-parietal function. In this task, single digits appear in a pseudo-random order at a rate of 100 digits per minute in a box at the center of the screen. Participants were to detect a 3-digit target sequence (e.g. 2-4-6) and respond by pressing a button at the bottom of the screen when the final number of the sequence appears on the screen. A' was defined as the standardized score for target sequence detection, ranging from 0-1. Higher score indicated better performance.

Time frame: Baseline, Weeks 18 and 49

Part B: Change From Baseline in the RVP Task of the CANTAB: A'

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. RVP measured the ability to sustain attention over time and was a sensitive measure of frontal-parietal function. In this task, single digits appear in a pseudo-random order at a rate of 100 digits per minute in a box at the center of the screen. Participants were to detect a 3-digit target sequence (e.g. 2-4-6) and respond by pressing a button at the bottom of the screen when the final number of the sequence appears on the screen. A' was defined as the standardized score for target sequence detection, ranging from 0-1. Higher score indicated better performance.

Time frame: Baseline, Week 49

Part A: Change From Baseline in the RVP Task of the CANTAB: Probability of Hit

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. RVP measured the ability to sustain attention over time and was a sensitive measure of frontal-parietal function. In this task, single digits appear in a pseudo-random order at a rate of 100 digits per minute in a box at the center of the screen. Participants were to detect a 3-digit target sequence (e.g. 2-4-6) and respond by pressing a button at the bottom of the screen when the final number of the sequence appears on the screen. Probability of Hit was defined as proportion of correct sequence responses divided by total number of sequences. Higher rate indicates better performance.

Time frame: Baseline, Weeks 18 and 49

Part B: Change From Baseline in the RVP Task of the CANTAB: Probability of Hit

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. RVP measured the ability to sustain attention over time and was a sensitive measure of frontal-parietal function. In this task, single digits appear in a pseudo-random order at a rate of 100 digits per minute in a box at the center of the screen. Participants were to detect a 3-digit target sequence (e.g. 2-4-6) and respond by pressing a button at the bottom of the screen when the final number of the sequence appears on the screen. Probability of Hit was defined as proportion of correct sequence responses divided by total number of sequences. Higher rate indicates better performance.

Time frame: Baseline, Week 49

Part A: Change From Baseline in the Spatial Working Memory (SWM) Task of the CANTAB

The ability to retain spatial information and manipulate remembered items in working memory was measured with SWM task. Task was self-ordered and assessed the individual's ability to strategize heuristically. The test was a sensitive measure of frontal lobe and executive dysfunction. The test began with a number of colored squares (boxes) shown on the screen. By selecting the boxes and using a process of elimination, the participant should find one yellow 'token' in each of a number of boxes and use them to fill up an empty column on the right-hand side of the screen. The outcome measures to be presented for each assessment of the task as follows: Total errors- number of times a box was selected that was certain to not have any tokens, across all trials ranging 0 (very good) to 66 (poor/impaired). Strategy (6 to 8 boxes)- number of times a participant begins a new search pattern from same box they started with previously, ranging 0 to 13. Higher score indicated a very poor strategy.

Time frame: Baseline, Weeks 18 and 49

Part B: Change From Baseline in the SWM Task of the CANTAB

The ability to retain spatial information and manipulate remembered items in working memory was measured with SWM task. Task was self-ordered and assessed the individual's ability to strategize heuristically. The test was a sensitive measure of frontal lobe and executive dysfunction. The test began with a number of colored squares (boxes) shown on the screen. By selecting the boxes and using a process of elimination, the participant should find one yellow 'token' in each of a number of boxes and use them to fill up an empty column on the right-hand side of the screen. The outcome measures to be presented for each assessment of the task as follows: Total errors- number of times a box was selected that was certain to not have any tokens, across all trials ranging 0 (very good) to 66 (poor/impaired). Strategy (6 to 8 boxes) - number of times a participant begins a new search pattern from same box they started with previously, ranging 0 to 13. Higher score indicated a very poor strategy.

Time frame: Baseline, Week 49

Part A: Change From Baseline in the Stop Signal Task (SST) Task of the CANTAB: Stop Signal Reaction Time and Median Reaction Time

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. SST measured response inhibition or control. The participant must respond to an arrow stimulus by touching either of 2 choices depending on the direction the arrow points. If an audio tone was present, the participant should not respond. Stop signal reaction time was defined as the estimate of time where an individual can successfully inhibit responses 50 percent (%) of the time. Median reaction time (All Go Trials) was defined as the median reaction time taken across all Go trials within an assessment. Higher time indicated worse performance.

Time frame: Baseline, Weeks 18 and 49

Part B: Change From Baseline in the SST Task of the CANTAB: Stop Signal Reaction Time and Median Reaction Time

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. SST measured response inhibition or control. The participant must respond to an arrow stimulus by touching either of 2 choices depending on the direction the arrow points. If an audio tone was present, the participant should not respond. Stop signal reaction time was defined as the estimate of time where an individual can successfully inhibit responses 50% of the time. Median reaction time (All Go Trials) was defined as the median reaction time taken across all Go trials within an assessment. Higher time indicated worse performance.

Time frame: Baseline, Week 49

Part A: Change From Baseline in the SST Task of the CANTAB: Direction Error (Go Trials), Direction Error (Stop Trials) and Missed Trials

The neurocognitive function effects of TAK-503 on adolescents and children was evaluated using the CANTAB assessments. SST measured response inhibition or control. The participant must respond to an arrow stimulus by touching either of 2 choices depending on the direction the arrow points. If an audio tone was present, the participant should not respond. Direction Error (Go Trials) was defined as the total number of trials where the participant pressed the wrong button to the direction of the arrow stimulus on a "Go" trial. Direction Error (Stop Trials) was defined as the total number of trials where the participant pressed the wrong button to the direction of the arrow stimulus on a "Stop" trial. Missed Trials was defined as the total number of trials which the participant missed. Higher value indicated worse performance.

Time frame: Baseline, Weeks 18 and 49

Part B: Change From Baseline in the SST Task of the CANTAB: Direction Error (Go Trials), Direction Error (Stop Trials) and Missed Trials

Time frame: Baseline, Week 49

Part A: Change From Baseline in the Delayed Matching to Sample (DMS) Task of the CANTAB: Percentage of Correct Responses

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. DMS measured both simultaneous matching and short-term visual memory. The participant was shown a complex visual pattern (the sample) and after a brief delay, 4 similar patterns. The participant must identify the pattern that matches the sample. Percentage of Correct Responses was defined as the percentage of trials during which the participant chose the correct response on the first attempt. Higher rate indicated better performance.

Time frame: Baseline, Weeks 18 and 49

Part B: Change From Baseline in the DMS Task of the CANTAB: Percentage of Correct Responses

Time frame: Baseline, Week 49

Part A: Change From Baseline in the DMS Task of the CANTAB: Mean Correct Latency

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. DMS measured both simultaneous matching and short-term visual memory. The participant was shown a complex visual pattern (the sample) and after a brief delay, 4 similar patterns. The participant must identify the pattern that matches the sample. Mean Correct Latency was defined as the average time between the presentation of the response stimuli objects and the participants selecting the correct box on their first attempt. Higher time indicated worse performance.

Time frame: Baseline, Week 18 and 49

Part B: Change From Baseline in the DMS Task of the CANTAB: Mean Correct Latency

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. DMS measured both simultaneous matching and short-term visual memory. The participant was shown a complex visual pattern (the sample) and after a brief delay, 4 similar patterns. The participant must identify the pattern that matches the sample. Mean Correct Latency was defined as the average time between the presentation of the response stimuli objects and the participants selecting the correct box on their first attempt. Higher time indicated worse performance.

Time frame: Baseline, Week 49

Part A: Change From Baseline in the DMS Task of the CANTAB: Mean Choices to Correct

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. DMS measured both simultaneous matching and short-term visual memory. The participant was shown a complex visual pattern (the sample) and after a brief delay, 4 similar patterns. The participant must identify the pattern that matches the sample. Mean choices to correct was defined as the mean number of choices that the participant made on each trial, including the correct choice. Higher number of choices indicated worse performance.

Time frame: Baseline, Weeks 18 and 49

Part B: Change From Baseline in the DMS Task of the CANTAB: Mean Choices to Correct

The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with ADHD was evaluated using the CANTAB cognitive assessments. DMS measured both simultaneous matching and short-term visual memory. The participant was shown a complex visual pattern (the sample) and after a brief delay, 4 similar patterns. The participant must identify the pattern that matches the sample. Mean choices to correct was defined as the mean number of choices that the participant made on each trial, including the correct choice. Higher number of choices indicated worse performance.

Time frame: Baseline, Week 49

Parts A and B: Sexual Maturation Assessed Using Tanner Stage

The stage of puberty or sexual maturation was evaluated for each participant according to Tanner staging. The Tanner stage for genitals (male, stages I-V), breasts (females, stages I-V), and pubic hair (both sexes, stages I-V) was documented. Tanner staging was self-assessed. Self-assessment in this study was defined as participants or parents indicating which drawing of the scale corresponds to participants sexual maturation stage at the time of the specific visit.

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Week 49

Parts A and B: Change From Baseline in Weight

Weight was measured in kg using a calibrated scale.

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Week 49

Parts A and B: Change From Baseline in Height

A calibrated stadiometer was used for all height measurements and was measured in centimeter (cm).

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Week 49

Parts A and B: Change From Baseline in Body Mass Index (BMI)

BMI was a measure of body fat based on height and weight. BMI = (weight in kg x10,000)/(height in cm\^2).

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Week 49

Parts A and B: Number of Participants With Clinically Significant Changes in Vital Signs: Pulse Rate, Blood Pressure (BP), Temperature, and Respiratory Rate

Vital signs assessments included pulse rate (beats/minutes), supine and standing BP (millimeters of mercury \[mmHg\]), oral or tympanic temperature (degrees Celsius \[C\]), and respiratory rate (breaths per minute). The number of participants was calculated based on number of participants with non-missing results for a given parameter at Baseline and at least 1 post-Baseline assessment.

Time frame: Part A: From start of study drug administration up to Week 52; Part B: From start of study drug administration up to follow-up (Week 53)

Parts A and B: Number of Participants With Clinically Significant Changes in Electrocardiogram (ECG)

The heart rate (HR), PR interval, QRS interval, and QT interval were measured from all ECGs and the QTcB and QTcF were assessed.

Time frame: Part A: From start of study drug administration up to Week 52; Part B: From start of study drug administration up to follow-up (Week 53)

Parts A and B: Number of Participants With Treatment-emergent Adverse Events (TEAEs)

An Adverse event (AE) was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. A TEAE was defined as any event emerging or manifesting at or after the initiation of treatment with an investigational product or medicinal product or any existing event that worsened in either intensity or frequency following exposure to the investigational product or medicinal product. TEAEs were defined as AEs whose onset occurs, severity worsens, or intensity increases after receiving the blinded trial intervention and up to 3 days after the last dose of double-blind trial medication.

Time frame: Part A: From start of study drug administration up to Week 52; Part B: From start of study drug administration up to follow-up (Week 53)

Part A: Psychiatric Symptoms Assessed Using Brief Psychiatric Rating Scale for Children (BPRS-C): Total Score

Psychiatric symptoms were measured by the BPRS-C. The 21 items were grouped across 7 scales: Behavior Problems \[Questions 1 to 3\], Depression \[Questions 4 to 6\], Thinking Disturbance \[Questions 7 to 9\], Psychomotor Excitation \[Questions 10 to 12\], Withdrawal \[Questions 13 to 15\], Anxiety \[Questions 16 to 18\] and Organicity \[Questions 19 to 21\]. Each of the 21 items was rated on a 7-point severity Likert scale from 0 to 6 (not present=0; very mild=1; mild=2; moderate=3; moderately severe=4; severe=5; extremely severe=6). A total score was calculated by summing the values across the 21 items, ranging from 0 to 126. Higher scores indicated higher severity.

Time frame: Baseline, Weeks 18 and 49

Part B: Psychiatric Symptoms Assessed Using BPRS-C: Total Score

Time frame: Baseline, Weeks 23, 36 and 49

Parts A and B: Number of Participants With Suicidal Ideation (SI) or Behavior Assessed Using Columbia- Suicide Severity Rating Scale (CSSRS)

The C-SSRS was a structured tool used to assess SI and behavior. A maximum of 19 items were completed as follows: 7 items were required, a potential 10 additional items were completed upon a positive response to a required item, and 2 items were completed if suicide or suicide-like behavior was observed during the interview. Suicidal ideation, including intensity of ideation, behavior, \& attempts with actual/potential lethality. Categories have binary responses (yes/no) \& include Wish to be Dead; Non-specific Active Suicidal Thoughts; Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act; Active Suicidal Ideation with Some Intent to Act, without Specific Plan; Active Suicidal Ideation with Specific Plan and Intent, Preparatory Acts and Behavior; Aborted Attempt; Interrupted Attempt; Actual Attempt (non-fatal); Completed Suicide. Score of 1 or higher= suicidal ideation/behavior. Only non-zero categories were reported.

Time frame: Baseline up to Week 52

Parts A and B: Number of Participants With Side Effects Assessed Using Udvalg for Kliniske Undersøgelser (UKU) Side Effect Rating Scale: Asthenia or Lassitude or Increased Fatigability

UKU rating scale was developed for clinicians to assess side effects of psychopharmacological medications based on interviews and other relevant source information. UKU items relevant to the established safety profile of TAK-503 such as Asthenia/Lassitude/lncreased Fatiguability, Sleepiness/Sedation, Increased Duration of Sleep, and Orthostatic Dizziness were queried. Each side effect was categorized for severity, ranging from 0 (Normal) to 3 (Severe).

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Weeks 23, 36, 49, 50, 51 and 52

Parts A and B: Number of Participants With Side Effects Assessed Using UKU Side Effect Rating Scale: Sleepiness or Sedation

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Weeks 23, 36, 49, 50, 51 and 52

Parts A and B: Number of Participants With Side Effects Assessed Using UKU Side Effect Rating Scale: Increased Duration of Sleep

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Weeks 23, 36, 49, 50, 51 and 52

Parts A and B: Number of Participants With Side Effects Assessed Using UKU Side Effect Rating Scale: Orthostatic Dizziness

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Weeks 23, 36, 49, 50, 51 and 52

Part A: Sedative Effects Assessed Using Pediatric Daytime Sleepiness Scale (PDSS): Total Score

The PDSS was a self-reported assessment of daytime sleepiness in children aged 11 to 15 years. PDSS questionnaire was designed to be easy to administer, score, and interpret. Sleepiness-related questions were based on previous research of situations that can be sensitive to sleep loss in this age group. The 8 questions were scored on Likert-scale from 0 to 4 (never=0; seldom=1; sometimes=2; frequently=3; always=4). The total score on the PDSS was derived by summing the values from the 8 questions and ranged from 0 (never sleepy) to 32 (always sleepy), with higher scores representing greater severity of excessive sleepiness.

Time frame: Baseline, Weeks 18 and 49

Part B: Sedative Effects Assessed Using PDSS: Total Score

Time frame: Baseline, Weeks 23, 36 and 49

Parts A and B: Symptoms Assessed Using ADHD-Rating Scale-5 (ADHD-RS-5): Total Score

The ADHD-RS-5 was used widely by mental health, educational, and medical practitioners in screening, diagnosis, and treatment evaluation to determine the frequency and severity of ADHD symptoms and impairments in children and adolescents. The ADHD-RS-5 was based on the diagnostic criteria for ADHD as described in the DSM-5 and consisted of 2 symptom subscales, inattention and hyperactivity-impulsivity, each with 9 items and a total scale of 18 items. Each item in the subscale was scored with a value ranging from 0 (no symptoms) to 3 (severe symptoms). Total score was obtained from summing the scores of each item and ranged from 0 to 54. Higher score indicated a worse outcome.

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Week 49

Parts A and B: Symptoms Assessed Using ADHD-RS-5: Inattention Subscale Score

The ADHD-RS-5 was used widely by mental health, educational, and medical practitioners in screening, diagnosis, and treatment evaluation to determine the frequency and severity of ADHD symptoms and impairments in children and adolescents. The ADHD-RS-5 was based on the diagnostic criteria for ADHD as described in the DSM-5 and consisted of 2 symptom subscales, inattention and hyperactivity-impulsivity, each with 9 items and a total scale of 18 items. Each item in the subscale was scored with a value ranging from 0 (no symptoms) to 3 (severe symptoms). The ADHD-RS-5 subscale scores ranged from 0 to 27. Higher score indicated a worse outcome.

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Week 49

Parts A and B: Symptoms Assessed Using ADHD-RS-5: Hyperactivity-Impulsivity Subscale Score

The ADHD-RS-5 was used widely by mental health, educational, and medical practitioners in screening, diagnosis, and treatment evaluation to determine the frequency and severity of ADHD symptoms and impairments in children and adolescents. The ADHD-RS-5 was based on the diagnostic criteria for ADHD as described in the DSM-5 and consisted of 2 symptom subscales, inattention and hyperactivity-impulsivity, each with 9 items and a total scale of 18 items. Each item in the subscale was scored with a value ranging from 0 (no symptoms) to 3 (severe symptoms). The ADHD-RS-5 subscale scores ranged from 0 to 27. Higher score indicated a worse outcome.

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Week 49

Parts A and B: Number of Participants Assessed for Severity of Mental Illness Using Clinical Global Impression-Improvement (CGI-I)

Global clinical measurement of ADHD improvement as measured by CGI-I using the Clinical Global Impression-Severity (CGI-S) to establish baseline. The CGI-S was administered to assess the severity of mental illness at baseline. The CGI-I was administered to assess any improvement in symptoms and to guide the clinician on dosing adjustments. The CGI-I was scored on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). Higher score indicated worst improvement.

Time frame: Part A: Baseline, Weeks 1, 18 and 49; Part B: Baseline, Weeks 23, 36 and 49

Parts A and B: Participants Functioning and Well-being Assessed Using Child Health and Illness Profile - Child Edition: Parent Report Form (CHIP-CE:PRF): Global Score

Parent Report Form of CHIP-CE:PRF was administered to provide information on self-esteem \& school functioning. The 5 domains, 12 subdomains covered 76 items: Satisfaction: with health (7items)\& self (4items); Comfort: physical (9items)\& emotional symptoms (9items) \& activity restrictions (4items) due to illness; Resilience: behaviors\& family involvement (8items) in activities likely to enhance health, Social problem-solving (5items),Physical activity (6items); Risk avoidance: behaviors that if not avoided are likely to pose risks to health: Individual risk avoidance (4items), Threats to achievement (10items); Achievement: developmentally appropriate role functioning in school \& with peers: Academic performance (5items), Peer relations (5items). For each domain/subdomain, means were calculated by taking average of each non-missing item in domain/subdomain. Global score was an average of scores for 5 domains. Each item uses a 5-response format (scored 1-5). Higher score=greater health.

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Weeks 23, 36 and 49

Parts A and B: Behavioral, Social, and Academic Issues Assessed Using Conners 3 Parent Short Form (C3PS): Total Score

The Conners 3 was a focused tool for the assessment of ADHD and associated learning, behavior, and emotional problems in children 6 to 18 years of age. The C3PS was completed by a child's parent/guardian and comprised of 45 items with subsets of items related to six content scales: inattention, hyperactivity/impulsivity, executive functioning, learning problems, defiance/aggression and peer relations. The parent rated his/her child on the first 43 items of the C3PS using a 4-point Likert scale (0-3; where 0=not at all true \[never, seldom\] and 3=very much true \[very often, very frequently\]) based on past month; the last 2 items were fill-in-the-blank and do not contribute to the raw score(s). Total scores were evaluated by summing the 43 numeric items, resulting in a range of 0 to 129, where higher score indicated a greater frequency of issues

Time frame: Part A: Baseline, Weeks 18 and 49; Part B: Baseline, Weeks 23, 36 and 49