Trial Outcomes & Findings for A Study of TAK-503 in Children and Teenagers With Attention Deficit Hyperactivity Disorder (ADHD) (NCT NCT04085172)

Participants took part in the study at 29 investigative sites in Austria, Belgium, Germany, Netherlands, Portugal, Spain and the United States of America from 18 September 2019 to 02 September 2025. A total of 396 participants were screened, of which 288 were randomized and 108 were screen failures.

The study was conducted in 2 parts: Part A (Double-blinded Period) and Part B (Open-label Period). In Part A, pediatric participants were 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 directly rolled over to Trial Part B for an additional 52 weeks of open-label TAK-503 treatment.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Weight was measured in kg using a calibrated scale.

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

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

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.

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

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.

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.

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.

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.

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).

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).

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).

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).

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.

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.

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.

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.

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.

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.

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.