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
Phase: PHASE4
Conditions: Attention Deficit Hyperactivity Disorder
Sponsor: Shire

NCT Number: NCT04085172
Title: 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 
Study Number: SPD503-401
Document Version and Date: Protocol Amendment 8.0, 12 Apr 2024
Certain information within this document has been redacted (ie, specific content is masked 
irreversibly from view) to protect either personally identifiable information or company 
confidential information. 
Clinical Study Protocol
For non-commercial use only

CONFIDENTIAL 
PROTOCOL: SPD503-401 
TITLE: 
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 
DRUG: 
TAK-503 (SPD503) 
IND No: 
63,551 
EUDRACT 
Number: 
2018-000821-29 
EU CT Number 
(abbreviated): 
2022-502630-71 
SPONSOR: 
Takeda Development Center Americas, Inc. 
95 Hayden Avenue 
Lexington, MA 02421 USA 
PRINCIPAL/ 
COORDINATING 
INVESTIGATOR: 
, MD 
Universitätsmedizin Mainz 
Klinik und Poliklinik für Kinder-und Jugendpsychiatrie 
und - psychotherapie 
Langenbeckstrasse 1 
Geb. 406, 2. OG 
55131 Mainz, Rheinland-Pfalz 
Germany 
PROTOCOL 
HISTORY: 
Protocol Amendment 8.0: 12 April 2024 
Protocol Amendment 7.0: 02 Feb 2024 
Protocol Amendment 6.0: 10 May 2023 
Protocol Amendment 5.0: 08 Jun 2021 
Protocol Amendment 4.0: 08 Jun 2020 
Protocol Amendment 3.0: 09 Sep 2019 
Protocol Amendment 2.1: 11 Jul 2019 
Protocol Amendment 2: 28 May 2019 
Protocol Amendment 1.1: 10 Apr 2019 
Protocol Amendment 1: 02 May 2018 
Original Protocol: 08 Feb 2018; Endorsed by PRAC: 14 Sep 2017 
Confidentiality Statement 
PPD
For non-commercial use only

CONFIDENTIAL 
This document contains confidential and proprietary information of Takeda and is disclosed pursuant to 
confidentiality and nondisclosure obligations. This information should be used solely for the purposes 
for which it was provided and should not be copied, shared with, or disclosed to any third party without 
the express written consent of Takeda. 
For non-commercial use only

For non-commercial use only

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CONFIDENTIAL 
EMERGENCY CONTACT INFORMATION 
In the event of a serious adverse event (SAE), the investigator must fax or e-mail the “Safety 
Report Form” within 24 hours of awareness to the sponsor’s Global Drug Safety Department. 
Applicable fax numbers and e-mail address can be found on the fax cover sheet (sent under a 
separate cover).  
Fax: 1-484-595-8155 
Email: GPSE@takeda.com 
 
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CONFIDENTIAL 
PRODUCT QUALITY COMPLAINTS 
Investigators are required to report investigational product quality complaints or non-medical 
complaints to the sponsor within 24 hours. If requested, defective product(s) will be returned to 
the sponsor for inspection and analysis. 
A product quality complaint includes any instances where there is an allegation or report relating 
to sponsor-licensed or investigational products, received in writing, electronically, or orally, 
which indicates an impact to a product’s strength, identity, safety, purity, or quality, or which 
suggests that a product did not meet the criteria defined in the regulatory applications, licenses, 
or marketing authorizations for the product. Examples of investigational product quality 
complaints include, but are not limited to, the following: 
Unit issues 
• Capsule fill empty or overage 
• Bottle/vial fill shortage or overage 
• Capsule/tablet damaged/broken 
• Syringe/vial cracked/broken 
• Syringe leakage 
• Missing components 
• Product discoloration 
• Device malfunction 
Labeling 
• Label missing 
• Leaflet or Instructions For Use 
(IFU) missing  
• Label illegible 
• Incomplete, inaccurate, or 
misleading labeling 
• Lot number or serial number 
missing 
Packaging 
• Damaged packaging (eg, 
secondary, primary, bag/pouch) 
• Tampered seals 
• Inadequate or faulty closure 
• Missing components within 
package 
Foreign 
material 
• Contaminated product 
• Particulate in bottle/vial 
• Particulate in packaging 
 
Please report the product quality complaint using the “Product Complaint Data Collection Form” 
via the email address: 
pqc@takeda.com  
 
For instructions on reporting AEs related to product complaints, see Section 8.2. 
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CONFIDENTIAL 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE .................................................................................................3 
SUMMARY OF CHANGES ...........................................................................................................4 
EMERGENCY CONTACT INFORMATION ................................................................................5 
PRODUCT QUALITY COMPLAINTS..........................................................................................6 
TABLE OF CONTENTS .................................................................................................................7 
LIST OF TABLES .........................................................................................................................12 
LIST OF FIGURES .......................................................................................................................12 
LIST OF APPENDICES ................................................................................................................12 
ABBREVIATIONS .......................................................................................................................13 
STUDY SYNOPSIS ......................................................................................................................15 
STUDY SCHEDULES ..................................................................................................................23 
1. 
BACKGROUND INFORMATION .......................................................................................31 
1.1 
Indication and Current Treatment Options ...............................................................31 
1.2 
Product Background and Clinical Information ........................................................32 
1.2.1 
Anticipated Benefits and Risks ...........................................................................34 
2. 
STUDY OBJECTIVES AND PURPOSE ..............................................................................36 
2.1 
Rationale for the Study .............................................................................................36 
2.2 
Study Objectives ......................................................................................................36 
2.2.1 
Primary Objectives ..............................................................................................36 
2.2.2 
Secondary Objectives ..........................................................................................36 
3. 
STUDY DESIGN ...................................................................................................................38 
3.1 
Study Design and Flow Chart ..................................................................................38 
3.2 
Duration and Study Completion Definitions ............................................................42 
3.3 
Sites and Regions .....................................................................................................42 
4. 
STUDY POPULATION .........................................................................................................43 
4.1 
Study Part A Inclusion/Exclusion Criteria ...............................................................43 
4.1.1 
Study Part A Inclusion Criteria ...........................................................................43 
4.1.2 
Study Part A Exclusion Criteria ..........................................................................44 
4.2 
Study Part B Inclusion/Exclusion Criteria ...............................................................46 
4.2.1 
Study Part B Inclusion Criteria ............................................................................46 
4.2.2 
Study Part B Exclusion Criteria ..........................................................................46 
4.3 
Restrictions ...............................................................................................................47 
4.4 
Reproductive Potential .............................................................................................47 
4.4.1 
Female Contraception ..........................................................................................47 
4.4.2 
Male Contraception .............................................................................................48 
4.5 
Discontinuation of Subjects .....................................................................................48 
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4.5.1 
Reasons for Discontinuation/Withdrawal ............................................................49 
4.5.2 
Subjects “Lost to Follow-up” Before the Last Scheduled Visit ..........................49 
5. 
PRIOR AND CONCOMITANT TREATMENT ...................................................................50 
5.1 
Prior Treatment ........................................................................................................50 
5.2 
Concomitant Treatment ............................................................................................50 
5.2.1 
Permitted Treatment ............................................................................................50 
5.2.2 
Prohibited Treatment ...........................................................................................51 
5.2.2.1 
Medications Prohibited Based on TAK-503 Use (Study 
Parts A and B) ........................................................................................52 
5.2.2.2 
Medications Prohibited Based on Atomoxetine Use (Study Part 
A only) ....................................................................................................52 
5.2.2.3 
Washout Schedule for Prohibited Medications ......................................52 
6. 
INVESTIGATIONAL MEDICINAL PRODUCT(S) ............................................................54 
6.1 
Identity of Investigational Medicinal Product(s) .....................................................54 
6.1.1 
Blinding of the Treatment Assignment (Study Part A only) ...............................54 
6.2 
Administration of the Investigational Medicinal Product(s) ....................................55 
6.2.1 
Interactive Response Technology for Investigational Medicinal Product 
Management ........................................................................................................55 
6.2.2 
Allocation of Subjects to Treatment Arm ...........................................................55 
6.2.3 
Dosing Periods .....................................................................................................56 
6.2.3.1 
Dose-optimization Period .......................................................................56 
6.2.3.2 
Dose-maintenance Period .......................................................................58 
6.2.3.3 
Dose-taper Period ...................................................................................58 
6.2.4 
Unblinding of the Treatment Assignment ...........................................................59 
6.2.5 
Labeling, Packaging, Storage, Handling, and Accountability .............................60 
6.2.5.1 
Labeling ..................................................................................................60 
6.2.5.2 
Packaging ...............................................................................................60 
6.2.5.3 
Storage ....................................................................................................60 
6.2.5.4 
Special Handling ....................................................................................61 
6.2.6 
Drug Accountability ............................................................................................61 
6.3 
Subject Compliance ..................................................................................................62 
7. 
STUDY PROCEDURES ........................................................................................................63 
7.1 
Study Schedule .........................................................................................................63 
7.1.1 
Screening .............................................................................................................63 
7.1.2 
Baseline ...............................................................................................................64 
7.1.3 
Treatment Periods: Dose-optimization, Dose-maintenance, and Dose-taper ......65 
7.1.3.1 
Dose-optimization Period .......................................................................65 
7.1.3.2 
Dose-maintenance Period .......................................................................66 
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7.1.3.3 
Dose-taper Period ...................................................................................66 
7.1.4 
Follow-up Period .................................................................................................66 
7.1.5 
Additional Care of Subjects After the Study .......................................................67 
7.2 
Study Evaluations and Procedures ...........................................................................67 
7.2.1 
Demographic and Other Baseline Characteristics ...............................................67 
7.2.1.1 
Demographics .........................................................................................67 
7.2.1.2 
Medical and Medication History ............................................................67 
7.2.1.3 
Prior Stimulant Medicine Questionnaire ................................................68 
7.2.1.4 
Kiddie Schedule for Affective Disorders and Schizophrenia – 
Present and Lifetime Version .................................................................68 
7.2.2 
Safety Assessments .............................................................................................69 
7.2.2.1 
Physical Examination (Including Height and Weight) ..........................69 
7.2.2.2 
Tanner Staging .......................................................................................70 
7.2.2.3 
Adverse Event Collection .......................................................................70 
7.2.2.4 
Vital Signs ..............................................................................................71 
7.2.2.5 
Clinical Laboratory Evaluations .............................................................71 
7.2.2.6 
Urine Drug and Alcohol Screen .............................................................72 
7.2.2.7 
Pregnancy Test .......................................................................................72 
7.2.2.8 
Electrocardiogram ..................................................................................73 
7.2.2.9 
The Columbia-Suicide Severity Rating Scale ........................................73 
7.2.2.10 
Suitability of the Subject to Remain in the Study ..................................74 
7.2.2.11 
Brief Psychiatric Rating Scale for Children ...........................................74 
7.2.2.12 
Pediatric Daytime Sleepiness Scale .......................................................75 
7.2.2.13 
The Udvalg for Kliniske Undersøgelser Side Effect Rating Scale ........75 
7.2.2.14 
The Cambridge Automated Neuropsychological Test Battery ..............76 
7.2.3 
Efficacy Assessments ..........................................................................................76 
7.2.3.1 
The ADHD-Rating Scale-5 ....................................................................76 
7.2.3.2 
Clinical Global Impressions ...................................................................77 
7.2.3.3 
Child Health and Illness Profile – Child Edition: Parent Report Form ..77 
7.2.3.4 
Conners 3 Parent Short Form .................................................................78 
7.2.4 
Volume of Blood to Be Drawn from Each Subject .............................................79 
7.3 
Remote Visits and Assessments ...............................................................................79 
8. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................81 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events .......................................................................................................................81 
8.1.1 
Severity Categorization .......................................................................................81 
8.1.2 
Relationship Categorization ................................................................................82 
8.1.3 
Outcome Categorization ......................................................................................82 
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CONFIDENTIAL 
8.1.4 
Symptoms of the Disease Under Study ...............................................................82 
8.1.5 
Clinical Laboratory and Other Safety Evaluations ..............................................82 
8.1.6 
Pregnancy ............................................................................................................83 
8.1.7 
Abuse, Misuse, Overdose, and Medication Error ................................................83 
8.2 
Serious Adverse Event Procedures ..........................................................................84 
8.2.1 
Reference Safety Information ..............................................................................84 
8.2.2 
Reporting Procedures ..........................................................................................85 
8.2.3 
Serious Adverse Event Definition .......................................................................85 
8.2.4 
Serious Adverse Event Collection Time Frame ..................................................86 
8.2.5 
Serious Adverse Event Onset and Resolution Dates ...........................................86 
8.2.6 
Fatal Outcome .....................................................................................................86 
8.2.7 
Safety Reporting to Investigators, Institutional Review Boards or 
Independent Ethics Committees, and Regulatory Authorities ............................86 
9. 
DATA MANAGEMENT AND STATISTICAL METHODS ...............................................87 
9.1 
Data Collection .........................................................................................................87 
9.2 
Clinical Data Management .......................................................................................87 
9.3 
Data Handling Considerations..................................................................................87 
9.4 
Statistical Analysis Process ......................................................................................87 
9.5 
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee ......88 
9.6 
Sample Size Calculation and Power Considerations ................................................88 
9.7 
Study Analysis Set ...................................................................................................89 
9.8 
Study Analyses .........................................................................................................89 
9.8.1 
Study Part A: Double-blinded Evaluation ...........................................................90 
9.8.2 
Study Part B: Open-label Evaluation ..................................................................91 
9.9 
Study Endpoints .......................................................................................................91 
9.9.1 
Safety Endpoints ..................................................................................................91 
9.9.2 
Efficacy Endpoints ..............................................................................................91 
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES ...........................................93 
10.1 
Sponsor’s Responsibilities .......................................................................................93 
10.1.1 
Good Clinical Practice Compliance ....................................................................93 
10.1.2 
Indemnity/Liability and Insurance ......................................................................93 
10.1.3 
Public Posting of Study Information ...................................................................93 
10.1.4 
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees .....................94 
10.1.5 
Study Suspension, Termination, and Completion ...............................................94 
10.2 
Investigator’s Responsibilities .................................................................................94 
10.2.1 
Good Clinical Practice Compliance ....................................................................94 
10.2.2 
Protocol Adherence and Investigator Agreement ................................................95 
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CONFIDENTIAL 
10.2.3 
Documentation and Retention of Records ...........................................................95 
10.2.3.1 
Case Report Forms .................................................................................95 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study 
Documents ..............................................................................................95 
10.2.3.3 
Audit/Inspection .....................................................................................96 
10.2.3.4 
Financial Disclosure ...............................................................................96 
10.3 
Ethical Considerations ..............................................................................................96 
10.3.1 
Informed Consent ................................................................................................96 
10.3.2 
Institutional Review Board or Ethics Committee ................................................97 
10.3.3 
Serious Breach of Protocol for EU Clinical Trial Regulation .............................98 
10.4 
Privacy and Confidentiality ......................................................................................98 
10.5 
Study Results/Publication Policy .............................................................................99 
11. REFERENCES .....................................................................................................................101 
 
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CONFIDENTIAL 
LIST OF TABLES 
Table 1 
Study Part A – Double-blinded Evaluation: TAK-503, Atomoxetine, 
and Placebo through Week 18A ....................................................................23 
Table 2 
Study Part B – Open-label Evaluation of TAK-503 ......................................27 
Table 3 
Common Excluded Treatments and Associated Washout Period .................53 
Table 4 
Dose-optimization Schedule for TAK-503: Study Parts A and B .................57 
Table 5 
Dose-optimization Schedule for Atomoxetine: Study Part A .......................58 
Table 6 
Dose-taper Schedule for TAK-503 in Study Parts A and B ..........................59 
Table 7 
Selected Tasks from CANTAB to Assess Neurocognition ...........................76 
Table 8 
Domains and Subdomains of the CHIP – CE:PRF .......................................78 
Table 9 
Volume of Blood to Be Drawn from Subjects Randomized to Active 
IMP Treatments in Study Part A and Part B .................................................79 
 
LIST OF FIGURES 
Figure 1 
Study Design Flow Chart ..............................................................................41 
 
LIST OF APPENDICES 
Appendix 1 
Table of Evaluation Scales ..........................................................................104 
Appendix 2 
DSM-5 criteria for Attention Deficit/Hyperactivity Disorder .....................105 
Appendix 3 
Brief Psychiatric Rating Scale for Children ................................................107 
Appendix 4 
Prior Stimulant Medication Questionnaire ..................................................111 
Appendix 5 
Blood Pressure for Boys by Age and Height Percentile ..............................112 
Appendix 6 
Blood Pressure for Girls by Age and Height Percentile ..............................114 
Appendix 7 
Tanner Staging Self-assessment ..................................................................116 
Appendix 8 
Examples of Clinically relevant CYP3A4 Inhibitors and Inducers .............119 
Appendix 9 
Protocol History ...........................................................................................120 
 
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CONFIDENTIAL 
ABBREVIATIONS 
Abbreviation 
Definition 
ADHD 
attention-deficit/hyperactivity disorder 
ADHD-RS-5 
ADHD-Rating Scale-5 
AE 
adverse event 
AMOME 
abuse, misuse, overdose, or medication error 
-hCG 
beta-human chorionic gonadotropin 
BMI 
body mass index 
BP 
blood pressure 
BPRS-C-21 
Brief Psychiatric Rating Scale for Children  
BRI 
Behavioral Regulation Index (subscale of the BRIEF scale) 
BRIEF 
Behavior Rating Inventory of Executive Function 
C3PS 
Conners 3 Parent Short Form 
CANTAB 
Cambridge Neuropsychological Test Automated Battery 
CDC 
Centers for Disease Control 
CGI-I 
Clinical Global Impression–Improvement 
CGI-S 
Clinical Global Impression–Severity 
CHIP-CE:PRF 
Child Health and Illness Profile – Child Edition: Parent Report Form 
CI 
confidence interval 
CNS 
central nervous system 
COVID-19 
coronavirus disease 2019 
CRA 
clinical research associate 
CRO 
contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTR 
Clinical Trial Regulation 
CTRS-R 
Conners’ Teaching Rating Scale - Revised 
CYP 
cytochrome P450 
DMS 
Delayed Matching to Sample (CANTAB task) 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
DTP 
direct-to-patient 
(e)consent 
electronic consent 
EC 
ethics committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EF 
executive function 
EMA 
European Medicines Agency 
ET 
early termination 
EU 
European Union 
FAS 
full analysis set 
FDA 
Food and Drug Administration 
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CONFIDENTIAL 
Abbreviation 
Definition 
FOCP 
females of childbearing potential 
GCP 
Good Clinical Practice 
GEC 
Global Executive Composite (subscale of the BRIEF scale) 
HR 
heart rate 
IB 
investigator’s brochure 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
K-SADS-PL 
Kiddie-Schedule for Affective Disorders-Present and Lifetime Version 
LAR 
legally authorized representative 
LS 
least squares 
MDMA 
methylenedioxy-methamphetamine 
MedID 
medication identification 
MI 
Metacognition Index (subscale of the BRIEF scale) 
MMRM 
mixed-effects model for repeated measures 
OCD 
obsessive compulsive disorder 
PASS 
postapproval safety study 
PDSS 
Pediatric Daytime Sleepiness Scale 
PPS 
per-protocol set 
PSMQ 
Prior Stimulant Medication Questionnaire 
PTSD 
post-traumatic stress disorder 
QD 
once daily 
RTI 
Reaction Time/5-Choice Reaction Time (CANTAB task) 
RVP 
Rapid Visual Information Processing (CANTAB task) 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SARI 
serotonin antagonist and reuptake inhibitor 
SmPC 
Summary of Product Characteristics 
SNRI 
selective norepinephrine reuptake inhibitor 
SSRI 
selective serotonin reuptake inhibitor 
SST 
Stop Signal Task (CANTAB task) 
SWM 
Spatial Working Memory (CANTAB task) 
TEAE 
treatment-emergent adverse event 
UKU 
Udvalg for Kliniske Undersøgelser 
WFIRS-P 
Weiss Functional Impairment Rating Scale – Parent 
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STUDY SYNOPSIS 
Protocol number: SPD503-401 
Drug: TAK-503 (SPD503) (guanfacine hydrochloride 
extended-/prolonged-release) 
EUDRACT Number: 2018-000821-29 
EU CT Number (abbreviated): 2022-502630-71 
Title of the study: 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 
Number of subjects (total and for each treatment arm): Approximately 288 children and adolescents aged 6 to 
17 years inclusive diagnosed with attention-deficit/hyperactivity disorder (ADHD) by Diagnostic and Statistical 
Manual of Mental Disorders, Fifth Edition (DSM-5) will be enrolled in Study Part A (96 subjects per treatment arm). 
Approximately 25% of all subjects will be aged 13 to 17 years. Approximately 25% of all subjects will be female. 
Once 120 subjects have entered into Study Part B, only subjects in the placebo arm in Study Part A will enter Study 
Part B, to assure that all placebo arm subjects have the opportunity to enter into the 1-year TAK-503 open-label 
treatment arm. 
Investigators: Multicenter study 
Sites and Region: Approximately 55 sites in Europe and the United States  
Study period: 2019 to 2027 
Clinical phase: 
4 
Objectives 
UPrimary objectiveU: To evaluate the comparative long-term safety of TAK-503 (formerly known as SPD503) 
treatment in children and adolescents aged 6 to 17 years diagnosed with ADHD for whom stimulants are not suitable, 
not tolerated, or shown to be ineffective: 
• 
To evaluate TAK-503 compared with atomoxetine after 12 months of once daily (QD) treatment on 
psychomotor speed and attention as measured by the Cambridge automated neuropsychological test battery 
(CANTAB) reaction time (RTI) task, using the mixed-effects model for repeated measures (MMRM). The 
effect of TAK-503 on cognition will be assessed and interpreted on the totality of the data. 
USecondary objectives: 
Secondary safety objectives 
• 
Cognitive domain, sustained attention as measured by CANTAB Rapid Visual Information Processing 
(RVP) task 
• 
Cognitive domain, Spatial Working Memory (SWM), a component of executive function (EF), as measured 
by the CANTAB SWM task between errors 
• 
Cognitive domain, response control/inhibition as measured by the CANTAB Stop Signal Task (SST) 
• 
Cognition domain, recognition memory as measured by the CANTAB Delayed Matching to Sample (DMS) 
task 
• 
Sexual maturation as measured by Tanner stage 
• 
Growth as measured by weight, height, and body mass index (BMI) 
• 
Incidence of treatment-emergent adverse events (TEAE) 
• 
Vital sign and electrocardiogram (ECG) results 
• 
Psychiatric symptoms as measured by the Brief Psychiatric Rating Scale for Children (BPRS-C) total score 
and factors for Depression, Anxiety, Psychomotor Excitation, Behavior Problems, Withdrawal, Thinking 
Disturbance, and Organicity 
• 
Suicidal ideation/behavior as measured by the Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Asthenia/Lassitude/Increased Fatigability, Sleepiness/Sedation, Increased Duration of Sleep, and 
Orthostatic Dizziness based on the ratings of specific Udvalg for Kliniske Undersøgelser (UKU) scale items 
• 
Sedative effects as measured by subject ratings on the Pediatric Daytime Sleepiness Scale (PDSS) 
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Secondary efficacy objectives 
• 
Attention-deficit/hyperactivity disorder symptoms as measured by the investigator-administered 
ADHD-Rating Scale-5 (ADHD-RS-5) total score and hyperactivity/impulsivity and inattention subscale 
scores 
• 
Global clinical measurement of ADHD improvement as measured by Clinical Global 
Impression-Improvement (CGI-I) using the Clinical Global Impression–Severity (CGI-S) to establish 
baseline 
• 
Function as measured by the Child Health and Illness Profile – Child Edition: Parent Report Form 
(CHIP-CE:PRF) domains of satisfaction, comfort, resilience, risk avoidance, and achievement. The effect of 
TAK-503 on all subdomains will be summarized, including the subdomain satisfaction with self, using 
parental ratings of the child’s self-esteem. 
• 
Assessment of behavioral, social, and academic issues with the Conners 3 Parent Short Form (C3PS) Total 
Score and the Learning Problems and Executive Functioning subscale scores.  
Rationale: Study SPD503-401 has been designed to evaluate the long-term safety and efficacy of TAK-503 with a 
specific focus on neurocognition, growth, and sexual maturation. In Study Part A, an atomoxetine arm has been 
included as an active comparator and a placebo treatment arm as a control for assay sensitivity. 
Benefits and Risks: Overall, the clinical development program has demonstrated a favorable benefit-risk profile of 
TAK-503 in treatment of ADHD in children and adolescents. The efficacy of TAK-503 for the treatment of ADHD 
compared to placebo has been rigorously demonstrated with several well controlled studies. Post-marketing reports 
have continued to indicate that TAK-503 is generally safe and well tolerated in the majority of subjects, and the 
incidence and nature of the adverse events remains in accordance with the current reference safety information for 
the product and the known clinical characteristics of the treated patient population. 
Investigational product, dose, and mode of administration 
UStudy Part A: Double-blind Evaluation 
The investigational medicinal products (IMPs) include TAK-503, atomoxetine, and placebo. The IMPs will be 
administered using a double-blinded double-dummy design. Dosing of IMP will be flexibly optimized to maximize 
potential benefits while minimizing risk of TEAEs. 
Eligible subjects will be randomized at baseline (Day 0/Visit 2A) in a 1:1:1 ratio among TAK-503, atomoxetine, and 
placebo treatment arms. Allocation to treatment arm will be stratified by sex (male or female) and age subgroup 
(6-12 years or 13-17 years) to facilitate between-treatment balance within each stratum. 
Subjects randomized to the TAK-503 treatment arm will receive TAK-503 tablet(s) and atomoxetine-matched 
placebo capsule(s). Subjects randomized to the atomoxetine treatment arm will receive TAK-503-matched placebo 
tablet(s) and atomoxetine capsule(s). Subjects randomized to the placebo treatment arm will receive TAK-503-
matched placebo tablet(s) and atomoxetine-matched placebo capsule(s). 
TAK-503, an extended-/prolonged-release tablet formulation of guanfacine hydrochloride, is designed for QD oral 
administration. TAK-503 will be provided by the sponsor in 1-, 2-, 3-, and 4-mg strength tablets. 
Atomoxetine hydrochloride, the marketed comparator product, is designed for QD administration. The sponsor will 
provide 10-, 18-, 25-, 40-, and 60-mg strength atomoxetine capsules.  
The sponsor will provide TAK-503-matched placebo tablets and atomoxetine-matched placebo capsules.  
UStudy Part B: Open-label Evaluation 
TAK-503 will be the only IMP administered in Study Part B. The dose-optimization schedule and dose levels of 
TAK-503 in Study Part B will be identical to those in Study Part A. 
Methodology 
Study SPD503-401 is a phase 4, multicenter, dose-optimization postapproval safety study (PASS) and will be 
conducted in 2 parts: Study Part A and Study Part B. Study Part A will be a randomized, double-blinded, 
parallel-group, placebo- and active comparator-controlled, 3-treatment arm safety and efficacy evaluation of 
TAK-503. Pediatric subjects with ADHD will be randomized in a 1:1:1 ratio among TAK-503, atomoxetine, and 
placebo treatment arms for 18 weeks of double-blinded treatment and evaluation. At the end of the 18 weeks (Week 
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18A/Visit 11A), all subjects will roll over to Study Part B directly for an additional 52 weeks of open-label TAK-503 
treatment.  
Once 120 subjects have entered into Study Part B, only subjects in the placebo arm in Study Part A will enter Study 
Part B, to assure that all placebo arm subjects have the opportunity to enter into the 1-year TAK-503 open-label 
treatment arm. 
Study Part A will consist of the following 5 periods elapsing up to 23 weeks: 
1. 
UScreening/washoutU: Day -35A to Day -3A (up to 5 weeks). 
2. 
UDose-optimization period U: IMP will be dose-optimized from Week 0A through Week 4A for children aged 
6 to 12 years and through Week 7A for adolescents aged 13 to 17 years. 
3. 
UDose-maintenance period U: Subjects will continue with QD dosing from Week 5A for children and Week 8A 
for adolescents through Week 18A.  
4. Dose-taper period: Scheduled 3-week fixed-dose taper of IMP. All subjects randomized in the TAK-503 or 
atomoxetine treatment arms will undergo a scheduled 3-week dose taper to ensure proper downward dose 
titration of TAK-503 at the end of the dose-maintenance period or ET.  
5. 
UFollow-up periodU: Follow-up visit 1 week after the last IMP tapered dose 
• 
Subjects randomized to TAK-503 or atomoxetine treatment arms will participate in a follow-up 
visit and begin rescreening/washout procedures for Study Part B. 
Placebo subjects can skip the follow-up visit after completion of Study Part A assessments at Visit 11A (Week 18A), 
and proceed immediately to baseline visit assessments for Study Part B. 
Before enrollment in Study Part A, subjects will be screened based on inclusion/exclusion criteria to establish 
eligibility for study participation. Subjects who meet eligibility requirements will undergo a medication washout 
period, if applicable. 
In Study Part A, subjects with a baseline ADHD-RS-5 total score ≥28 and CGI-S score of ≥4 will be eligible for 
enrollment. During the dose-optimization period, clinic visits will be scheduled once every 7 days to assess IMP 
safety and tolerability and to allow investigators to titrate IMP to an optimal dose that maximizes potential benefits 
while minimizing risk of TEAEs. If necessary, the investigator will be allowed to lower the subject’s dose once 
during the dose optimization period in Study Parts A and B. 
Subjects randomized to TAK-503 will begin dosing at 1 mg, which will be dose-titrated upward in weekly 1-mg 
increments until an optimal dose is reached. Children aged 6 to 12 years will not be permitted to titrate to a daily 
dose >4 mg QD and adolescents aged 13 to 17 years will not be permitted to titrate to a dose greater than the 
maximum allowed dose QD as presented in the following baseline weight groups: 
UBaseline weight 
UMaximum TAK-503 dose QD  
25.0 to 41.4 kg 
4 mg 
41.5 to 49.4 kg 
5 mg 
49.5 to 58.4 kg 
6 mg 
≥58.5 kg 
7 mg 
 
 
Subjects optimized to a TAK-503 daily dose between 1 and 4 mg will take 1 TAK-503 tablet QD (or 
TAK-503-matched placebo tablet). Subjects optimized to a TAK-503 daily dose between 5 and 7 mg will take 
2 TAK-503 tablets QD (or 2 TAK-503-matched placebo tablets). 
Subjects randomized to the atomoxetine treatment arm who weigh <70 kg at baseline will begin dosing with 
approximately 0.5 mg/kg atomoxetine QD. If well-tolerated after 1 week minimum, this dose may be increased to the 
target dose of 1.2 mg/kg QD. The total daily dose will not exceed 1.4 mg/kg QD. With limited dosage forms, this 
upper limit is necessary to achieve appropriate weight-based dosing. Permitted doses of atomoxetine for subjects 
who weigh <70 kg at baseline are 10, 18, 25, 40, 60, and 80 mg QD and depend on subject’s baseline weight 
(Visit 2A). 
Subjects randomized to the atomoxetine treatment arm who weigh ≥70 kg at baseline will begin dosing with 40 mg 
atomoxetine QD. If well-tolerated after 1 week minimum, this dose may be increased to 80 mg QD. After a 1-week 
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minimum, if the 80 mg daily dose is well-tolerated, then the dose may be increased to 100 mg QD. The total dose in 
children and adolescents who weigh ≥70 kg at baseline will not be permitted to exceed 100 mg QD. 
Subjects optimized to an atomoxetine daily dose greater than 60 mg QD will take 2 atomoxetine or 
atomoxetine-matched placebo capsules QD. Subjects optimized to a daily dose ≤60 mg will take 1 atomoxetine or 
atomoxetine-matched placebo capsule QD. 
Subjects will continue daily treatment with the optimal IMP dose during the dose-maintenance period. The 
investigator will not be permitted to adjust the IMP dose during the dose-maintenance period of Study Part A. The 
dose-maintenance period will be followed by a 3-week dose-taper period. 
After the last IMP tapered dose, subjects will return to the site for a follow-up visit. The follow-up visit will serve as 
the Study Part B screening visit for subjects randomized to the TAK-503 and atomoxetine treatment arms. 
Study Part B will consist of 5 periods: 
1.  Screening/washout: Day -35B to Day -3B (up to 5 weeks) 
2. 
UDose-optimization period U: TAK-503 will be dose-optimized from Week 0B through Week 4B for children 
aged 6 to 12 years and through Week 7B for adolescents aged 13 to 17 years. 
3. 
UDose-maintenance period U: Dose-optimized TAK-503 will be administered QD from Week 5B for children 
and from Week 8B for adolescents through Week 49B for both age groups. 
4. 
UDose-taper periodU: Scheduled 3-week dose-taper of TAK-503 through Weeks 50B, 51B, and 52B 
5. 
UFollow-up periodU: Last dose of TAK-503 to the follow-up visit at Week 53B 
During the follow-up visit in Study Part A, subjects will undergo a partial rescreening of study criteria to confirm 
eligibility for continued participation in Study Part B. Subjects who complete Study Part A and roll over into Study 
Part B should do so without a gap except for washout. Subjects (except those randomized to placebo) must undergo a 
washout period of ≥30 days between the last IMP dose in Study Part A and the first dose of TAK-503 in Study Part 
B. Eligibility for Study Part B will be confirmed at the baseline visit (Visit 2B). 
During the dose-optimization period of Study Part B, clinic visits will be scheduled once every 7 days to assess 
safety and tolerability and to allow investigators to titrate subjects to an optimal TAK-503 dose based on clinical 
judgment of tolerability and efficacy using the totality of all available clinical and safety data. All subjects will begin 
with 1 mg TAK-503 QD and dose-titrated upward in 1-mg increments weekly until an optimal dose is reached. 
Children aged 6 to 12 years will not be permitted to titrate to a daily dose greater than 4 mg and adolescents aged 
≥13 years will not be permitted to titrate to a daily dose above the maximum allowed dose per baseline weight group. 
Following titration to an optimal dose of TAK-503, subjects will continue with TAK-503 administration through the 
dose-maintenance period (ie, Week 49B). Visits to the site will occur at intervals of 13 weeks. During the 
dose-maintenance period, the investigator may make further dose adjustments as needed based upon TEAEs and 
clinical judgment of tolerability and efficacy. These dose adjustments can be to a higher dose, based on the subject’s 
current age and weight. Children who turn 13 years or older during the dose-maintenance period may be permitted to 
increase the daily dose higher than 4 mg based on weight at the Study Part B baseline. The dose can be adjusted in 
1 mg increments (increased or decreased) at any scheduled or unscheduled visit (not more frequently than every 
3 days) during the study if deemed appropriate by the investigator. 
All subjects randomized to either the TAK-503 or atomoxetine treatment arm will undergo a scheduled 3-week dose 
taper to ensure proper downward dose titration of TAK-503 at the end of the dose-maintenance period or ET in both 
Study Parts A and B, as applicable. 
Each subject’s last visit will be 7 (+2) days after the last TAK-503 dose in Study Part B, to measure blood pressure 
and heart rate, and to follow up on concomitant medications and safety assessments, including TEAEs, which may 
have been ongoing at the previous visit. Treatment-emergent adverse events reported up to the time of the follow-up 
visit will be documented and appropriate follow-up will continue until all safety concerns are resolved as judged by 
the investigator. 
Inclusion and exclusion criteria (Study Part A – see full protocol for Study Part B eligibility criteria) 
UInclusion CriteriaU 
1. Subject is a male or female aged 6 to 17 years inclusive at the time of consent/assent. 
2. Subject must meet 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). 
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3. Subject 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). 
4. Subject has an ADHD-RS-5 total score ≥28 at baseline (Visit 2A). 
5. Subject has a baseline (Visit 2A) CGI-S score ≥4. 
6. Subject 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 childbearing potential is defined as any 
female subject who is at least aged 9 years or younger than 9 years and postmenarchal. 
7. Subject’s parent or legally authorized representative (LAR) must provide signature of informed consent. 
Documentation of assent (if applicable) must be provided by the subject indicating that the subject is aware 
of the investigational nature of the study and the required procedures and restrictions in accordance with the 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use 
(ICH) Good Clinical Practice (GCP) Guideline E6[R2] and applicable regulations, before completing any 
study-related procedures. 
8. Subject 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 IMP dose each morning when the subject awakens. 
9. Subject has supine and standing blood pressure (BP) measurements less than the 95th
P percentile for age, sex, 
and height at both screening (Visit 1A) and baseline (Visit 2A). 
10. Subject is functioning at an age-appropriate level intellectually, as judged by the investigator. 
11. Subject is able to swallow intact tablets and capsules. 
UExclusion Criteria 
1. Subject 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): 
a. 
Posttraumatic stress disorder (PTSD) 
b. Bipolar illness, psychosis, or family history in either biological parent 
c. 
Pervasive developmental disorder 
d. Obsessive-compulsive disorder (OCD) 
e. 
Psychosis/schizophrenia 
f. 
Serious tic disorder or a family history of Tourette’s disorder 
2. Subject 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. 
3. Subject 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. 
4. Subject has a clinically important abnormality on the urine drug and alcohol screen (except for the subject’s 
current ADHD stimulant, if applicable) at screening (Visit 1A). 
5. Subject has been physically, sexually, and/or emotionally abused. 
6. Subject has any other disorder that as judged by the investigator could contraindicate TAK-503 or confound 
the results of the safety and efficacy assessments. 
7. Subject 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 subject and/or could confound the interpretation of study 
results. 
8. Subject 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. 
9. Subject 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. 
10. Children aged 6 to 12 years with a body weight <25.0 kg or adolescents aged ≥13 years with a body weight 
<34.0 kg at screening (Visit 1A) or baseline (Visit 2A). 
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11. Subject 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
P percentile. 
12. Subject has a known history or presence of: structural cardiac abnormalities, serious heart rhythm 
abnormalities, syncope, cardiac conduction problems (eg, clinically significant heart block or QT interval 
prolongation), bradycardia, or exercise-related cardiac events including syncope and presyncope. 
13. Subject has clinically significant ECG findings, as judged by the investigator, at baseline (Visit 2A). 
14. Subject 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.) 
15. Subject has a known family history of sudden cardiac death or ventricular arrhythmia. 
16. Subject 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 (ie, 
antihistamines). 
17. Subject has a medical condition except ADHD that requires treatment with any medication that affects the 
CNS. 
18. Subject is female and pregnant or currently lactating. 
19. Subject has taken another investigational product or participated in a clinical study within 30 days before 
screening (Visit 1A). 
20. Subject 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. 
21. Subject has a history of a seizure disorder (except for a single childhood febrile seizure episode that 
occurred before the age of 3 years). 
22. Subject is well-controlled on his/her current ADHD medication with acceptable tolerability, and the 
parent/treating physician does not object to the current medication. 
23. Subject has ALT >2 x upper limit of normal (ULN) or AST >2 x ULN or bilirubin >1.5 x ULN at screening. 
Maximum duration of subject involvement in the study (per Amendment 7) 
UStudy Part A 
• 
Planned duration of screening and washout: Up to 35 days 
• 
Planned duration of the dose-optimization period: 4 weeks (children), 7 weeks (adolescents) 
• 
Planned duration of the dose-maintenance period: 14 weeks (children), 11 weeks (adolescents) 
• 
Planned duration of the dose-taper period: 3 weeks 
• 
Planned duration of the follow-up period: 7 (+2) days 
UStudy Part B 
• 
Planned duration of washout: Up to 35 days 
• 
Planned duration of the dose-optimization period: 4 weeks (children), 7 weeks (adolescents) 
• 
Planned duration of the dose-maintenance period: 45 weeks (children), 42 weeks (adolescents) 
• 
Planned duration of the dose-taper period: 3 weeks 
• 
Planned duration of the follow-up period: 7 (+2) days 
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Endpoints and statistical analysis 
UStudy Analysis Population Sets 
The randomized set will be defined as all randomized subjects in Study Part A. Any subject who is not randomized 
will be considered a screen failure. 
The double-blind safety set will be defined as all randomized subjects in Study Part A who receive ≥1 IMP dose. The 
double-blind safety set will be used for safety analysis (except for CANTAB domains) for Study Part A. 
The open-label safety set will be defined as all subjects who receive ≥1 dose of TAK-503 in Study Part B. All safety 
and efficacy presentations for Study Part B will be based on the open-label safety set.  
The full analysis set (FAS) will be defined as all subjects in the double-blind safety set with ≥1 postbaseline 
CANTAB assessment. 
The per-protocol set (PPS) will be defined as all subjects in the FAS who complete the study and were deemed 
protocol-compliant. To be protocol-compliant, no significant protocol deviations occurred during the study that could 
affect the assessment of the primary safety endpoint, the CANTAB RTI task. 
UStudy Endpoints 
The primary safety endpoint will be the change from baseline in the CANTAB RTI task. 
Secondary safety endpoints will include the following: 
• 
CANTAB tasks: RVP, SWM between errors, DMS, and SST 
• 
Tanner stage, weight, height, BMI 
• 
Vital signs (BP and pulse) and ECG results 
• 
BPRS-C total score and scales for Depression, Anxiety, Psychomotor Excitation, Behavior Problems, 
Withdrawal, Thinking Disturbance, and Organicity 
• 
C-SSRS 
• 
Specified UKU side effect rating scale items: Asthenia/Lassitude/Increased Fatigability, 
Sleepiness/Sedation, Increased Duration of Sleep, and Orthostatic Dizziness 
• 
PDSS 
Primary efficacy endpoint: Not applicable for this PASS. 
Secondary efficacy endpoints will include the following: 
• 
ADHD-RS-5 total score and subscale scores for hyperactivity/impulsivity and inattention domains 
• 
CGI-I 
• 
CHIP-CE:PRF 
• 
C3PS Total Score and scores for Learning Problems and Executive Functioning subscales 
UStudy Analyses 
The analyses of the safety CANTAB domains for Study Part A will be based on the FAS and PPS. The analyses of 
efficacy endpoints will be based on the FAS only. Other safety analyses for Study Part A will be based on the safety 
set; the safety and efficacy analysis for Study Part B will be based on the open-label safety set. 
UStudy Part A: Double-blinded Evaluation 
The primary safety endpoint will be the change from baseline in the CANTAB RTI task. The endpoint will be 
analyzed over the FAS and PPS with a MMRM with treatment arm, visit, sex (male or female), age group 
(6 to 12 years or 13 to 17 years), region (Europe or US) and the interaction of treatment with visit as factors, the 
corresponding baseline value as a covariate, and the interaction between baseline value and visit adjusted in the 
model. The analysis will be done for subjects who complete 18 weeks (Week 18A) and for subjects (TAK-503 and 
atomoxetine treatment arms only) who complete Study Part A Week 49A. The least squares (LS) mean difference for 
each treatment arm will be calculated with the 95% confidence interval (CI) reported. 
As suggested by European Medicines Agency (EMA), using data up to 18 weeks, the superiority to placebo 
comparisons including TAK-503 and atomoxetine, separately, will be performed using MMRM as specified for the 
primary endpoint. Statistical tests will be conducted at the nominal 2-sided 0.05 level without adjustment for 
multiplicity. If TAK-503 is superior to placebo, then a negative impact on cognition can be excluded. If atomoxetine 
is superior to placebo, then assay sensitivity has been demonstrated. 
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Results for the TAK-503 and atomoxetine comparison at Week 49A (Visit 14A), which were collected for patients 
who were enrolled prior to the implementation of Protocol Amendment 7, will be evaluated in a descriptive fashion, 
without the performance of inferential hypothesis testing. 
Similarly, the other secondary CANTAB safety endpoints will be analyzed in the same manner as the primary 
CANTAB safety endpoint. CANTAB results for all parameters will be evaluated together for totality of the 
CANTAB data. 
Adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Treatment-emergent AEs will be summarized by treatment arm across system organ class and preferred term. 
Treatment-emergent AEs leading to withdrawal from study and serious adverse event will be summarized similarly. 
To account for differences in expected exposure durations between placebo and active arms, time adjusted event 
rates (per 100 years) will be presented in the overall summary tables, as well. 
Other safety data will be summarized descriptively by study period, with details provided in the statistical analysis 
plan. 
The efficacy measurement of ADHD-RS-5 will be assessed based on the FAS using the MMRM as the primary 
safety endpoint. The CGI-I will be summarized. 
UStudy Part B: Open-label Evaluation 
Safety data for Study Part B will be summarized descriptively. Z-scores for CANTAB measures will be calculated 
using age- and gender-specific normative data if available. Both observed values and z-scores will be summarized 
descriptively. 
Efficacy and other endpoints will be summarized by time point. 
USample Size Calculation and Power Considerations 
In this safety study, a descriptive analysis of TAK-503 and atomoxetine will be performed after 12 months of 
double-blinded treatment using results from the CANTAB RTI task. The effect of TAK-503 on cognition will be 
assessed and interpreted on the totality of the data. 
The sample size was estimated using the assumed difference of 0 msec with a noninferiority margin of 30 msec and a 
common standard deviation of 63.4 for the comparison between TAK-503 and atomoxetine at Week 49A on the RTI 
in Study Part A. The assumed common standard deviation on RTI is based on a prior study SPD503-206: a 
randomized, double-blinded, placebo-controlled efficacy study of TAK-503 in children and adolescents with ADHD. 
The assumed margin of 30 msec is close to the value (29.3 msec) of change from baseline in reported results from an 
adolescent study with atomoxetine. The assumed margin was used for sample size only and will not be applied in the 
noninferiority evaluation. 
A total of 216 subjects, 72 subjects per arm, will be required to provide 80% power for a 2-sided 95% CI. Expecting 
a nonevaluable rate of 25%, including postrandomization dropout, during the double-blinded period, the 
randomization target has been set to 288 subjects total or 96 subjects per treatment arm. 
As of Amendment 7, TAK-503 and atomoxetine will be evaluated after 12 months of double-blinded treatment using 
results from the CANTAB RTI task via the MMRM; however, inferential hypothesis testing via the non-inferiority 
framework at the Week 49A timepoint will no longer be performed due to challenges with retaining an evaluable 
sample size that would allow for sufficient power for this comparison. Superiority to placebo comparisons of 
TAK-503 and atomoxetine at the 18-week timepoint, separately, will still be performed, as in the original protocol. 
The number of subjects projected to participate in Study Part B is 120, which will be sufficient to have at least 
90% power to obtain a 95% confidence interval for the change from baseline RTI value that excludes the value 0, 
given the assumed response values for TAK-503 based on Study SPD503-206 (mean=20.7, SD=63.11). 
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1. 
BACKGROUND INFORMATION 
1.1 
Indication and Current Treatment Options 
Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurobehavioral disorder 
and the essential feature of ADHD, as described in the Diagnostic and Statistical Manual of 
Mental Disorders, 5th edition (DSM-5), is a persistent pattern of inattention and/or 
hyperactivity-impulsivity that is more frequent and severe than is typically observed in 
individuals at a comparable level of development. The following clinical symptoms must also be 
present: some hyperactive-impulsive or inattentive symptoms that cause impairment must have 
been present before age 12 years, impairment must be present in a least 2 settings (eg, school and 
home), and there must be clear evidence of interference with developmentally appropriate social, 
academic, or occupational functioning. Core symptoms of ADHD in preschool children (aged 
3 to 5 years) are similar to those observed in school-age children (aged 6 to 12 years) and include 
the following: difficulty in sustaining attention, excessive motor activity, low frustration 
tolerance, and impulsivity. Children with ADHD have trouble completing tasks that require 
executive function (EF) skills (Willcutt et al. 2005). As these children mature into adolescents, 
the ADHD symptoms associated with hyperactivity may begin to mitigate, but a higher risk 
remains for defiance, aggression, and antisocial behaviors as well as substance dependence  
(Barkley et al. 1991; Elkins et al. 2007). 
The exact etiology of ADHD is unknown. Neurotransmitter deficits (Arnsten and Pliszka 2011), 
genetics (Arnsten 2006; Brown 2003), environment (Kahn et al. 2003), and perinatal 
complications (Bhutta et al. 2002) may all be contributing factors. Medications effective at 
reducing ADHD symptoms act by raising the levels of neurotransmitters like norepinephrine, 
dopamine and/or precursors at the synapse by either facilitating neurotransmitter release, 
decreasing neurotransmitter reuptake, or binding to and activating the postsynaptic receptor  
(Kratochvil et al. 2001; Wang et al. 2007). 
Psychostimulant medications such as methylphenidate and amphetamine have been used to treat 
behavior problems in children since 1937 (Wilens and Biederman 1992), including ADHD and 
its diagnostic precursors. Medication management was superior to behavioral treatment and to 
routine community care that included medication for the immediate to long-term (eg, 14 months) 
treatment of children and adolescents with ADHD (The MTA Cooperative Group 1999). 
Despite the effectiveness of psychostimulants, several potential confounders to treatment can 
arise in some individuals, including intolerable side effects; possible exacerbation of common 
comorbid conditions, such as anorexia, tics, and insomnia; concern about abuse potential; and 
lack of efficacy (Olfson 2004). Nonstimulant medications are an alternative option for treating 
individuals with ADHD who may not be candidates for stimulant treatment or who prefer 
nonstimulant pharmacotherapy. TAK-503 (formerly known as SPD503) is a nonstimulant 
medication and the only pharmacotherapeutic agent approved for ADHD that is an 
2A-adrenergic receptor agonist. 
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1.2 
Product Background and Clinical Information 
TAK-503 (extended-/prolonged-release guanfacine hydrochloride) is a nonstimulant medication 
with a novel mechanism of action. 
TAK-503 is indicated for the treatment of children and adolescents with ADHD. Guanfacine is 
believed to exert its effect on ADHD symptoms by modulating the signaling in the prefrontal 
cortex and basal ganglia through direct modification of synaptic noradrenalin transmission at the 
α2-adrenergic receptors (Intuniv 2015). 
In this phase 4 postapproval safety study (PASS), the long-term safety of TAK-503 on selected 
domains of cognition will be evaluated in children and adolescents with ADHD for whom 
stimulants are not suitable, not tolerable, or shown to be ineffective. 
Results of tests and scales implemented in previous studies have shown that guanfacine does not 
have a deleterious effect on impact on cognitive performance. In one of the first double-blinded, 
placebo-controlled study of guanfacine in children with ADHD and a tic disorder, significant 
improvement was observed with guanfacine treatment on a Continuous Performance Task, a 
computer-administered and -scored measure of sustained visual attention and motor response 
inhibition (Scahill et al. 2001). Commission errors decreased by 22% and omission errors by 
17% in the guanfacine group, compared with increases of 29% in commission errors and of 
31% in omission errors in the placebo group. In the phase 2, randomized, double-blinded, 
placebo-controlled, dose-optimization study SPD503-206, doses of TAK-503 that resulted in 
significant improvement in ADHD symptoms did not impair subject ability to perform cognitive 
tasks (Kollins et al. 2011). Despite mild to moderate sedative events, which occurred early and 
resolved over the treatment period, no worsening was observed on measures of psychomotor 
functioning and alertness with guanfacine compared to placebo as tested using the Reaction 
Time (RTI) task of the Cambridge automated neuropsychological test battery (CANTAB). 
Furthermore, selected doses of TAK-503 did not elicit sedation that resulted in adverse effects on 
cognitive performance (Kollins et al. 2011). 
Meaningful improvement in classroom behavior in subjects treated with TAK-503 was 
demonstrated in the phase 3, randomized, double-blinded, placebo-controlled, fixed-dose clinical 
study SPD503-301. Of the 345 subjects enrolled and randomized, 215 subjects completed the 
study: 53 subjects in the placebo treatment arm and 58, 55, and 49 subjects in the 2, 3, and 4 mg 
dose groups of the TAK-503 treatment arm, respectively. Approximately 4 hours, and again 
8 hours, after subjects were administered study medication, teachers completed the Conners’ 
Teaching Rating Scale – Revised (CTRS-R) as an independent assessment of classroom 
behavior. No worsening in classroom behavior, a proximal indirect measure of adverse effects on 
overall cognitive function, was observed by teachers among students administered TAK-503. 
The least squares (LS) mean placebo-adjusted changes in the afternoon total score 8 hours after 
dosing were significantly improved in all TAK-503 dose groups, as follows: 
• 2 mg TAK-503 dose group improved by 10.90 points (p=0.0001) 
• 3 mg TAK-503 dose group improved by 13.84 points (p<0.0001) 
• 4 mg TAK-503 dose group improved by 15.25 points (p<0.0001) 
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In the phase 3, randomized, double-blinded, placebo-controlled, dose-optimization clinical study 
SPD503-312 in adolescents aged 13 to 17 years with ADHD, no worsening was reported in EF 
behaviors in the 157 subjects randomized to TAK-503 treatment according to the parent-reported 
Behavior Rating Inventory of Executive Function (BRIEF).  
Compared to placebo-treated peers, clinically significant improvements were observed in 
subjects treated with TAK-503 on the following parameters: 
• Improvements observed at Week 7 on the following BRIEF indices: 
o Global Executive Composite (GEC) scale (p<0.001) 
o Behavioral Regulation Index (BRI) (p=0.001) 
o Metacognition Index (MI) (p <0.001) 
• Improvements observed at Week 9 on the following BRIEF indices: 
o GEC (p=0.016) 
o MI (p=0.004) 
Although trends for improvements were observed for all 3 indices at Week 13 in 
TAK-503-treated subjects compared to placebo-treated subjects, the changes from baseline 
t-scores were not statistically significant between the 2 treatment arms. The t-score LS mean 
differences for these indices were -2.3 for GEC, -0.9 for BRI, and -2.7 for MI. 
In the phase 3, randomized, double-blinded, placebo-controlled, dose-optimization study 
SPD503-316 in 337 children and adolescents aged 6 to 17 years with ADHD that included an 
active-reference arm, a statistically significant and clinically meaningful improvement was 
shown relative to placebo on the learning and school domain of the Weiss Functional 
Impairment Rating Scale-Parent (WFIRS-P). The treatment effect size (95% confidence 
interval [CI]; p-value) at Week 10 for children and Week 13 for adolescents relative to 
placebo for the TAK-503 group was 0.42 (0.15, 0.70; 0.003). In the phase 3, 
randomized-withdrawal, double-blinded, placebo-controlled, dose-optimization, longer-term 
maintenance of efficacy study SPD503-315, a nominally significant improvement was 
measured compared to placebo in the TAK-503 group at Week 39 in the WFIRS-P learning 
and school domain (p=0.032). 
Due to the group heterogeneity of individuals diagnosed with ADHD, describing any cognitive 
deficits in general terms is difficult. Correlated variables of intelligence, academic achievement, 
and symptoms of comorbid disorders makes it difficult to ensure that the neuropsychological 
impairments associated with ADHD cannot be explained by group differences in these variables  
(Lahey et al. 1998a; Lahey et al. 1998b). No approved medications are available for the 
treatment of cognitive dysfunction in individuals with ADHD. Furthermore, the efficacy and 
safety of other approved ADHD medications on proposed cognitive domains (ie, to worsen or 
improve) have not been established in the proposed study population from which information on 
treatment with guanfacine will be derived; namely, subjects for whom stimulants are not 
suitable, not tolerated, or shown to be ineffective, as described in the European Summary of 
Product Characteristics (SmPC). The established safety profile for particular approved 
medications could influence neurocognitive function, rendering interpretation of differences 
across treatment arms difficult. 
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Also, comparisons with approved medications would be compromised because TAK-503 is 
indicated for second line therapy whereas the comparison could be indicated for first line 
therapy. Other confounders of ADHD medication effects on cognitive domains include dose, 
duration of follow-up, and composition of ADHD subtypes in the study subjects (predominantly 
inattentive symptoms or predominantly hyperactive/impulsive symptoms) and comorbid 
psychiatric disorders. 
1.2.1 Anticipated Benefits and Risks 
Overall, the clinical development program has demonstrated a favorable benefit-risk profile of 
TAK-503 in treatment of ADHD in children and adolescents. Guanfacine was approved in the 
EU in September 2015 for the treatment of ADHD in children and adolescents 6 to 17 years old 
for whom stimulants are not suitable, not tolerated, or have been shown to be ineffective; it must 
be used as a part of a comprehensive ADHD treatment program, typically including 
psychological, educational, and social measures. Guanfacine is also approved in: US, Canada, 
Japan, Australia, and Switzerland. 
The total cumulative worldwide exposure as of Jun 2018 was estimated to be 
1,119,675 person-years of treatment cumulatively since launch. Post-marketing reports have 
continued to indicate that TAK-503 is generally safe and well tolerated in the majority of 
subjects, and the incidence and nature of the adverse events remains in accordance with the 
current reference safety information for the product and the known clinical characteristics of the 
treated patient population.  
The efficacy of TAK-503 for the treatment of ADHD compared to placebo has been rigorously 
demonstrated on the primary efficacy measure for all well controlled studies designed to provide 
substantial evidence of efficacy. In studies enrolling children and adolescents, TAK-503 was 
associated with a statistically significant, clinically meaningful improvement in ADHD 
symptoms compared to placebo, as demonstrated using a variety of study designs, a variety of 
validated assessments, and with data provided by investigators, parents, teachers, trained raters, 
and self-reports. Improvement in ADHD symptoms by TAK-503 compared with placebo is 
associated with improvement in functional measures in clinical trials. TAK-503 is effective 
among inattentive ADHD subtype compared with placebo as demonstrated by improvement in 
ADHD-RS-IV subscale change in the TAK-503 fixed dose studies. The therapeutic benefit of 
TAK-503 in pediatric subjects (6-17 years) with ADHD was demonstrated for flexible dose 
optimization of TAK-503 (1-7 mg). Treatment effects were generally similar between children 
and adolescents, males and females, and between whites and non-whites. Statistically significant 
improvements were demonstrated with either morning or evening dosing compared to placebo, 
and in a comparative study including STRATTERA (atomoxetine) the respective treatment 
effect sizes for the efficacy parameter were generally greater for TAK-503. Maintenance of 
efficacy for subjects treated with TAK-503 has been demonstrated with lower treatment failure 
rates compared to placebo.  
To date, 20 phase 2 and 3 studies have been completed with TAK-503 in children and 
adolescents with ADHD. In these studies, TAK-503 at doses of 1-7 mg has been demonstrated 
safe and well tolerated in children (up to 4 mg) and adolescents (up to 7 mg) in the short-term 
fixed-dose, flexible-dose and long-term studies. 
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The most frequently reported treatment emergent adverse events (TEAEs) among subjects 
treated with TAK-503 were somnolence, headache, fatigue, sedation, and upper abdominal pain. 
Most TEAEs were mild or moderate in severity and the frequency of serious adverse events 
(SAEs) was low. In the short-term monotherapy study pool (SPD503-301 and SPD503-304), 
discontinuations due to AEs were more common for TAK-503 overall (11.9%) than for placebo 
(4.0%). The most frequent AEs that led to discontinuation of TAK-503 treatment were 
somnolence (3.7%), sedation (2.1%), and fatigue (1.6%). In the long-term study pool 
(SPD503-303 and SPD503-305), 17.5% of subjects discontinued due to AEs over 2 years. The 
most frequent AEs that led to discontinuation of TAK-503 treatment in the long term studies 
were somnolence (3.4%) and weight increased (1.8%). Sedative events including somnolence, 
sedation, fatigue, lethargy, asthenia and hypersomnia were commonly reported in clinical studies 
in children and adolescents with ADHD. In company-sponsored randomized double-blind 
Phase 2-3 clinical studies, the incidences of sedative events in the TAK-503 group were 31.7%, 
8.4%, and 0.2% for somnolence, sedation, and hypersomnia, respectively. The vast majority of 
these events were mild or moderate and did not prompt or require discontinuation of TAK-503. 
None of the events were serious. Also, in the adjunctive therapy study SPD503-313, TAK-503 
plus psychostimulant was well tolerated in general. No new safety signals emerged following the 
administration of TAK-503 in adjunct with psychostimulants (amphetamine or methylphenidate) 
compared with TAK-503 administered alone.  
Psychiatric TEAEs occurred with very low frequencies in both the TAK-503 and placebo groups. 
The events that did occur are expected in ADHD or are commonly occurring co-morbidities.  
No deaths have occurred in the TAK-503 clinical development program.  
See the latest version of the TAK-503 investigator’s brochure (IB) for the overall risk/benefit 
assessment and the most accurate and current information regarding the drug metabolism, 
pharmacokinetics, efficacy, and safety of TAK-503. 
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2. 
STUDY OBJECTIVES AND PURPOSE 
2.1 
Rationale for the Study 
Study SPD503-401 has been designed to evaluate the long-term safety and efficacy of TAK-503, 
with a specific focus on neurocognition, growth, and sexual maturation. In Study Part A, an 
atomoxetine arm has been included as an active comparator and a placebo treatment arm as a 
control for assay sensitivity. 
2.2 
Study Objectives 
2.2.1 Primary Objectives 
The primary safety objective of this study is to evaluate the comparative long-term safety of 
TAK-503 treatment in children and adolescents aged 6 to 17 years diagnosed with ADHD for 
whom stimulants are not suitable, not tolerated, or shown to be ineffective: 
• To evaluate TAK-503 compared with atomoxetine after 12 months of once daily (QD) 
treatment on psychomotor speed and attention as measured by the Cambridge automated 
neuropsychological test battery (CANTAB) reaction time (RTI) task, using the 
mixed-effects model for repeated measures (MMRM). The effect of TAK-503 on 
cognition will be assessed and interpreted on the totality of the data. 
A primary efficacy objective is not applicable for this PASS. 
2.2.2 Secondary Objectives 
USecondary safety objectives 
• Cognitive domain, sustained attention as measured by CANTAB Rapid Visual Information 
Processing (RVP) task 
• Cognitive domain, Spatial Working Memory (SWM), a component of EF, as measured by 
the CANTAB SWM task between errors 
• Cognitive domain, response control/inhibition as measured by the CANTAB Stop Signal 
Task (SST) 
• Cognition domain, recognition memory as measured by the CANTAB Delayed Matching to 
Sample (DMS) task 
• Sexual maturation as measured by Tanner stage 
• Growth as measured by weight, height, and body mass index (BMI) 
• Incidence of treatment-emergent adverse events (TEAEs) 
• Vital sign and electrocardiogram (ECG) results 
• Psychiatric symptoms as measured by the Brief Psychiatric Rating Scale for Children 
(BPRS-C) total score and factors for Depression, Anxiety, Psychomotor Excitation, Behavior 
Problems, Withdrawal, Thinking Disturbance, and Organicity 
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• Suicidal ideation/behavior as measured by the Columbia-Suicide Severity Rating Scale  
(C-SSRS) 
• Asthenia/Lassitude/Increased Fatigability, Sleepiness/Sedation, Increased Duration of Sleep, 
and Orthostatic Dizziness based on the ratings of specific Udvalg for Kliniske Undersøgelser 
(UKU) scale items 
• Sedative effects as measured by subject ratings on the Pediatric Daytime Sleepiness Scale 
(PDSS) 
USecondary efficacy objectives 
• Attention-deficit/hyperactivity disorder symptoms as measured by the 
investigator-administered ADHD-Rating Scale-5 (ADHD-RS-5) total score and 
hyperactivity/impulsivity and inattention subscale scores 
• Global clinical measurement of ADHD improvement as measured by Clinical Global 
Impression-Improvement (CGI-I) using the Clinical Global Impression-Severity (CGI-S) to 
establish baseline 
• Function as measured by the Child Health and Illness Profile – Child Edition: Parent Report 
Form (CHIP-CE:PRF) domains of satisfaction, comfort, resilience, risk avoidance, and 
achievement. The effect of TAK-503 on all subdomains will be summarized, including the 
subdomain satisfaction with self, using parental ratings of the child’s self-esteem. 
• Assessment of behavioral, social, and academic issues with the Conners 3 Parent Short Form 
(C3PS) Total Score and the Learning Problems and Executive Functioning subscale scores.  
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3. 
STUDY DESIGN 
3.1 
Study Design and Flow Chart 
Study SPD503-401 is a phase 4, multicenter, dose-optimization PASS and will be conducted in 
2 parts: Study Parts A and B. Study Part A will be a randomized, double-blinded, parallel-group, 
placebo- and active comparator-controlled, 3-treatment arm safety and efficacy evaluation of 
TAK-503. Pediatric subjects with ADHD will be randomized 1:1:1 among TAK-503, 
atomoxetine, and placebo treatment arms for 18 weeks of double-blinded treatment and 
evaluation. At the end of the 18 weeks (Week 18A/Visit 11A), all subjects will roll over to Study 
Part B directly for an additional 52 weeks of open-label TAK-503 treatment. Once 120 subjects 
have entered into Study Part B, only subjects in the placebo arm in Study Part A will enter Study 
Part B, to assure that all placebo arm subjects have the opportunity to enter into the 1-year TAK-
503 open-label treatment arm. 
Study Part A will consist of the following 5 periods elapsing up to 23 weeks: 
1. Screening/washout: Day -35A to Day -3A (up to 5 weeks). 
2. Dose-optimization period: Investigational medicinal product (IMP) will be 
dose-optimized from Week 0A through Week 4A for children aged 6 to 12 years and 
through Week 7A for adolescents aged 13 to 17 years.  
3. Dose-maintenance period: Subjects will continue with QD dosing from Week 5A for 
children and Week 8A for adolescents through Week 18A.  
4. Dose-taper period: Scheduled 3-week fixed-dose taper of IMP. All subjects randomized 
in the TAK-503 or atomoxetine treatment arms will undergo a scheduled 3-week dose 
taper to ensure proper downward dose titration of TAK-503 at the end of the 
dose-maintenance period or at ET. 
5. Follow-up period: Follow-up visit 1 week after the last IMP tapered dose 
• Subjects randomized to TAK-503 or atomoxetine treatment arms will participate in a 
follow-up visit and begin rescreening/washout procedures for Study Part B.  
Placebo subjects can skip the follow-up visit after completion of Study Part A assessments at 
Visit 11A (Week 18A) and proceed immediately to baseline visit assessments for Study Part B. 
Before enrollment in Study Part A, subjects will be screened based on inclusion/exclusion 
criteria to establish eligibility for study participation. Approximately 25% of all subjects will be 
aged 13 to 17 years. Approximately 25% of all subjects will be female. Subjects who meet 
eligibility requirements will undergo a medication washout period, if applicable, according to 
the schedule presented in Table 3. In Study Part B, subjects randomized to active IMP in 
Study Part A must undergo a washout period of ≥30 days between the last IMP tapered dose in 
Study Part A and the first TAK-503 dose in Study Part B. 
In Study Part A, subjects with a baseline ADHD-RS-5 total score ≥28 and CGI-S score of 
≥4 will be eligible for enrollment. During the dose-optimization period, clinic visits will be 
scheduled every 7 days to assess IMP safety and tolerability and to allow investigators to titrate 
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the IMP to an optimal dose that maximizes potential benefits while minimizing risk of TEAEs. If 
necessary, the investigator will be allowed to lower the subject’s dose once during the dose 
optimization period in Study Parts A and B. 
Subjects randomized to TAK-503 will begin dosing at 1 mg and dose-titrated upward in weekly 
1-mg increments until an optimal dose is reached. Children aged 6 to 12 years will not be 
permitted to titrate to a daily dose >4 mg QD and adolescents aged 13 to 17 years will not be 
permitted to titrate to greater than the maximum allowed daily dose per baseline weight group 
presented in Table 4. The dose-optimization schedule for TAK-503 can be found in Table 4. 
Subjects optimized to a TAK-503 daily dose between 1 and 4 mg will take 1 TAK-503 tablet QD 
(or TAK-503-matched placebo tablet). Subjects optimized to a TAK-503 daily dose between 
5 and 7 mg will take 2 TAK-503 tablets QD (or 2 TAK-503-matched placebo tablets). 
Subjects randomized to the atomoxetine treatment arm weighing <70 kg at baseline will begin 
daily dosing at approximately 0.5 mg/kg QD. If well-tolerated after 1 week minimum, this dose 
may be increased to the target daily dose of 1.2 mg/kg QD. The total daily dose will not exceed 
1.4 mg/kg QD. With limited dosage forms, this upper limit is necessary to achieve appropriate 
weight-based doses. Permitted daily doses of atomoxetine for subjects weighing <70 kg at 
baseline are 10, 18, 25, 40, 60, and 80 mg QD depending on subject’s baseline weight (Visit 2A). 
Subjects randomized to the atomoxetine treatment arm weighing ≥70 kg at baseline will begin 
daily dosing at 40 mg atomoxetine QD. If well-tolerated after 1 week minimum, this daily dose 
may be increased to 80 mg QD. After a 1-week minimum, if the 80 mg daily dose is 
well-tolerated, then the daily dose may be increased to 100 mg QD. The total daily dose in 
children and adolescents ≥70 kg will not be permitted to exceed 100 mg QD. 
Subjects optimized to an atomoxetine daily dose greater than 60 mg QD will take 2 atomoxetine 
or atomoxetine-matched placebo capsules QD. Subjects optimized to a daily dose ≤60 mg will 
take 1 atomoxetine or atomoxetine-matched placebo capsule QD. The dose-optimization 
schedule for atomoxetine can be found in Table 5. 
Subjects will continue daily treatment with the optimal IMP dose during the dose-maintenance 
period, during which time the investigator will not be permitted to adjust the IMP dose in 
Study Part A. For subjects randomized to active IMP, the dose-maintenance period will be 
followed by a 3-week dose-taper period. 
After the last IMP tapered dose, subjects will return to the site for a follow-up visit. The follow 
up visit will serve as the Study Part B screening assessments for subjects randomized to the 
TAK-503 and atomoxetine treatment arms. 
Study Part B will consist of 5 periods: 
1. Screening/washout: Day -35B to Day -3B (up to 5 weeks) 
2. Dose-optimization period: TAK-503 will be dose-optimized from Week 0B through 
Week 4B for children aged 6 to 12 years and through Week 7B for adolescents 
aged 13 to 17 years. 
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3. Dose-maintenance period: Dose-optimized TAK-503 will be administered QD from 
Week 5B for children and from Week 8B for adolescents through Week 49B for both age 
groups. 
4. Dose-taper period: Scheduled 3-week downward-titration of TAK-503 dose through 
Weeks 50B, 51B, and 52B 
5. Follow-up period: Last dose of TAK-503 to the follow-up visit at Week 53B 
During the Study Part A follow-up visit, subjects will undergo a partial rescreening of study 
criteria to confirm eligibility for continued participation in Study Part B. Subjects who complete 
Study Part A should roll over into Study Part B without a gap except for washout. Subjects 
(except those randomized to placebo) must undergo a washout period of ≥30 days between the 
last IMP tapered dose in Study Part A and the first dose of TAK-503 in Study Part B. Eligibility 
to continue in Study Part B will be confirmed at Visit 2B, Study Part B baseline. Once 
120 subjects have entered into Study Part B, only subjects in the placebo arm in Study Part A 
will enter Study Part B, to assure that all placebo arm subjects have the opportunity to enter into 
the 1-year TAK-503 open-label treatment arm. 
During the dose-optimization period, clinic visits will be scheduled once every 7 days to assess 
safety and tolerability and to allow investigators to titrate subjects to an optimal TAK-503 dose 
based on clinical judgment of tolerability and efficacy using the totality of the available clinical 
and safety data. All subjects will begin with 1 mg TAK-503 QD and dose-titrated upward in 
1 mg increments weekly until an optimal dose is reached. Children aged 6 to 12 years will not be 
permitted to titrate to a daily dose greater than 4 mg and adolescents aged ≥13 years will not be 
permitted to titrate to a daily dose above the maximum allowed dose per baseline weight group. 
Following titration to an optimal dose of TAK-503, subjects will continue with TAK-503 
administration through the dose-maintenance period (ie, Week 49B). Visits to the site will occur 
at intervals of 13 weeks. During the dose-maintenance period, the investigator may make further 
dose adjustments as needed based upon TEAEs and clinical judgment of tolerability and 
efficacy. These dose adjustments can be to a higher dose, based on the subject’s current age and 
weight. Children who turn 13 years or older during the dose-maintenance period may be 
permitted to increase the daily dose higher than 4 mg based on weight at the Study Part B 
baseline. The dose can be adjusted in 1 mg increments (increased or decreased) at any scheduled 
or unscheduled visit during the study if deemed appropriate by the investigator. 
All subjects who receive active treatment (blinded TAK-503 or atomoxetine in Part A or 
unblinded TAK-503 in Part B) will undergo a scheduled 3-week dose taper to ensure proper 
downward dose titration of TAK-503 at the end of the dose-maintenance period or ET in both 
Study Parts A and B, as applicable. 
Each subject’s last visit will be 7 (+2) days after the last TAK-503 dose in Study Part B, to 
measure blood pressure and heart rate, and to follow up on concomitant medications and safety 
assessments, including TEAEs, which may have been ongoing at the previous visit. 
Treatment-emergent adverse events reported up to the time of the follow-up visit will be 
documented and appropriate follow-up will continue until all safety concerns are resolved as 
judged by the investigator. 
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3.2 
Duration and Study Completion Definitions 
For subjects enrolled under Protocol Amendment 7, an individual subject’s maximum duration 
of participation, including washout periods, is expected to be approximately 97 weeks (Study 
Part A + Study Part B). For subjects enrolled under prior versions of the protocol, an individual 
subject’s maximum duration of participation, including washout periods, is expected to be 
approximately 128 weeks (Study Part A + Study Part B). The study will be completed in 
approximately 9 years. 
The study completion date is defined as the date the final subject, across all sites, completes their 
final protocol-defined assessment. Please note that this includes the follow-up visit or contact, 
whichever is later. The study completion date will be used to ascertain timing for study results 
posting and reporting. 
3.3 
Sites and Regions 
This study will be conducted at approximately 55 sites in Europe and the United States. 
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4. 
STUDY POPULATION 
Approximately 288 children and adolescents aged 6 to 17 years inclusive diagnosed with ADHD 
by the DSM-5 will be enrolled in Study Part A (96 subjects per treatment arm). Approximately 
25% of all subjects will be aged 13 to 17 years. Approximately 25% of all subjects will be 
female. Once 120 subjects have entered into Study Part B, only subjects in the placebo arm in 
Study Part A will enter Study Part B, to assure that all placebo arm subjects have the opportunity 
to enter into the 1-year TAK-503 open-label treatment arm. 
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed. See Section 10.3.1 
for further consenting instructions. 
4.1 
Study Part A Inclusion/Exclusion Criteria 
4.1.1 Study Part A Inclusion Criteria 
The subject will not be considered eligible to enroll in study SPD503-401 without meeting all of 
the following inclusion criteria: 
1. Subject is a male or female aged 6 to 17 years inclusive at the time of consent/assent. 
2. Subject must meet the 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). 
3. Subject 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). 
4. Subject has an ADHD-RS-5 total score ≥28 at baseline (Visit 2A). 
5. Subject has a baseline (Visit 2A) CGI-S score ≥4. 
6. Subject 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 
(See Section 4.4). Female of childbearing potential is defined as any female subject who is at 
least aged 9 years or younger than 9 years and postmenarchal. 
7. Subject’s parent or legally authorized representative (LAR) must provide signature of 
informed consent. Documentation of assent (if applicable) must be provided by the subject 
indicating that the subject is aware of the investigational nature of the study and the required 
procedures and restrictions in accordance with the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice 
(GCP) Guideline E6[R2] and applicable regulations, before completing any study-related 
procedures. 
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8. Subject 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 IMP dose each morning 
when the subject awakens. 
9. Subject 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). 
10. Subject is functioning at an age-appropriate level intellectually, as judged by the investigator. 
11. Subject is able to swallow intact tablets and capsules. 
4.1.2 Study Part A Exclusion Criteria 
The subject will be excluded from the study if any of the following exclusion criteria are met: 
1. Subject 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): 
a. Post-traumatic stress disorder (PTSD) 
b. Bipolar illness, psychosis, or family history in either biological parent 
c. Pervasive developmental disorder 
d. Obsessive-compulsive disorder (OCD) 
e. Psychosis/schizophrenia 
f. Serious tic disorder or a family history of Tourette’s disorder 
2. Subject 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. 
3. Subject 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. 
4. Subject has a clinically important abnormality on the urine drug and alcohol screen 
(except for the subject’s current ADHD stimulant, if applicable) at screening (Visit 1A). 
5. Subject has been physically, sexually, and/or emotionally abused. 
6. Subject has any other disorder that, as judged by the investigator, could contraindicate 
TAK-503 or confound the results of the safety and efficacy assessments. 
7. Subject 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 
subject and/or could confound the interpretation of study results. 
8. Subject 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. 
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9. Subject 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. 
10. Children aged 6 to 12 years with a body weight <25.0 kg or adolescents aged ≥13 years 
with a body weight <34.0 kg at screening (Visit 1A) or baseline (Visit 2A). 
11. Subject 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 
95PthP percentile. 
12. Subject has a known history or presence of: structural cardiac abnormalities, serious heart 
rhythm abnormalities, syncope, cardiac conduction problems (eg, clinically significant 
heart block or QT interval prolongation), bradycardia, or exercise-related cardiac events 
including syncope and presyncope. 
13. Subject has clinically significant ECG findings, as judged by the investigator, at baseline 
(Visit 2A). 
14. Subject 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.) 
15. Subject has a known family history of sudden cardiac death or ventricular arrhythmia. 
16. Subject is currently using any medication that violates protocol-specified washout criteria 
at baseline visit (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 (ie, antihistamines). 
17. Subject has a medical condition except ADHD that requires treatment with any 
medication that affects the CNS. 
18. Subject is female and pregnant or currently lactating. 
19. Subject has taken another investigational product or participated in a clinical study within 
30 days before screening (Visit 1A). 
20. Subject 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. 
21. Subject has a history of a seizure disorder (except for a single childhood febrile seizure 
episode that occurred before the age of 3 years). 
22. Subject is well-controlled on his/her current ADHD medication with acceptable 
tolerability, and the parent/treating physician does not object to the current medication. 
23. Subject has ALT >2 x upper limit of normal (ULN) or AST >2 x ULN or  
bilirubin >1.5 x ULN at screening. 
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4.2 
Study Part B Inclusion/Exclusion Criteria 
4.2.1 Study Part B Inclusion Criteria 
The subject will not be considered eligible to enroll in Study Part B without meeting all of the 
following inclusion criteria: 
1. Female subjects 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 subject who is at least aged 9 years or younger than 
9 years and postmenarchal. 
2. Subject has a supine and standing BP measurement less than the 95Pth
P percentile for age, 
sex, and height. 
4.2.2 Study Part B Exclusion Criteria 
Subjects will be excluded from Study Part B if any of the following exclusion criteria are met: 
1. Subject failed screening, voluntarily withdrew, or was discontinued from Study Part A 
for protocol nonadherence, subject noncompliance, or TEAE or SAE. 
2. Subject had any clinically significant TEAE during Study Part A that, as judged by the 
investigator, would preclude exposure to TAK-503. 
3. Subject 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. 
4. Subject 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 (ie, antihistamines) in violation of the protocol-specified washout criteria at 
baseline. 
5. Subject has a known or suspected allergy, hypersensitivity, or clinically significant 
intolerance to guanfacine hydrochloride, or any components found in TAK-503. 
6. Subject has taken any IMP except placebo in Study Part A within the 30 days before 
baseline of Study Part B (Visit 2B). 
7. Subject is significantly overweight based on the CDC BMI-for-age sex-specific charts at 
screening. Significantly overweight is defined as a BMI >95PthP percentile. 
8. Subject 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) 
9. Subject 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 subject and/or confound the interpretation of study results. 
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10. Subject 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. Subjects with intermittent passive suicidal ideation are not necessarily excluded 
based on the assessment of the investigator. 
11. Subject has clinically significant ECG findings, as judged by the investigator, at baseline 
(Visit 2B). 
12. Subject has a known history or presence of structural cardiac abnormalities, serious heart 
rhythm abnormalities, syncope, cardiac conduction problems (eg, clinically significant 
heart block), exercise-related cardiac events including syncope and presyncope, or 
clinically significant bradycardia. 
13. Subject 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.) 
14. Subject 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. 
15. Subject has a medical condition except ADHD, which requires treatment with any 
medication that affects the CNS. 
16. Subject has ALT >2 x ULN or AST >2 x ULN or bilirubin >1.5 x ULN at screening. 
4.3 
Restrictions 
1. Subjects should abstain from substance abuse during the study. 
2. Subjects should abstain from the consumption of grapefruit or grapefruit juice during the 
study. 
3. Subjects should not drive or operate heavy equipment until they know how the IMP 
affects them (ie, suspend driving and operation of heavy equipment until the subject is on 
a stable, well-tolerated dose for a minimum of 1 week). 
4. Tablets and capsules should not be crushed, chewed, or broken before swallowing. 
5. Subjects should avoid becoming dehydrated or overheated. 
4.4 
Reproductive Potential 
4.4.1 Female Contraception 
Sexually active FOCP should be using an acceptable form of contraception. Females of 
childbearing potential must be advised to use acceptable contraceptives throughout the study 
period and for 30 days following the last IMP dose. Hormonal contraceptives, if used, should be 
administered according to the package insert. Females of childbearing potential who are not 
currently sexually active must agree to use acceptable contraception if becoming sexually active 
during the study and continue use for 30 days following the last IMP dose. Acceptable 
contraceptive methods are defined below. 
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Female children and adolescent subjects should be either: 
• Premenarchal and either Tanner stage 1 or younger than aged 9 years, or 
• Females of childbearing potential must have a negative urine and/or serum -hCG 
pregnancy test at screening (Study Parts A and B) and before randomization in 
Study Part A. Females of childbearing potential must agree to abstain from sexual 
activity that could result in pregnancy or agree to use acceptable methods of 
contraception. 
The following methods of contraception are sufficient: 
• Intrauterine devices plus condoms 
• Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam) 
• Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring) stabilized for 
≥30 days before screening, plus condoms. Note: Any subject who becomes sexually 
active during the study should use one of the other acceptable methods indicated above in 
addition to hormonal contraceptive until it has been stabilized for 30 days. 
4.4.2 Male Contraception 
Male subjects will either abstain from sex or use condoms. 
4.5 
Discontinuation of Subjects 
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from IMP with the medical monitor when 
possible. 
If IMP is discontinued, regardless of the reason, the final evaluations listed for the following 
visits will be performed as completely as possible: 
• Study Part A: ET; Visit 15A, Visit 16A, and Visit 17A (dose-taper visits)  
• Study Part B: Visit 13B/ET at Week 49B; Visit 14B at Week 50B, Visit 15B at 
Week 51B, and Visit 16B at Week 52B (dose-taper visits) 
If the subject discontinues IMP and will not undergo the dose-taper as stated in the protocol, the 
medical monitor must be contacted immediately. 
Whenever possible, all discontinued subjects (including those who were randomized to placebo) 
should also undergo the protocol-specified followup. Comments (spontaneous or elicited) or 
complaints made by the subject must be recorded in the source documents. The reason for 
termination, date of stopping IMP, and total amount of IMP taken must be recorded in the 
electronic case report form (eCRF) and source documents. 
Subjects who discontinue/withdraw from the study will not be replaced. 
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4.5.1 Reasons for Discontinuation/Withdrawal 
The reason for discontinuation/withdrawal must be recorded in the subject’s medical record and 
on the eCRF. If a subject is withdrawn for more than 1 reason, each reason should be 
documented in the source document and the most clinically relevant reason should be entered on 
the eCRF. 
If a TEAE is a reason for discontinuation, then the event must be recorded as the reason for 
discontinuation on the eCRF. If the decision is made to withdraw the subject due to lack of 
response, the reason for discontinuation should be recorded as lack of efficacy (as per eCRF 
completion guidelines). If the decision is made to withdraw the subject due to intolerability, the 
reason for discontinuation should be recorded as a TEAE. 
Reasons for discontinuation/withdrawal include but are not limited to: 
• TEAE 
• Protocol significant deviation 
• Withdrawal by subject  
• Lost to follow-up 
• Lack of efficacy 
• Other (the reason must be specified on the eCRF), including, but not limited to: 
o Pregnancy 
o Hypertension 
o ALT >2 x ULN or AST >2 x ULN or bilirubin >1.5 x ULN 
If a subject chooses to withdraw from study participation due to personal concerns related to a 
dire, exceptional situation such as the COVID-19 pandemic (other than a COVID-19-related 
AE), this requires documentation as the reason for subject withdrawal in the eCRF.  
4.5.2 Subjects “Lost to Follow-up” Before the Last Scheduled Visit 
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point before the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that the 
subject return to the site for final safety evaluations and to return any unused IMP. 
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5. 
PRIOR AND CONCOMITANT TREATMENT 
All nonstudy treatment, including but not limited to herbal treatments, vitamins, behavioral 
treatment, and nonpharmacological treatment, such as psychotherapy, received within 30 days 
before screening (Visit 1A/1B) (or pharmacokinetic equivalent of 5 half-lives, whichever is 
longer) and through the final study contact (including protocol-defined follow-up period) must 
be recorded on the appropriate eCRF field. 
5.1 
Prior Treatment 
Prior treatment includes both pharmacologic and nonpharmacologic interventions received 
within 30 days (or pharmacokinetic equivalent of 5 half-lives, whichever is longer) of screening 
and any treatments received between screening and baseline. 
Prior treatment information will be recorded on the appropriate eCRF page and in the subject’s 
medical record. For all prior pharmacologic interventions, the drug name, indication, and dates 
of use will be recorded. 
Prior ADHD medication: The subject’s lifetime psychoactive medication history will also be 
documented at screening. Entries for all prior psychoactive medications will include the drug 
name, indication, and dates of use. 
Prior ADHD nonpharmacological interventions: The subject’s lifetime nonpharmacological 
interventions (eg, behavioral therapy) for ADHD will also be documented during screening 
(Visit 1A: Day -35 to Day -3) and baseline (Visit 2B). Entries for all of nonpharmacological 
interventions for ADHD will include type(s) and dates of occurrence. 
5.2 
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first IMP dose and 
the end of the follow-up period, inclusive. Concomitant treatment information must be recorded 
in the appropriate eCRF field. 
If a FOCP uses hormonal contraception as her acceptable method of birth-control, the minimum 
time period for use of the hormonal contraception is 30 days before baseline to ensure 
effectiveness in preventing pregnancy. 
5.2.1 Permitted Treatment 
Medications and therapies that will be allowed during the study include the following: 
• Stable doses of inhaled bronchodilator inhaler (oral corticosteroids, β2-agonists [Part A 
only], and theophylline will be prohibited) 
• Antibiotics and over-the-counter medications that do not affect BP, HR, or the CNS and are 
considered necessary for the subject’s welfare are allowable at the discretion of the 
investigator (medications that are known cytochrome P450 (CYP) 3A4 inhibitors will not 
be allowed [eg, macrolide or quinolone antibiotics]) 
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• Nonsedating antihistamines such as fexofenadine, loratadine, and cetirizine hydrochloride 
• Over-the-counter nonstimulant cold remedies 
• Continued participation in behavioral therapy, provided that the subject has been receiving 
the therapy for at least 1 month at the time of baseline. The behavioral therapy must remain 
stable throughout the study and any changes planned to the behavioral therapy must be 
discussed with the medical monitor. 
The administration of all medications, including those listed above, must be recorded in the 
appropriate section of the source documents and eCRF. 
5.2.2 Prohibited Treatment 
The concomitant use of drugs listed below may interfere with the assessment of efficacy, safety, 
or tolerability of the IMP and will not be allowed throughout the study. A washout schedule for 
prohibited medications is presented in Table 3. 
• All investigational medications other than the IMP 
• Any other formulations or sources of guanfacine that are not the IMP 
• All anti-hypertensive medication 
• Appetite suppressants  
• Cough/cold preparations that contain amphetamine or pemoline, or that contain 
adrenergic or noradrenergic agonists such as pseudoephedrine or phenylephrine 
• Tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake 
inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), antipsychotics, 
neuroleptics, anxiolytics, benzodiazepines or benzodiazepine derivatives, and 
psychostimulants (including sympathomimetics) 
• Modafinil, quinidine, and pemoline 
• α2-adrenergic agonists (eg, clonidine) 
• Anticonvulsant medications, sedatives, sedative hypnotics such as zopiclone, sedating 
antihistamines (as a single preparation or in combination), and melatonin 
• Any medication or herbal preparations that affects the CNS, cognitive performance, 
and/or BP or HR (such as, but not limited to, certain quinolone antibiotics) 
• Medications that are contraindicated for concomitant use with TAK-503 use 
(Section 5.2.2.1) 
• Medications that are contraindicated for concomitant use with atomoxetine 
(Section 5.2.2.2) 
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5.2.2.1 
Medications Prohibited Based on TAK-503 Use (Study Parts A and B) 
Medications known to be CYP3A4/5 inducers or inhibitors may interact with TAK-503. 
Examples of CYP3A4/5 inhibitors and inducers are provided in Appendix 8. Any new use of 
CYP3A4/5 inhibitors or inducers after baseline is prohibited; however, if use is planned for the 
duration of the study and a stable dose has been established for ≥14 days before baseline, then 
the treatment may be given concomitantly throughout the study, with no planned changes in use. 
Drugs that prolong the QT interval (eg, neuroleptics, class IA and III anti-arrhythmics, 
moxifloxacin, erythromycin, methadone, mefloquine, tricyclic antidepressants, lithium, and 
cisapride) will be prohibited. 
5.2.2.2 
Medications Prohibited Based on Atomoxetine Use (Study Part A only) 
Medications known to be CYP2D6 inhibitors (eg, bupropion, cinacalcet, fluoxetine, paroxetine, 
quinidine, duloxetine, sertraline, and terbinafine) may interact with atomoxetine and will be 
prohibited during Study Part A. 
Other prohibited medications include the following: 
• Medications that that lower seizure threshold, such as antidepressants, neuroleptics, 
mefloquine, bupropion, or tramadol 
• Medications that affect noradrenaline, such as imipramine, venlafaxine, mirtazapine, 
pseudoephedrine, or phenylephrine 
• Pressor agents 
• β2-agonists 
5.2.2.3 
Washout Schedule for Prohibited Medications 
The washout period for some of the prohibited medications is provided in Table 3. At a 
minimum, the washout period for all prohibited medications must be at least 5 times the half-life 
of the medication. Instruction to washout a medication can be given to a subject only after 
informed consent/assent has been obtained. 
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Table 3 
Common Excluded Treatments and Associated Washout Period 
 
UMinimum Number of Days Before Baseline 
Treatment 
7 
14 
30 
Antihypertensives 
X 
 
 
Antihistamines 
X 
 
 
Psychostimulants 
X 
 
 
Amphetamines and amphetamine-like agents 
X 
 
 
Cough/cold preparations containing 
stimulants/sympathomimetic agents 
X 
 
 
Melatonin 
X 
 
 
Grapefruit/grapefruit juice 
X 
 
 
Monoamine oxidase inhibitors 
 
X 
 
Anxiolytics 
 
 
X 
Antidepressants, including SSRIs and SARIs 
 
 
X 
Antipsychotics 
 
 
X 
SNRIs 
 
 
X 
Sedatives 
 
 
X 
α2-adrenergic agonists 
 
 
X 
CYP3A/4 inhibitors and inducers 
 
 
X 
CYP2D6 inhibitors 
 
 
X 
Investigational compounds 
 
 
X 
CYP=cytochrome P450; SARI=serotonin antagonist and reuptake inhibitor; SNRI=selective norepinephrine 
reuptake inhibitor; SSRI=selective serotonin reuptake inhibitor 
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6. 
INVESTIGATIONAL MEDICINAL PRODUCT(S) 
6.1 
Identity of Investigational Medicinal Product(s) 
In Study Part A, the IMPs are TAK-503, atomoxetine, and placebo. Placebo will be 
TAK-503 matched placebo tablets and atomoxetine-matched placebo over-encapsulated 
capsules. 
TAK-503, an extended-/prolonged-release tablet formulation of guanfacine hydrochloride is 
designed for QD oral administration. TAK-503 will be provided by the sponsor in 1-, 2-, 3-, and 
4-mg strength tablets with the following visual features: 
• 1-mg tablet is round and white 
• 2-mg tablet is oblong and white 
• 3-mg tablet is round and green 
• 4-mg tablet is oblong and green 
Subjects will take 1 TAK-503 tablet or 1 TAK-503-matched placebo tablet if dose-optimized to 
1 to 4 mg QD or 2 TAK-503 tablets or 2 TAK-503-matched placebo tablets if dose-optimized to 
5 to 7 mg QD. 
Atomoxetine hydrochloride, the marketed comparator product, is designed for QD 
administration. The sponsor will provide 10-, 18-, 25-, 40-, and 60 mg-strength atomoxetine 
capsules. Subjects randomized to the atomoxetine treatment arm will take 1 atomoxetine capsule 
or 1 atomoxetine-matched placebo capsule if dose-optimized to ≤60 mg QD or 2 atomoxetine 
capsules or 2 atomoxetine-matched placebo capsules if dose-optimized to >60 mg QD. 
The sponsor will provide TAK-503-matched placebo tablets and atomoxetine-matched placebo 
capsules. 
TAK-503 will be the only IMP administered in Study Part B. 
Additional information for TAK-503 is provided in the Intuniv IB and the Intuniv SmPC. 
Additional information for atomoxetine hydrochloride is provided in the atomoxetine 
hydrochloride SmPC. 
6.1.1 Blinding of the Treatment Assignment (Study Part A only) 
This is 2-part study in which Study Part A is a double-blinded, double-dummy, 
placebo-controlled study with an active reference arm. Actual treatment given to individual 
subjects will be determined by the randomization schedule. Treatment assignments of 
individual subjects will be assigned automatically using the interactive response technology 
(IRT). 
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Eligible subjects will be randomized at baseline (Day 0/Visit 2A) in a 1:1:1 ratio among 
TAK-503, atomoxetine, and placebo treatment arms. Subjects randomized to the TAK-503 
treatment arm will receive TAK-503 tablet(s) and atomoxetine-matched placebo capsule(s). 
Subjects randomized to the atomoxetine treatment arm will receive TAK-503-matched placebo 
tablet(s) and atomoxetine capsule(s). Subjects randomized to the placebo treatment arm will 
receive TAK-503-matched placebo tablet(s) and atomoxetine-matched placebo capsule(s). 
Placebo will include TAK-503-matched placebo tablet and atomoxetine-matched placebo 
capsule. TAK-503-matched placebo will be provided in 1-, 2-, 3-, and 4-mg TAK-503 dummy 
strength tablets to protect the blind between TAK-503 tablets and TAK-503-matched placebo 
tablets. Atomoxetine capsules and atomoxetine-matched placebo capsules will be 
over-encapsulated to protect the blind between atomoxetine and atomoxetine-matched placebo 
capsules. 
Study Part B will be open-label TAK-503. 
6.2 
Administration of the Investigational Medicinal Product(s) 
6.2.1 Interactive Response Technology for Investigational Medicinal Product 
Management 
An IRT system will be used in this study to manage the tracking and confirmation of shipment, 
supply, inventory, ordering, IMP expiration, site assignments, subject randomization, IMP 
returns, unblinding of active treatment versus placebo at Week 18A, and emergency unblinding 
of IMP (TAK-503 or atomoxetine). 
The IRT provider will supply a user manual of the IRT to each site. 
If a subject is unable to reach a site to be dispensed IMP due to unavoidable dire 
circumstances (eg, a widespread disease outbreak such as the COVID-19 pandemic or natural 
disaster), alternative study drug delivery to trial participants may be necessary. Drug may be 
shipped directly to participants’ residences by a contracted logistics provider or distributor 
(direct-to-patient [DTP] shipment) in compliance with national, state, and local laws or 
temporary national emergency measures and the sponsor’s processes. Such exceptional 
instances should be duly justified and documented in the study records. 
6.2.2 Allocation of Subjects to Treatment Arm 
Allocation to treatment arm will be stratified by sex (male or female) and age subgroup 
(6 to 12 years or 13 to 17 years) to facilitate between-treatment balance within each stratum. 
The IMP packaging identification numbers, separate from randomization numbers/unique 
identifiers, may also be assigned to subjects for specific treatment assignment as dictated by the 
study. In these cases, the same IMP packing identification number may not be assigned to more 
than 1 subject. 
Subject numbers will be assigned to subjects as they consent to participate in the study using an 
IRT. A unique 3-digit number will be assigned to each site and a 4-digit number will be assigned 
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in an ordinal series for each subject in order of presentation. The full subject number will be a 
combination of site and presentation number. For example, the third subject consenting to study 
participation at Site 002 will be assigned the following number: 002-0003. 
Once a unique subject number has been assigned, then that number will not be used again even 
if, for example, a subject withdraws from the study. If the unique subject number is allocated 
incorrectly, the clinical research associate (CRA)/study monitor must be notified as soon as the 
error is discovered. 
6.2.3 Dosing Periods 
During Study Part A, the IMP will be dosed in a double-dummy design. Subjects randomized 
to TAK-503 will receive TAK-503 tablet(s) and atomoxetine-matched placebo capsule(s). 
Subjects randomized to atomoxetine will receive atomoxetine capsule(s) and 
TAK-503-matched placebo tablet(s). 
Subjects randomized to placebo will receive TAK-503-matched placebo tablet(s) and 
atomoxetine-matched placebo capsule(s). Double-blinded treatment will be for up to 18 weeks, 
plus the dose-taper period (except for subjects on placebo). 
All subjects in this study will be instructed to take assigned medication QD in the morning orally 
and consistently with respect to time of eating and type of food eaten. Administering the IMP 
with a high-fat meal should be avoided. Subjects should not drive or operate heavy equipment 
until the effects of IMP are known (ie, suspend driving and operation of heavy equipment until 
the subject is on a stable and well-tolerated dose for a minimum of 1 week). 
6.2.3.1 
Dose-optimization Period 
Investigational medicinal product dosing will be flexibly optimized to maximize the potential 
benefits while minimizing risk of TEAEs. The investigator will consider the efficacy, safety, and 
tolerability profile when determining the optimal dose for an individual subject. 
In Study Part A, subjects who achieve at least a 30% reduction in ADHD-RS-5 total score from 
baseline (Day 0A) and a CGI-I of 1 or 2 at a given tolerated dose will be considered to be at an 
optimal IMP dose. Subjects who do not achieve this amount of reduction at a given tolerated 
dose may be titrated to a higher dose at the investigator’s discretion. Also, if a ≥30% reduction in 
ADHD-RS-5 total score from baseline is reached and the dose is well tolerated, then the IMP 
dosage strength may be increased if the investigator believes the subject could potentially receive 
further symptom reduction with a higher dose, not to exceed the maximum dose as shown in 
Table 4 and Table 5. 
The dose-optimization schedule and dose levels of TAK-503 in Study Part B will be identical to 
those in Study Part A. Dose-optimization of TAK-503 will be guided by investigator judgment 
based on emerging TEAEs and clinical assessments of tolerability and efficacy by reviewing 
TEAE incidence(s) and changes in CGI-I and ADHD-RS-5 scores. 
If necessary, the investigator will be permitted to reduce the subject’s dose once during the 
dose-optimization periods of Study Parts A and B, respectively. 
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TAK-503 Dose-optimization (Study Parts A and B) 
All subjects will undergo dose-optimization during Study Parts A and B. Regardless of study 
part, dose-optimization will occur during the first 4 weeks for children aged 6 to 12 years and the 
first 7 weeks for adolescents aged 13 to 17 years. 
Subjects randomized to TAK-503 will begin dosing at 1 mg QD and dose-titrated upward in 
weekly 1-mg increments until an optimal dose is reached. Children aged 6 to 12 years will not be 
permitted to titrate to a dose greater than 4 mg QD and adolescents aged 13 to 17 years will not 
be permitted to titrate to greater than the maximum allowed QD dose per the baseline weight 
group as shown in Table 4. 
Table 4 
Dose-optimization Schedule for TAK-503: Study Parts A and B 
Subject Baseline Weight 
Study Week 
1A/B 
2A/B 
3A/B 
4A/B 
5A/B 
6A/B 
7A/B 
Children aged 6 to 12 years 
≥25.0 kg 
(4 mg QD max dose) 
1 mg 
2 mg 
3 mg 
4 mg 
Enter dose-maintenance period at optimized 
dose ≤4 mg 
Adolescents aged 13 to 17 years 
34.0 to 41.4 kg 
(4 mg QD max dose) 
1 mg 
2 mg 
3 mg 
4 mg 
optimized 
dose ≤4 mg 
optimized 
dose ≤4 mg 
optimized 
dose ≤4 mg 
41.5 to 49.4 kg 
(5 mg QD max dose) 
1 mg 
2 mg 
3 mg 
4 mg 
5 mg 
optimized 
dose ≤5 mg 
optimized 
dose ≤5 mg 
49.5 to 58.4 kg 
(6 mg QD max dose) 
1 mg 
2 mg 
3 mg 
4 mg 
5 mg 
6 mg 
optimized 
dose ≤6 mg 
≥58.5 kg 
(7 mg QD max dose) 
1 mg 
2 mg 
3 mg 
4 mg 
5 mg 
6 mg 
7 mg 
Max=maximum; QD=once daily 
Atomoxetine Dose-optimization (Study Part A only) 
The dose of atomoxetine will be optimized in Part A, since Part B will entail open-label 
treatment with TAK-503. 
Subjects who weigh <70 kg at baseline and randomized to the atomoxetine treatment arm will 
begin dosing at approximately 0.5 mg/kg QD. If well-tolerated after 1 week minimum, this dose 
may be increased to the target dose of 1.2 mg/kg QD. The dose-optimization schedule for 
atomoxetine is provided in Table 5. The total atomoxetine dose will not exceed 1.4 mg/kg QD. 
With limited dosage forms, this upper limit is necessary to achieve appropriate weight-based 
doses. Permitted doses of atomoxetine for subjects weighing <70 kg at baseline are 10, 18, 25, 
40, 60, and 80 mg QD, depending on the subject’s baseline weight (Visit 2A). 
Atomoxetine dosing in children and adolescents who weigh ≥70 kg at baseline will begin at 
40 mg QD. If well-tolerated after a minimum of 1 week, then this dose may be increased to 
80 mg QD. After a 1-week minimum, if the daily dose at 80 mg is well tolerated, then the dose 
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may be increased to 100 mg QD. The total dose in children and adolescents who weigh ≥70 kg at 
baseline (Visit 2A) will not exceed 100 mg QD. Subjects optimized to a dose greater than 60 mg 
QD will take 2 atomoxetine or atomoxetine-matched placebo capsules QD. Subjects optimized to 
a daily dose ≤60 mg QD will take 1 atomoxetine or atomoxetine-matched placebo capsule QD. 
Table 5 
Dose-optimization Schedule for Atomoxetine: Study Part A 
 
Weight Range 
(kg) 
First dose 
First dose 
increase 
Second dose increase 
0.5 mg/kg 
1.2 mg/kg 
 
Subjects <70 kg at 
Baseline 
25.0-29.9 
10 mg 
25 mg 
Not Applicable 
30.0-44.5 
18 mg 
40 mg 
Not Applicable 
44.6-64.5 
25 mg 
60 mg 
Not Applicable 
64.6-69.9 
40 mg 
80 mg 
Not Applicable 
Subjects ≥70 kg at 
Baseline 
≥70 
40 mg 
80 mg 
100 mg 
 
6.2.3.2 
Dose-maintenance Period 
In Study Part A, following titration to an optimal dose, all subjects randomized will continue 
taking morning doses through Week 18A. The investigator will not adjust the IMP dose during 
the dose-maintenance period of Study Part A. 
Subjects in Study Part B will continue to take morning doses of open-label optimized TAK-503 
through Week 49B. The investigator may make further dose adjustments as needed based upon 
TEAEs and clinical judgment of tolerability and efficacy. These dose adjustments can be to a 
higher dose, based on the subject’s current age and weight. The daily dose, based on the 
Study Part B baseline weight, may be increased to >4 mg in subjects who turn 13 years or older 
during the dose-maintenance period. The dose can be increased or decreased by 1-mg increments 
at any scheduled or unscheduled visit during the study if deemed appropriate by the investigator. 
6.2.3.3 
Dose-taper Period 
All subjects randomized in active treatment arms will undergo a scheduled 3-week dose taper to 
ensure proper downward dose titration of TAK-503 at the end of the dose-maintenance period or 
at ET in both Study Parts A and B, as applicable. Subjects will be dispensed a tapering dose 
based on the last maintenance of dose of TAK-503 as presented in Table 6. Subjects will return 
IMP upon return to the study site for the third dose-tapering visit. 
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Table 6 
Dose-taper Schedule for TAK-503 in Study Parts A and B 
Last TAK-503 
Maintenance 
Dose 
Visit 15A and Visit 14B 
UVisit 16A and Visit 15B 
Visit 17A and Visit 16B 
Days 1 to 
4Pa 
Days 5 to 7Pa 
Days 8 to 
11Pa 
Days 12 to 14 Pa 
Days 15 to 
18Pa 
Days 19 to 
21Pa 
1 mg 
1 mg 
1 mg 
1 mg 
1 mg 
1 mg 
1 mg 
2 mg 
2 mg 
2 mg 
2 mg 
1 mg 
1 mg 
1 mg 
3 mg 
2 mg 
2 mg 
2 mg 
1 mg 
1 mg 
1 mg 
4 mg 
3 mg 
3 mg 
2 mg 
2 mg 
1 mg 
1 mg 
5 mg 
4 mg 
4 mg 
3 mg 
3 mg 
2 mg 
1 mg 
6 mg 
5 mg 
4 mg 
3 mg 
3 mg 
2 mg 
1 mg 
7 mg 
6 mg 
5 mg 
4 mg 
3 mg 
2 mg 
1 mg 
a 
Days 1 through 21 of the 3-week dose-taper. During Study Parts A and B, days 1 to 21 refer to weeks 50, 51, and 52. 
Week 50 corresponds to Visit 15A in Study Part A and Visit 14B in Study Part B. Week 51 corresponds to Visit 16A in 
Study Part A and Visit 15B in Study Part B. Week 52 corresponds to Visit 17A in Study Part A and Visit 16B in 
Study Part B. 
Dose-tapering will not be required for subjects randomized to the placebo treatment arm. 
6.2.4 Unblinding of the Treatment Assignment 
In this study, blinding to treatment assignment (TAK-503, atomoxetine, placebo) is used to avoid 
bias in Part A, in which the comparator arms (atomoxetine, placebo) have been included as 
controls for assay sensitivity. 
Part A (blinded, placebo-controlled): The treatment assignment (TAK-503, atomoxetine, 
placebo) must not be broken for subjects during their participation in Part A of the study, except 
in emergency situations when the identification of the IMP is required for further treatment of 
the subject. If IMP unblinding is required, the treatment assignment should be broken using the 
IRT system. The investigator should contact the medical monitor before unblinding if feasible 
and by all means as soon as possible after IMP unblinding. 
Transition from Part A to Part B: In Part A, Week 18A, the IRT system will notify the site to 
transfer subjects to Part B of the study. 
Part B (open-label): Upon entry into Part B of the study, all subjects will receive open-label 
TAK-503. However, subjects who received active treatment in Part A must remain blinded 
regarding which drug they received in Part A, in order to avoid influencing data queries related 
to these subjects’ data in Part A. 
If the treatment assignment is broken for any reason, then the date, the signature of the person 
who broke the code and the reason for breaking the code will be recorded using the source 
documents. Upon study-blind breaking, the subject will be withdrawn from the study but will be 
followed-up for safety purposes. Any code-breaks that occur must be reported to the contract 
research organization (CRO) and sponsor. After subject’s blinding is broken, the code-break 
information will be held by the pharmacist/designated person at the site and by the CRO’s 
medical monitor for the study or designee. 
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6.2.5 
Labeling, Packaging, Storage, Handling, and Accountability 
6.2.5.1 
Labeling 
A computer-generated booklet label containing study information will be affixed to the primary 
container of the IMP. 
All IMP will be labeled at a minimum with protocol number, medication identification (MedID) 
number, dosage form (including product name and quantity in pack), directions for use, storage 
conditions, expiration date (if applicable), batch number and/or packaging reference, the 
statements “For clinical trial use only”, and/or “CAUTION: New Drug - Limited by Federal (or 
United States) Law to Investigational Use”, and “Keep out of reach of children”, and the 
sponsor's name and address as per local regulation. 
Any additional labeling requirements for participating countries will also be included on the 
label. Space will be allocated on the label so that the site representative can record the unique 
subject identifier. 
Additional labels may, on a case-by-case basis, be applied to the IMP to satisfy local or 
institutional requirements, but must not do the following: 
• Contradict the clinical trial label 
• Obscure the clinical trial label 
• Identify the name of the subject 
Additional labels may not be added without the sponsor’s prior full agreement. 
6.2.5.2 
Packaging 
The sponsor will provide all TAK-503 in 1-, 2-, 3-, and 4-mg strength tablets and 
TAK-503-matched placebo tablets. 
The sponsor will provide atomoxetine in 10-, 18-, 25-, 40-, and 60-mg over-encapsulated 
capsules and atomoxetine-matched placebo capsule, which will also be over-encapsulated. 
Primary packaging for all IMP will be in 9-count, child-resistant bottles. 
Changes to sponsor-supplied packaging before dosing may not occur without full agreement by 
the sponsor obtained in advance. 
6.2.5.3 
Storage 
The investigator will have overall responsibility for ensuring that IMP is stored in a secure and 
limited-access location. Limited responsibility may be delegated to the pharmacy or member of 
the study team, but this delegation must be documented. The IMP will be distributed by the 
pharmacy or a nominated member of the study team who will enter the unique subject identifier 
on the IMP bottle/carton labels as they are distributed. 
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All IMP must be stored according to labeled storage conditions. Temperature monitoring 
will be required at the storage location to ensure that the IMP is maintained within an 
established temperature range. The investigator will be responsible for ensuring that the 
temperature is monitored throughout the duration of the study and that records are 
maintained; the temperature should be monitored continuously by using either an in-house 
system, a mechanical recording device, such as a calibrated chart recorder, or by manual means, 
such that both minimum and maximum thermometric values over a specific time period can be 
recorded and retrieved as required. Such a device (ie, certified minimum/maximum 
thermometer) would require manual resetting upon each recording. The sponsor must be notified 
immediately upon discovery of any excursion from the established temperature range. 
Temperature excursions will require site investigation as to cause and remediation. The sponsor 
will determine the ultimate impact of excursions on the IMP and will provide supportive 
documentation as necessary. Under no circumstances should the product be dispensed to subjects 
until the impact has been determined and the product is deemed appropriate by the sponsor for 
subject use. 
The sponsor should be notified immediately if any changes are made to the storage area of the 
IMP that could affect the integrity of the products (eg, fumigation of a storage room). 
6.2.5.4 
Special Handling 
No IMP stock or returned inventory from a company-sponsored trial may be removed 
from the site where originally shipped without prior knowledge and consent by the sponsor. 
When authorized, all applicable local, state, and national laws must be adhered to for the 
transfer. 
All documentation of delivery/drug receipts should be maintained by the site. If used, shipment 
return forms must be signed before shipment from the site. Validated electronic return systems 
(ie, IRT) will not require a shipment form. Returned IMP must be packed in a tamper-evident 
manner to ensure product integrity. Shipment of all returned IMP must comply with local, state, 
and national laws. 
6.2.6 
Drug Accountability 
Investigators will be provided with sufficient amounts of the IMP to execute this protocol for the 
agreed number of subjects. The investigator or designee will acknowledge receipt of the IMP and 
document shipment content and condition. Accurate records of all IMP dispensed, used, 
returned, and/or destroyed must be maintained as detailed further in this section. 
The investigator has overall responsibility for administering/dispensing IMP. If permissible, 
tasks may be delegated to a qualified designee (eg, a pharmacist) who has been adequately 
trained on the contents of the protocol and who works under the direct supervision of the 
investigator. This delegation must be documented in the applicable study delegation of authority 
form. 
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the IMP only to subjects enrolled in this study and 
will follow the procedures set out in the study protocol. Each subject will be given only the IMP 
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carrying his or her treatment assignment. All dispensed IMP will be documented on the eCRF 
and/or other IMP record. The investigator will be responsible for ensuring the retrieval of all 
study supplies from subjects. 
No IMP stock or returned inventory from a company-sponsored study may be removed from the 
site where originally shipped without prior knowledge and consent by the sponsor. If such 
transfer is authorized by the sponsor, then all applicable local, state, and national laws must be 
followed. 
In Study Part A, the sponsor or its representatives must be permitted access to review the 
supplies storage and distribution procedures and records, provided that the study-blind is not 
compromised. 
At the end of the study or as instructed by the sponsor, all unused stock, subject-returned IMP, 
and empty/used IMP packaging will be sent to a nominated contractor on behalf of the sponsor. 
The IMP returned to the sponsor’s designated contractors must be counted and verified by 
clinical site personnel and the sponsor (or designated CRO). All certificates of delivery/drug 
receipts should be signed by the site representative to confirm contents of shipment. 
For unused supplies in which the original supplied tamper-evident feature is verified as intact, 
the tamper-evident feature must not be broken; the labeled amount will be documented in lieu of 
counting. If used, shipment return forms must be signed before shipment from the site. Validated 
electronic return systems (ie, IRT) will not require a shipment form. Returned IMP(s) must be 
packed in a tamper-evident manner to ensure product integrity. The sponsor will be contacted to 
authorize the return of an IMP before shipment. The shipment of all returned IMP must comply 
with local, state, and national laws. 
Based on entries in the site drug accountability forms, it must be possible to reconcile IMP 
delivered with those used and returned. All IMP(s) must be accounted for and any discrepancies 
will be investigated and documented to the sponsor’s satisfaction. 
6.3 
Subject Compliance 
Subjects must be instructed to bring any unused IMP and empty/used IMP packaging to every 
visit. Drug accountability must be assessed at the container/packaging level for unused IMP that 
is contained within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the 
individual count level for opened containers/packaging. The pharmacist/nominated person will 
record details on the drug accountability form. 
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7. 
STUDY PROCEDURES 
7.1 
Study Schedule 
The timing of study procedures is provided in the Study Schedules. 
All subject discontinuations and alternative approaches to study procedures (ie, procedures not 
conducted per the Study Schedules) due to unavoidable dire circumstances (eg, a widespread 
disease outbreak such as the COVID-19 pandemic or natural disaster) must be documented in 
study records.  
7.1.1 Screening 
Before performing any study-related procedures, the investigator or designee must obtain written 
informed consent from the subject’s parent/LAR (see Section 10.3.1). Documentation of assent 
(as per local requirements) must indicate that the parent/LAR and the subject are aware of the 
investigational nature of the study and the required procedures and restrictions associated with 
participating in the study. Subjects must be reconsented if they reach the age of legal 
responsibility during the study, based on applicable local and national laws.  
A diagnosis of ADHD based on a psychiatric interview and mental status examination using the 
K-SADS-PL will be performed at screening (Visit 1A) by a trained child and adolescent 
psychiatrist, who is experienced with the scale and qualified to establish the aforementioned 
diagnoses. Any exception will require the approval of the sponsor or designee. Documentation of 
study training should be maintained in the site’s files. 
A washout period to discontinue any current psychoactive medication or current prohibited 
medication may be required before baseline of Study Part A and will be required before baseline 
of Study Part B. For Study Part A, the washout is intended to remove any medication that is 
prohibited in this study that the subject may have been receiving before enrollment. A subject 
cannot be instructed to washout any medication until after informed consent has been obtained. 
Schedules for medication requiring a washout are presented in Table 3. 
Except for subjects randomized to the placebo treatment arm, a washout period of ≥30 days but 
no more than 45 days from the last dose of IMP in Study Part A will be required for Study Part B 
to remove blinded IMP to which the subject was randomized in Study Part A. If more than 
45 days has elapsed between the follow-up visit in Study Part A and the baseline visit in 
Study Part B, then the subject will be discontinued from the study. 
Screening assessments may take place over several days to provide enough time to complete all 
procedures and confirm study eligibility. If screening assessments are performed on different 
dates, then the screening date will be recorded as the date signed on the source documents that 
consent was obtained as no study procedures should precede this date. 
The screening period will not be less than 3 days to allow for all screening results to be obtained 
and evaluated. If the screening period extends past 35 days, then certain assessments will be 
repeated (see Section 7.1.2). 
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If a subject discontinued from screening (and was thus considered a screen failure due to 
unavoidable dire circumstances, eg, a widespread disease outbreak such as the COVID-19 
pandemic or natural disaster), but was otherwise qualified to participate in the trial, the subject 
may be rescreened if the sponsor medical monitor agrees. Such exceptional circumstances 
require documentation in the eCRF. 
The procedures to be completed at screening are presented in the Study Schedules and clarified 
further below: 
• The investigator or assigned site staff will access the IRT to register the subject and 
obtain the assigned unique subject identification number. 
• Reporting of AEs will begin at the time informed consent is obtained. 
• Prior/concomitant medications will be reported as follows: 
• All lifetime psychoactive medications will be documented on the PSMQ. 
• Other medications used during the 30 days before screening (Visit 1A) will be 
documented. 
• Any abnormal physical examination finding(s) will be documented on the appropriate 
eCRF for medical history with enough detail to permit detection of change over time. See 
Section 7.2.2.1. 
• Historical and current nonpharmacological interventions for ADHD will be recorded. 
Note: Continued participation in behavioral therapy will be permitted if the subject has 
been receiving the therapy for at least 1 month at the time of baseline and therapy will 
remain stable throughout the study. Any unplanned changes to behavioral therapy must 
be discussed with the medical monitor. 
• Before baseline (Visit 2A), a site representative will contact the subject’s parent/LAR 
after successful screening to provide instruction(s) for discontinuing the subject’s 
psychoactive medication (if any) or current prohibited medication (if any). The minimum 
washout period for all prohibited medications is 5 times the half-life of the medication 
(see Table 3). 
A screen failure will be defined as a subject who has given informed consent and failed to meet 
the inclusion criteria and/or met at least 1 of the exclusion criteria and has not been randomized. 
The investigator or assigned study staff will use the IRT to record any subject designated as a 
screen failure. Any subject designated a screen failure under normal circumstances (ie, failure 
not related to a widespread disease outbreak such as the COVID-19 pandemic or natural disaster) 
will not be rescreened. Screen failures that are related to such exceptional circumstances require 
documentation in the eCRF and will be allowed to rescreen. 
7.1.2 Baseline 
Once all screening results, including clinical laboratory tests and ECGs, have been obtained and 
reviewed and after the subject has completed the required washout period (if necessary), subjects 
will return to the site for baseline (Visit 2A and Visit 2B). 
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Procedures to be completed at baseline are presented in the Study Schedules with further 
clarification provided as follows: 
• If the clinical laboratory tests to be completed for screening were not conducted within 
the 35 days before the baseline visits, then these tests must be repeated, and results 
obtained, prior to determining eligibility. 
• Concomitant and psychoactive medications will be documented as follows: 
• Medications used between screening and baseline 
• A minimum of 3 ECG measurements, with approximately 5 minutes between each 
measurement, will be collected at baseline to ensure that appropriate baseline intervals 
are established. The eligibility of a subject will be based on ECG measurements from the 
central reader (normal/abnormal) and the determination of the clinical significance of any 
ECG finding by the central reader by the investigator, in consultation with the medical 
monitor, if applicable. 
• A subject must have an ADHD-RS-5 total score of ≥28 and a CGI-S score ≥4 at baseline 
(Visit 2A) for inclusion (Study Part A only). 
If the subject is eligible for the study, then the investigator or assigned site staff will access the 
IRT to enroll the subject and obtain a MedID number to dispense IMP to the subject. The subject 
will take the first IMP dose on the morning after baseline (Visit 2A and Visit 2B). 
7.1.3 
Treatment Periods: Dose-optimization, Dose-maintenance, and Dose-taper 
For Study Parts A and B, the treatment periods comprise dose-optimization, dose-maintenance, 
and dose-taper. The treatment period will be double-blinded in Study Part A and open-label in 
Study Part B. 
7.1.3.1 
Dose-optimization Period 
In Study Parts A and B, dose-optimization of IMP will occur from Week 1A/B through 
Week 4A/B for children aged 6 to 12 years and through Week 7A/B for adolescents aged 13 to 
17 years. During the dose-optimization period, clinic visits will be scheduled every 7 days to 
assess IMP safety and tolerability and to allow investigators to titrate the IMP to an optimal dose 
that maximizes potential benefits while minimizing risk of TEAEs. The investigator will 
consider the efficacy, safety, and tolerability profile when determining the optimal dose for each 
subject. Subjects who achieve at least a 30% reduction in ADHD-RS-5 total score from baseline 
(Study Part A only) and a CGI-I of 1 or 2 at a given tolerated dose will be considered to be 
receiving an optimal dose. Subjects who do not achieve this level of reduction at a given 
tolerated dose may be titrated to a higher dose at the investigator’s discretion. Also, if a 
≥30% reduction in the ADHD-RS-5 total score from baseline is obtained and the dose is 
well-tolerated, then the IMP dosage strength may be increased if the investigator believes the 
subject could potentially receive further symptom reduction with a higher dose, though not to 
exceed the maximum dose shown in Table 4 and Table 5, as applicable. 
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In Study Part B, optimization of TAK-503 dosing will be guided by investigator judgment based 
on emerging TEAEs and clinical assessments of tolerability and efficacy by reviewing TEAE 
incidence(s) and changes in CGI-I and ADHD-RS-5 scores. 
If necessary, the investigator will be permitted to lower the subject’s dose once during the 
dose-optimization periods of Study Parts A and B. 
Procedures to be completed during the dose-optimization periods are presented in the  
Study Schedules. 
7.1.3.2 
Dose-maintenance Period 
Subjects will remain on an optimized IMP dose during the entirety of the dose-maintenance 
periods of Study Parts A and B. 
In Study Part A, subjects randomized to TAK-503 or atomoxetine treatment arms will continue 
with daily dosing at the optimized IMP dose from Week 5A for children and Week 8A for 
adolescents. At the principal investigator’s discretion, a subject may conduct up to 2 consecutive 
visits remotely. Note that this is not a cumulative limit on the total number of remote visits. A 
subject may have more than 2 remote visits throughout the entire course of the study, but cannot 
have 3 remote visits in a row (unless required due to unavoidable dire circumstances, eg, a 
widespread disease outbreak such as the COVID-19 pandemic or natural disaster). Such 
exceptional circumstances require documentation in the study records. 
Subjects randomized to the placebo treatment arm will continue with daily dosing from Week 5A 
for children and Week 8A for adolescents through Week 18A and complete procedures specified 
for Visit 11A (Week 18A) before rolling over to Study Part B. 
All subjects who complete the dose-maintenance period of Study Part A or who terminate early 
will undergo the procedures indicated for ET in the Study Schedules. Likewise, in Study Part B, 
all subjects who complete the dose-maintenance period or who terminate early will undergo the 
procedures indicated for Visit 13B (Week 49B) in the Study Schedules. 
7.1.3.3 
Dose-taper Period 
After completion of the dose-maintenance period, or upon ET, subjects who received TAK-503 
treatment (blinded active or placebo) in Study Part A and all subjects in Study Part B will be 
required to taper downward the last dose-maintenance dose over 3 weeks. The dose-taper 
schedule will be determined by the last maintenance dose of TAK-503 as presented in Table 6. 
7.1.4 Follow-up Period 
The follow-up period for this study is 7 (+2) days each for Study Part A and Study Part B 
(Week 53B). The procedures to be performed at the follow-up visit are presented in the Study 
Schedules. 
If a subject refuses to return to the site for a follow-up visit, then the study site personnel will 
contact the subject 7 days after the subject’s last IMP dose to collect information on any ongoing 
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or emergent TEAEs, SAEs, and concomitant medications since the last IMP dose. Appropriate 
follow-up should continue until all safety concerns are resolved as judged by the investigator. 
All TEAEs and SAEs that are not resolved at the time of this contact will be followed until the 
event is closed (see Section 7.1). 
7.1.5 Additional Care of Subjects After the Study 
No aftercare is planned for this study; subjects will be referred to their primary care physician or 
psychiatrist for care after the follow-up.  
7.2 
Study Evaluations and Procedures 
All assessments described in the following subsections will be performed by the subject, 
parent/LAR, or clinician as indicated in the description of the assessment. Changes must not be 
made to subject or parent/LAR completed scales after the visit has been completed. Care must be 
taken by the investigator or documented designee to explain fully the scale before the subject or 
parent/LAR completes the scale and responses should be reviewed by the investigator or 
designee during the study visit. Corrections can only be made to scales by the subject or 
parent/LAR during a study visit. In the event that paper forms are used and the 
subject/parent/LAR marks an answer in error, the entry may be corrected by drawing a single 
line through the error and initialing and dating the change. Assessments are to be performed 
according to the schedules provided in the Study Schedules. 
Whenever possible, raters (including parent/LAR or caregiver, and the investigator or site 
designee) observing the subject’s behavior should be consistent from week to week throughout 
the study. 
7.2.1 
Demographic and Other Baseline Characteristics 
7.2.1.1 
Demographics 
The age at baseline, sex, ethnicity, and race will be recorded for each subject. Approximately 
25% of all subjects will be aged 13 to 17 years. Approximately 25% of all subjects will be 
female. 
7.2.1.2 
Medical and Medication History 
A complete medical history will be recorded at screening and will include a record of the 
subject’s medication history and all clinically or medically relevant information regardless of 
how much time has elapsed since the date of diagnosis. 
The medical and medication history should include, but will not be limited to the following: 
• Ingestion of medication, including a lifetime history of psychoactive medications and 
recent use of any other medication received during the 30 days before screening and 
between screening and baseline 
• History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, and any other diseases 
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• Complete psychiatric history 
• Any nonpharmacological interventions for ADHD 
7.2.1.3 
Prior Stimulant Medicine Questionnaire 
The PSMQ is a form designed to collect information on reasons for discontinuation of prior 
stimulant ADHD medications. This questionnaire will be administered at Study Part A screening 
only (Visit 1A). The PSMQ is provided in Appendix 4. 
7.2.1.4 
Kiddie Schedule for Affective Disorders and Schizophrenia – Present and 
Lifetime Version 
The K-SADS-PL is a semistructured diagnostic interview designed to assess current and past 
episodes of psychopathology in children and adolescents using the criteria from the DSM-5. 
Probes and objective criteria are provided to rate individual symptoms. The primary diagnoses 
assessed with the K-SADS-PL include, but are not limited to the following: 
• Major depression 
• Dysthymia  
• Mania  
• Bipolar disorders 
• Schizoaffective disorders  
• Panic disorders 
• Agoraphobia 
• Separation anxiety disorder 
• Avoidant disorder of childhood and adolescence  
• Simple phobia  
• Social phobia 
• Overanxious disorder 
• Generalized anxiety 
• Obsessive compulsive disorder 
• ADHD 
• Conduct disorder 
• Oppositional-defiant disorder 
 
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The K-SADS-PL will be administered at screening (Visit 1A) in Study Part A by a trained child 
and adolescent psychiatrist who is experienced with the scale and qualified to establish the 
aforementioned diagnoses. Any exception will require the approval of the sponsor or designee. 
Documentation of study training should be maintained in the site’s files. 
The K-SADS-PL will be administered by interviewing the subject and the subject’s 
parent(s)/LAR(s) and achieving summary ratings, which include all sources of information 
(parent, child/adolescent, school, chart, and other). When administering the instrument to 
children, the subject’s parent(s)/LAR(s) interview should be conducted first. 
7.2.2 
Safety Assessments 
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files. 
7.2.2.1 
Physical Examination (Including Height and Weight) 
A full physical examination will be performed by a qualified individual licensed in his/her 
respective country/state (eg, physician, physician assistant, or a nurse practitioner) at the visits 
identified in the Study Schedules. 
A full physical examination will include an assessment of the following: 
• General appearance 
• Skin 
• Head, eyes, ears, nose, and throat 
• Spine/neck/thyroid 
• Respiratory 
• Cardiovascular 
• Abdomen (including liver and kidneys) 
• Musculoskeletal 
• Neurological 
An abbreviated physical examination will include a review of general appearance and respiratory 
and cardiovascular systems. The results of the clinical laboratory tests and physical examination 
must be reviewed by the investigator before subject enrollment. 
Any abnormal physical examination findings will be documented in the subject’s source 
documents and on the medical history eCRF with enough detail to permit detection in changes 
during the course of the study (eg, lower right extremity weakness +2/5 or erythematous macule 
2 cm in diameter). 
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Any abnormalities or changes in intensity noticed upon the physical examination during the 
study will be documented in the subject’s medical record. New or worsening physical 
examination findings that are considered clinically significant will be recorded as a TEAE 
(Section 7.1). 
Height will be captured at the visits identified in the Study Schedules. A calibrated stadiometer 
should be used for all height measurements. Height should be measured in cm to the nearest 
0.5 cm, with the subject standing without shoes on a flat surface and with chin parallel to the 
floor. The body should be straight but not rigid. 
Weight will be captured at the visits identified in the Study Schedules. The same calibrated scale 
should be used for all weight measurements. Weight should be measured in kg without shoes and 
recorded to the nearest 0.1 kg. Bulky clothing items should be removed whenever possible to 
ensure that the most accurate weight is recorded. 
For all visits indicated in the Study Schedules, the subject’s BMI will be calculated using the 
following formula: 
BMI = (weight in kg x 10,000)/(height in cm)P2 
All height and weight measurements should be performed by the same site personnel 
(if possible) throughout the study. 
7.2.2.2 
Tanner Staging 
The stage of puberty/sexual maturation will be evaluated for each subject according to Tanner 
staging (Marshall and Tanner 1969; Marshall and Tanner 1970). The Tanner stage for genitals 
(male, stages I-V), breasts (females, stages I-V), and pubic hair (both sexes, stages I-V) will be 
documented at the times specified in the Study Schedules. More information on can be found in 
Appendix 7. 
Tanner staging will be self-assessed. Self-assessment in this study is defined as subjects or 
parents indicating which drawing of the scale corresponds to subject’s sexual maturation stage at 
the time of the specific visit. For this purpose, site staff (the principal investigator or a designee) 
reads the guidance and the text corresponding to each drawing and asks the subject or parent to 
choose the applicable drawing (see Appendix 7). The response from the subject or the parent will 
be documented in the Tanner Staging Form by the site staff. 
7.2.2.3 
Adverse Event Collection 
At each study visit, subjects will be questioned in a general way to ascertain if any TEAEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
Adverse events are collected from the time informed consent is signed. (Please refer to Section 8, 
Adverse and Serious Adverse Events Assessment.) 
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7.2.2.4 
Vital Signs 
For all visits indicated in the Study Schedules, vital sign measurements will include body 
temperature (oral or tympanic), supine BP and pulse (after 5 minutes of rest), and standing BP 
and pulse (after 2 minutes of standing from supine). If the subject expresses the need to sit-down 
before the 2-minute time point is reached, then care must be taken to adequately support the 
subject while taking the standing BP measurement. Tilt tables should not be used to adjust the 
subject’s position for the purpose of BP measurements. 
Blood pressure should be determined by cuff (using the same method, the same arm, and the 
same position throughout the study). Any clinically significant deviations from baseline vital 
sign measurements in Study Parts A and B that are deemed clinically significant by the 
investigator will be recorded as an AE. 
7.2.2.5 
Clinical Laboratory Evaluations 
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges will be supplied by the laboratory and used to assess the clinical laboratory 
data for clinical significance and out-of-range pathological changes. The investigator should 
assess out-of-range clinical laboratory values for clinical significance and indicating if the 
value(s) is/are clinically significant or not clinically significant. Abnormal clinical laboratory 
values that are unexpected or not explained by the subject’s clinical condition may, at the 
discretion of the investigator or sponsor, be repeated as soon as possible until confirmed, 
explained, or resolved. 
Biochemistry blood samples can be drawn with the subject in a fasting or non-fasting state. If 
fasting samples are drawn at the screening visit (Visit 1A), subsequent samples should be drawn 
with the subject in the same fasting status, at the visits indicated in the Study Schedules. 
The following clinical laboratory assessments will be performed: 
Biochemistry (approximately 7 mL blood sample) 
Cholesterol 
Total protein 
Phosphorus 
Aspartate transaminase  
Sodium 
Alanine transaminase  
Potassium 
Gamma glutamyl transferase  
Bicarbonate 
Uric acid 
Calcium 
Total bilirubin 
Blood urea nitrogen (BUN) 
Glucose 
Creatinine 
Lactate dehydrogenase  
Albumin 
Thyroid stimulating hormone  
Magnesium 
Thyroxine  
Chloride 
 
Serum β-hCG for females of childbearing potential at screening visits only 
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Hematology (approximately 2 mL blood sample) 
 
Hemoglobin 
Neutrophils 
Hematocrit 
Lymphocytes 
Red blood cells (RBC) 
Monocytes 
Platelet count 
Eosinophils 
White blood cell (WBC) count – total and differential  
Basophils 
Urinalysis (approximately 10 mL urine sample) 
 
Specific gravity 
Glucose 
BloodPa 
ProteinPa 
pH 
Ketones 
Bilirubin 
 
a If protein and/or blood are detected during urinalysis, then a microscopic examination will be conducted and the following 
parameters will be assessed: RBCs, WBCs, bacteria, casts 
 
The investigator will assess any out-of-range clinical laboratory values (ie, high or low) for 
clinical significance on the original clinical laboratory report. 
7.2.2.6 
Urine Drug and Alcohol Screen 
A urine drug and alcohol screen will be conducted at screening (Study Part A) by the central 
laboratory. Additional drug and alcohol screens may be performed at the investigator’s 
discretion. Urine samples (approximately 10 mL) will be collected for this testing. 
The following drugs/drug classes will be tested: 
Cocaine 
Cannabinoids 
Phencyclidine 
Benzodiazepines class 
Barbiturates class 
Opiates class 
Methamphetamine 
MDMA (3,4-methylenedioxy-methamphetamine; Ecstasy) 
Methadone 
Amphetamines 
Ethanol 
Oxycodone 
For the subject to be eligible for the study, the results from the urine drug and alcohol screen 
must be negative at screening (Study Part A) (except for the subject’s current ADHD 
psychostimulant, if applicable). The investigator and the medical monitor will evaluate the 
potential impact of a positive urine drug and alcohol screen result on the continued participation 
of the subject. 
7.2.2.7 
Pregnancy Test 
A serum β-hCG pregnancy test will be performed on all FOCP at the screening visits 
(Study Parts A and B). A urine pregnancy test will be performed on all FOCP (Study Parts A 
and B), and at the time points indicated in the Study Schedules. Additional urine pregnancy tests 
may be performed at the investigator’s discretion. 
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If at any time a subject has a positive pregnancy test result outside the study center, she should 
contact the study center immediately. If any subject tests positive for pregnancy at any time 
during the study, then the site staff should immediately contact the medical monitor/sponsor for 
guidance. Subjects receiving TAK-503 or TAK-503-matched placebo at a dose >3 mg QD must 
be tapered-off as advised by the medical monitor/sponsor. Any subject with a positive pregnancy 
test result will be discontinued from the study and complete the procedures indicated for the ET 
visits. 
7.2.2.8 
Electrocardiogram 
A minimum of 3 ECGs will be collected at baseline with approximately 5 minutes between each 
measurement to ensure that appropriate baseline intervals are established. The subject will be 
assessed while in a quiet state (after 5 minutes of rest) in the supine position. Subject eligibility 
will be based on the assessment of the ECG from the central reader (normal/abnormal) and the 
determination of the clinical significance by the investigator, in consultation with the medical 
monitor if the ECG is an abnormal alert value per the central reader. 
The HR, PR interval, QRS interval, and QT interval will be measured from all ECGs and the 
QTcB and QTcF will be calculated. 
All 12-lead ECGs will be performed using the central ECG provider’s equipment and sent to the 
central ECG provider laboratory electronically. The name and address of the central ECG 
laboratory will be maintained in the investigator’s files at each site and in the Trial Master File. 
The central ECG provider will send an initial report within 72 hours and a final report, including 
the ECG analysis, thereafter. The site will be required to print at least 1 copy of the original ECG 
tracing. The original ECG(s) and the final report provided by the central ECG laboratory should 
be signed by the investigator and maintained at the site with source documents. The investigator 
will be responsible for determining the clinical significance of each ECG (after review of both 
the ECG and the report provided by the central ECG laboratory) and for documenting any 
findings in the appropriate eCRF field. 
No ECG should be deleted by site personnel. All ECGs must be transmitted to the central ECG 
laboratory provider regardless of the quality, result, or number of ECGs taken at a respective 
visit. 
7.2.2.9 
The Columbia-Suicide Severity Rating Scale 
The C-SSRS is the prospective counterpart to the Columbia Classification Algorithm for Suicide 
Assessment suicidality categorization system. Through a semi-structured interview format, the 
occurrence, severity, and frequency of suicide-related thoughts and behaviors are captured 
during an assessment period (Posner 2007). The interview includes definitions and suggested 
questions to solicit the type of information needed to determine if a suicide-related thought or 
behavior occurred. A maximum of 19 items will be completed as follows: 7 items are required, a 
potential 10 additional items will be completed upon a positive response to a required item, and 
2 items completed if suicide/suicide-like behavior is observed during the interview. The C-SSRS 
uses dichotomous scales (ie, yes or no), Likert scales, and text or narrative to further describe 
thoughts or behaviors. 
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7.2.2.10 
Suitability of the Subject to Remain in the Study 
Following completion of each C-SSRS interview, the investigator or a medically qualified 
designee should assess whether it remains in the best interest of the subject to continue in the 
study and that it is safe for the subject to do so. As part of the assessment of the subject’s 
suitability to remain in the study, the investigator should assess the subject’s current potential for 
suicide, suicidal ideation, self-harm or harm to others. The investigator should make this 
assessment by conducting a clinical interview with the subject and by reviewing all other 
relevant sources available, including results of the C-SSRS. The investigator should also ensure 
that there is appropriate documentation of this suitability assessment in the subject’s source 
notes. As part of this assessment, if appropriate, the investigator should discuss risk factors for 
suicide with the subject. Where a subject has suffered an accidental injury, the investigator 
should ensure that this was a true accidental injury, rather than an episode of self-harming or a 
suicide attempt. 
The subject’s source notes should clearly document that the assessment of continued suitability, 
including an assessment of the subject’s current potential risk of suicide, suicidal ideation, 
feelings of hopelessness, drug use, self-harm, or harm to others, has taken place and should 
contain the decision on whether the subject is suitable to continue in the study. 
The investigator should pay particular attention to a positive score for questions 4 and/or 5 on the 
C-SSRS or any suicidal behavior. If a subject answered ‘yes’ to either of these questions, they 
must undergo further evaluation to ensure that they are not in any way at risk. This should be 
discussed with the Medical Monitor, and the registering of an AE considered. The evaluation and 
decision should be clearly documented in the subject’s source notes. 
As part of routine good clinical care, subjects will be provided with 24-hour emergency contact 
details in case of an emergency situation where the subject feels that they are acutely at risk. In 
addition, subjects who are recruited into the study will be advised of the location of their closest 
emergency room. 
7.2.2.11 
Brief Psychiatric Rating Scale for Children 
The BPRS-C-21 was developed to provide a concise symptom profile of psychiatric 
problems that can occur during childhood (Hughes et al. 2001; Hughes 2008; Overall and 
Pfefferbaum 1982). The 21 items of the clinician-rated BPRS-C are grouped into the following 
7 scales:
• Behavioral Problems 
• Depression 
• Thinking Disturbance 
• Psychomotor Excitation 
• Withdrawal 
• Anxiety 
• Organicity
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Each item of the 21 items is clinician-graded using the following 7-point severity Likert-scale:
• 0=not present 
• 1=very mild 
• 2=mild 
• 3=moderate 
• 4=moderately severe 
• 5=severe 
• 6=extremely severe
To provide accurate ratings, a licensed clinician will collect information from medical records, 
direct observation, school reports, and clinical interviews of parents/caregivers, other family 
members, and the subject. The clinician will aggregate the accumulated data to provide a blended 
rating of an average score over a defined time period. A licensed clinician is defined as a mental 
health professional (MD, PhD, or DO) who has been trained to assess children and adolescents 
using basic measurement principles. 
7.2.2.12 
Pediatric Daytime Sleepiness Scale 
The PDSS is a self-reported assessment of daytime sleepiness in children (Drake et al. 2003). 
The PDSS questionnaire was designed to be easy to administer, score, and interpret. 
Sleepiness-related questions are based on previous research of situations that can be sensitive to 
sleep loss in this age group (eg, trouble getting out of bed in the morning, somnolence during 
class).  
The 8 questions are scored on Likert-scale from 0 to 4 (never=0; seldom=1; sometimes=2; 
frequently=3; always=4). The total score on the PDSS can range from 0 (never sleepy) to 
32 (always sleepy). 
Subjects will complete the PDSS questionnaire at the study site at the time points indicated in the 
Study Schedules with assistance from the site staff if necessary. 
7.2.2.13 
The Udvalg for Kliniske Undersøgelser Side Effect Rating Scale 
Designed for use in both clinical trials and routine clinical practice, the UKU rating scale was 
developed for clinicians to assess side effects of psychopharmacological medications based on 
patient interviews and other relevant source information (Lingjaerde et al. 1987). Adverse events 
occurring within the 3 days before the interview are rated and described independently of drug 
causality. For each item recorded, the probability of the causal relationship (or lack of it) to the 
medication in question is indicated in a separate column, making this scale useful for subsequent 
course of action. 
The scale was developed initially to assess effects of antipsychotic medication and many of the 
subscale items, such as those related to movement disorders, are not relevant to this study. For 
this study, only the following items relevant to the established safety profile of TAK-503 will be 
queried: Asthenia /Lassitude /Increased Fatigability, Sleepiness/Sedation, Increased Duration of 
Sleep, and Orthostatic Dizziness. 
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7.2.2.14 
The Cambridge Automated Neuropsychological Test Battery 
The neurocognitive function effects of TAK-503 on adolescents and children diagnosed with 
ADHD will be evaluated using the CANTAB cognitive assessments.  
Tasks selected from the CANTAB suite are presented in Table 7. 
Table 7 
Selected Tasks from CANTAB to Assess Neurocognition 
Domain 
Task 
Memory 
Delayed Matching to Sample: The DMS task tests both simultaneous matching and 
short-term visual memory. The subject is shown a complex visual pattern (the sample) 
and after a brief delay, 4 similar patterns. The subject must identify the pattern that 
matches the sample. 
Attention 
Reaction time: The RTI task involves elements of decision-making and attention as 
measured by choice accuracy (Jäkälä et al. 1999) as well as motor responses, by 
measuring motor and mental response speeds, and assesses movement time, reaction 
time, response accuracy, and impulsivity. 
Rapid Visual Information Processing: The RVP task measures the ability to sustain 
attention over time and is 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. Subjects are to detect a 3-digit target sequence (eg, 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. 
Executive Function 
Spatial Working Memory: The ability to retain spatial information and manipulate 
remembered items in working memory are measured with the SWM task. The task is 
self-ordered and assesses the individual’s ability to strategize heuristically. The test is a 
sensitive measure of frontal lobe and executive dysfunction 
Stop Signal Task: The SST measures response inhibition. The subject must respond to 
an arrow stimulus by touching either of 2 choices depending on the direction the arrow 
points. If an audio tone is present, the subject is not to respond. 
CANTAB=Cambridge Automated Neuropsychological Test Battery; DMS=Delayed Matching to Sample; RTI=Reaction 
Time/5-Choice Reaction Time; RVP=Rapid Visual Information Processing; SST=Stop Signal Task; SWM=Spatial Working 
Memory 
These cognitive tasks are accepted and validated methods for assessing potentially deleterious 
and/or beneficial effects of psychopharmacologics in psychiatric disorders, including ADHD  
(Coghill et al. 2014). 
7.2.3 
Efficacy Assessments 
Efficacy will be evaluated by performing the assessments described in the following subsections 
and according to the times specified in the Study Schedules. 
7.2.3.1 
The ADHD-Rating Scale-5 
The ADHD-RS-5 (DuPaul et al. 2016) is 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. 
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The ADHD-RS-5 is based on the diagnostic criteria for ADHD as described in the DSM-5 and 
consists of 2 symptom subscales, inattention and hyperactivity-impulsivity, each with 9 items 
and a total scale of 18 items. Each item in the subscale is scored with a value ranging from 0 (no 
symptoms) to 3 (severe symptoms). The total score can range from 0 to 54. 
The following 6 domains of impairment common among children and adolescents with ADHD 
are also assessed with the ADHD-RS-5: 
• Relationships with significant others (such as family members and teachers) 
• Relationships with peers 
• Academic functioning 
• Behavioral functioning 
• Homework performance 
• Self-esteem 
The ADHD-RS-5 will be completed by a licensed clinician who is familiar with the scale, 
including physicians (MD or DO) or licensed psychologists (PhD). Any exception will require 
the approval of the sponsor or designee. 
7.2.3.2 
Clinical Global Impressions 
The CGI scale (Guy 1976) will be used to evaluate the severity of mental illness over time. 
The CGI-S will be administered to assess the severity of mental illness at baseline. During 
subsequent visits, the CGI-I will be administered to assess any improvement in symptoms and 
to guide the clinician on dosing adjustments. The CGI-S is scored on a 7-point scale ranging 
from 1 (normal, not at all ill) to 7 (among the most extremely ill subjects). The CGI-I is also 
scored on a 7-point scale ranging from 1 (very much improved) to 7 (very much worse). 
The CGI-I and CGI-S will be completed by the investigator or delegated sub-investigator who is 
a licensed clinician (MD, DO, or licensed psychologist with a PhD). 
7.2.3.3 
Child Health and Illness Profile – Child Edition: Parent Report Form 
The Parent Report Form of the Child Health and Illness Profile – Child Edition (CHIP-CE:PRF) 
will be administered to provide information on self–esteem and school functioning in pediatric 
subjects diagnosed with ADHD. As reported by a parent or caregiver, a child’s functioning and 
well-being as well as emotional, physical, and behavioral symptoms will be captured with this 
generic scale that is useful for monitoring symptoms and identifying improvements. The 
5 domains and 12 subdomains covered in the 76 items comprising the CHIP-CE:PRE are 
presented in Table 8. 
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Table 8 
Domains and Subdomains of the CHIP – CE:PRF 
Domain 
Subdomain 
Satisfaction: with health and self 
Satisfaction with health (7 items) 
Satisfaction with self (4 items) 
Comfort: physical and emotional symptoms and 
activity restrictions due to illness 
Physical comfort (9 items) 
Emotional comfort (9 items) 
Restricted activity (4 items) 
Resilience: behaviors and family involvement in 
activities likely to enhance health 
Family involvement (8 items) 
Social problem-solving (5 items) 
Physical activity (6 items) 
Risk avoidance: behaviors that if not avoided are 
likely to pose risks to health 
Individual risk avoidance (4 items) 
Threats to achievement (10 items) 
Achievement: developmentally appropriate role 
functioning in school and with peers 
Academic performance (5 items) 
Peer relations (5 items) 
CHIP-CE:PRF=Child Health and Illness Profile-Child Edition: Parent Report Form 
The effect of TAK-503 on all subdomains will be summarized, including the sub-domain 
satisfaction with self, using parent rated self-esteem items. Parents will assess each item in a 
5-point response format; higher scores indicate better health-related quality of life. The CHIP-CE 
is psychometrically robust over time in terms of consistency and structure (Schacht et al. 2011) 
and has been shown to be reliable and valid in socioeconomically and ethnically diverse 
populations in Spain (Rajmil et al. 2004) and the United States (Rajmil et al. 2004; Riley et al. 
2004). 
7.2.3.4 
Conners 3 Parent Short Form 
Subjects enrolled after Amendment 5 will be assessed with the C3PS (Conners 2008). This 
assessment is used to better understand certain behavioral, social, and academic issues in 
children between 6 and 18 years old. The scale aids in diagnosis by helping to delineate the 
child's issues as well as in what settings these issues are most troublesome. The C3PS has the 
following subscales: Inattention, Hyperactivity/Impulsivity, Learning Problems, Executive 
Functioning, Defiance/Aggression, Peer Relation and Validity Scores (Positive Impression and 
Negative Impression). 
In addition to the Total Score, analysis of Learning Problems subscale and Executive 
Functioning subscale data will be conducted as an alternative approach to obtain schoolwork 
performance-related data following removal of the APRS as a secondary efficacy endpoint. 
All the items included in the Learning Problems subscale and Executive Functioning subscale 
either directly or indirectly evaluate performance related to schoolwork.  
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In the current environment and for the foreseeable future, remote schooling either in part or in 
full will be prevalent in many areas. Parents/LARs will have the opportunity to very closely 
observe the performance of their children with schoolwork. Therefore, an assessment of 
schoolwork performance by a parent(s)/LAR(s) will be highly appropriate to obtain schoolwork 
performance-related data.  
The analyses of Conners 3 Parent Rating Scale data will be conducted for the Total Score that 
includes all subscales, as well as the scores for the Learning Problems and Executive 
Functioning subscales individually. 
The CP3S will be completed by a parent/LAR who is very familiar with the subject. 
7.2.4 Volume of Blood to Be Drawn from Each Subject 
As shown in Table 9, approximately 54 mL of blood is expected to be withdrawn from subjects 
randomized in Study Parts A and B for subjects enrolled under protocol amendment 7. For 
subjects enrolled under prior versions of the protocol, approximately 72 mL of blood is expected 
to be withdrawn from subjects randomized in Study Parts A and B.  
Table 9 
Volume of Blood to Be Drawn from Subjects Randomized to Active IMP 
Treatments in Study Part A and Part B 
Assessment 
Sample Volume 
Number of 
Samples in 
Part A 
Number of 
Samples in 
Part B 
Total 
Volume 
Safety: 
Biochemistry and -hCGPa 
7 mL 
4Pb 
2Pb 
42 mL 
Hematology 
2 mL 
4Pb 
2Pb 
12 mL 
Total volume extracted from each 
subject 
9 mL 
 
 
54 mL 
-hCG=beta-human chorionic gonadotropin 
a 
-hCG will be tested only in females. 
b 
An additional sample will be required if the baseline visit occurs more than 35 days after screening (applies to Study 
Parts A and B) or as requested by the investigator due to safety reason. 
The above amount of blood quoted for each assessment is an estimate and can vary according to 
the instructions provided by the manufacturer or laboratory for an individual assessment. 
7.3 
Remote Visits and Assessments 
If a subject is unable to participate in a visit on site due to unavoidable dire circumstances (eg, a 
widespread disease outbreak such as the COVID-19 pandemic or natural disaster), remote visits 
may be conducted by phone (eg, collection of AEs and monitoring), video conferencing 
(telehealth/telemedicine), or qualified site staff or qualified designees visiting the participant’s 
residence. Local visits and telemedicine must comply with local, state, and national laws.  
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The principal investigator is expected to evaluate the impact to the safety of the study 
participants and site personnel for subjects to continue. In evaluating such requests, the sponsor 
or designee will give the highest priority to the safety and welfare of the subjects. Subjects must 
be willing and able to continue taking study medication and remain compliant with the protocol. 
Assessments may be performed remotely when necessary. For home healthcare visits, collection 
of clinical laboratory samples (blood specimen collection or other diagnostic tests) may be 
performed by the investigator, qualified site staff, or qualified designees who can visit the trial 
participant’s residence. Such exceptional circumstances require specifications to be documented 
in study records. 
During the dose maintenance phase, subjects may participate in up to 2 consecutive remote 
visits. Note that this is not a cumulative limit on the total number of remote visits. A subject may 
have more than 2 remote visits throughout the course of the study, but cannot have 3 remote 
visits in a row (unless required due to unavoidable dire circumstances, eg, a widespread disease 
outbreak such as the COVID-19 pandemic or natural disaster). 
The type of alternative visit must be recorded in the eCRF. Data collected with alternative 
methods may be handled differently in the final data analyses. This will be documented in the 
statistical analysis plan (SAP).  
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8. 
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT 
8.1 
Definition of Adverse Events, Period of Observation, Recording of Adverse Events 
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product that does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal (investigational) 
product, whether or not related to the medicinal (investigational) product (ICH Guidance E2A 
1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.4. This includes events occurring during the screening period of the 
study, regardless of whether or not IMP was administered. Where possible, a diagnosis rather 
than a list of symptoms should be recorded. If a diagnosis has not been made, then each 
symptom should be listed individually. All AEs should be captured on the AE pages of the 
source documents and in the appropriate eCRF field. In addition to untoward AEs, unexpected 
benefits outside the IMP indication should also be captured on the AE eCRF field. 
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization is achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations will be performed so that 
resolution of the event(s) can be documented. 
8.1.1 Severity Categorization 
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pre-treatment events, after initiation of IMP, must be recorded as new AEs 
(for example, if a subject has mild intermittent dyspepsia before IMP dosing, but the dyspepsia 
becomes severe and more frequent after first dose of IMP has been administered, a new AE of 
severe dyspepsia [with the appropriate date of onset] is recorded on the appropriate eCRF field). 
The medical assessment of severity is determined by using the following definitions: 
Mild: 
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate: 
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject. 
Severe: 
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
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8.1.2 Relationship Categorization 
A physician/investigator must make the assessment of relationship to IMP for each AE. The 
investigator should decide whether, in his or her medical judgment, there is a reasonable 
possibility that the event may have been caused by the IMP. If there is no valid reason for 
suggesting a relationship, then the AE should be classified as “not related.” Otherwise, if there is 
any valid reason, even if undetermined or untested, for suspecting a possible cause-and-effect 
relationship between the IMP and the occurrence of the AE, then the AE should be considered 
“related.” The causality assessment must be documented in the source document. 
The following additional guidance may be helpful: 
Term 
Relationship Definition 
Related 
The temporal relationship between the event and the administration of the 
IMP is compelling and/or follows a known or suspected response pattern to 
that product, and the event cannot be explained by the subject’s medical 
condition, other therapies, or accident. 
Not Related 
The event can be readily explained by other factors such as the subject’s 
underlying medical condition, concomitant therapy, or accident and no 
plausible temporal or biologic relationship exists between the IMP and the 
event. 
8.1.3 Outcome Categorization 
The outcome of AEs must be recorded during the course of the study on the eCRF. Outcomes are 
as follows: 
• Fatal 
• Not recovered/Not resolved 
• Recovered/Resolved 
• Recovered/Resolved with sequelae 
• Recovering/Resolving 
• Unknown 
8.1.4 Symptoms of the Disease Under Study 
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE. 
8.1.5 Clinical Laboratory and Other Safety Evaluations 
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the IMP, a shift of a parameter is 
observed from a normal value to an abnormal value, or a further worsening of an already 
abnormal value.  
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When evaluating such changes, the extent of deviation from the reference range, the duration 
until return to the reference range, either while continuing treatment or after the end of treatment 
with the IMP, and the range of variation of the respective parameter within its reference range, 
must be taken into consideration. 
If, at the end of the treatment periods, there are abnormal clinical laboratory, vital sign, or ECG 
values that were not present at the start of study treatment, then further investigations should be 
performed until the value(s) return(s) to within the reference range or until a plausible 
explanation (eg, concomitant disease) has been found for the abnormal values. 
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE. 
8.1.6 Pregnancy 
All pregnancies are to be reported from the time that informed consent was signed until the 
defined follow-up period stated in Section 7.1.4. 
Any report of pregnancy in a female subject or in a female partner of a male subject must be 
reported within 24 hours to the sponsor’s Global Drug Safety Department using the “Pregnancy 
Report Form.” A copy of the “Pregnancy Report Form” (and any applicable follow-up reports) 
will also be sent to the CRO/sponsor medical monitor. Any female subject who becomes 
pregnant during the study must be withdrawn from the study. 
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days and 1 year 
postpartum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the “Safety Report Form”. Note: An elective 
abortion is not considered an SAE. 
In addition to the above, if the investigator determines that the pregnancy meets the seriousness 
criteria, then it must be reported as an SAE using the “Safety Report Form” as well as the 
“Pregnancy Report Form.” The test date of the first positive serum/urine β-hCG test or 
ultrasound result will determine the pregnancy onset date. 
8.1.7 Abuse, Misuse, Overdose, and Medication Error 
Any abuse, misuse, overdose, or medication error (AMOME) (as defined below) must be 
reported to the sponsor using the AMOME reporting procedure regardless if an AE/SAE 
resulted, as described in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not 
apply to reports of AMOMEs unless an SAE occurs due to the event. 
The categories below are not mutually exclusive as the event can meet more than 1 category. 
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Abuse – Persistent or sporadic intentional intake of IMP when used for a nonmedical purpose 
(eg, to alter one’s state of consciousness or get high) in a manner that may be detrimental to the 
individual and/or society 
Misuse – Intentional use of IMP at any dose that is not as directed or indicated (Note: this 
includes a situation where the IMP is not used as directed at the dose prescribed by the protocol.) 
Overdose – Intentional or unintentional intake of an IMP dose that exceeds in children aged 6 to 
12 years, the specified total daily dose of 4 mg TAK-503 and in adolescents aged 13 to 17 years 
exceeds the maximum allowable dose by baseline weight group as follows: 
• For children weighing 25.0 kg or more, the maximum TAK-503 dose is 4 mg QD 
• For adolescents weighing 34.0 to 41.4 kg, the maximum TAK-503 dose is 4 mg QD 
• For adolescents weighing 41.5 to 49.4 kg, the maximum TAK-503 dose is 5 mg QD 
• For adolescents weighing 49.5 to 58.4 kg, the maximum TAK-503 dose is 6 mg QD 
• For adolescents weighing 58.5 to 91.0 kg, the maximum TAK-503 dose is 7 mg QD 
Medication Error – An error made in prescribing, dispensing, administering, and/or using an 
IMP. For clinical studies, the medication errors that are reportable to the sponsor only are 
specified as follows: 
• Cases of subjects missing IMP doses are not considered reportable as medication errors. 
• Medication errors should be collected/reported for all products under investigation. 
• The administration and/or use of the unassigned treatment is/are always reportable as a 
medication error. 
• The administration and/or use of an expired IMP should be considered as a reportable 
medication error. 
The administration of IMP that has been provided to pediatric subjects should be supervised by 
the parent/LAR/caregiver. 
8.2 
Serious Adverse Event Procedures 
8.2.1 Reference Safety Information 
The reference for safety information for this study is the Intuniv IB, which the sponsor has 
provided to all investigators under a separate cover. 
The reference for safety information for the atomoxetine comparator product in this study is the 
atomoxetine hydrochloride SmPC, which the sponsor has provided to all investigators under a 
separate cover. 
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8.2.2 Reporting Procedures 
All initial and follow-up SAE reports must be reported by the investigator to the sponsor’s 
Global Drug Safety Department UandU the CRO/sponsor medical monitor within 24 hours of first 
awareness of the event. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of AMOMEs (see Section 8.1.7) unless an SAE results. 
For reporting SAEs, the investigator must complete, sign, and date the “Safety Report Form” and 
verify the accuracy of the information recorded on the form with the corresponding source 
documents (Note: Source documents are not to be sent unless requested) and fax or email the 
form to the sponsor’s Global Drug Safety Department. For reporting AMOMEs, the investigator 
must complete, sign, and date the “Special Situation Report Form” via the same method as 
reporting the SAEs. A copy of the “Safety Report Form” (and any applicable follow-up reports) 
will also be sent to the CRO/sponsor medical monitor. 
8.2.3 Serious Adverse Event Definition 
An SAE is any untoward medical occurrence (whether considered to be related to IMP or not) 
that at any dose: 
• Results in death 
• Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe. 
• Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s). 
• Results in persistent or significant disability/incapacity 
• Is a congenital abnormality/birth defect 
• Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
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8.2.4 Serious Adverse Event Collection Time Frame 
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.4 and must be reported 
to the sponsor’s Global Drug Safety Department and the CRO/sponsor medical monitor within 
24 hours of the first awareness of the event. 
In addition, any SAE(s) considered “related” to the IMP and discovered by the investigator at 
any interval after the study has completed must be reported to the sponsor’s Global Drug Safety 
Department within 24 hours of the first awareness of the event. 
8.2.5 Serious Adverse Event Onset and Resolution Dates 
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
date the event is considered chronic. In the case of hospitalizations, the hospital admission and 
discharge dates are considered the onset and resolution dates, respectively. 
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate. 
8.2.6 Fatal Outcome 
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded. 
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another IMP action was previously taken (eg, drug interrupted, reduced, withdrawn), the action 
taken with the IMP should be recorded as “dose not changed” or “not applicable” (if the subject 
never received IMP). The IMP action of “withdrawn” should not be selected solely as a result of 
the subject’s death. 
8.2.7 Safety Reporting to Investigators, Institutional Review Boards or 
Independent Ethics Committees, and Regulatory Authorities 
The sponsor will be responsible for identifying and reporting all suspected unexpected serious 
adverse reactions (SUSARs) and any other applicable SAEs to regulatory authorities, including 
the specific regulatory authority(ies), investigators, and Institutional Review Boards (IRBs) and 
Independent Ethics Committee (IECs) in accordance with national regulations in the countries 
where the study is conducted. Timelines and format of reporting SUSARs to Eudravigilance are 
as follows: 
• SUSARs will be submitted to Eudravigilance Clinical Trial Module in E2B 
• Initial Fatal/or Life-Threatening SUSARs will be reported in 7 days and all other 
SUSARs will be reported in 15 days. 
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9. 
DATA MANAGEMENT AND STATISTICAL METHODS 
9.1 
Data Collection 
The investigators’ authorized site personnel must enter the information required by the protocol 
on the eCRF. A study monitor will visit each site in accordance with the monitoring plan and 
review the eCRF data against the source data for completeness and accuracy. Discrepancies 
between source data and data entered on the eCRF will be addressed by qualified site personnel. 
When a data discrepancy warrants correction, the correction will be made by authorized site 
personnel. Data collection procedures will be discussed with the site at the site initiation visit 
and/or at the investigator’s meeting. Once a subject is randomized, it is expected that site 
personnel will complete the eCRF entry within approximately 3 business days of the subject’s 
visit. 
9.2 
Clinical Data Management 
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database. 
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner. 
9.3 
Data Handling Considerations 
Data that may potentially unblind the treatment assignment in Part A (ie, IMP serum 
concentrations, treatment allocation, and IMP preparation/accountability data) will be handled 
with special care during the data cleaning and review process. These data will be handled in such 
a way that, prior to unblinding, any data that may unblind study team personnel will be presented 
as blinded information or otherwise will not be made available. If applicable, unblinded data may 
be made available to quality assurance representatives for the purposes of conducting 
independent drug audits. 
9.4 
Statistical Analysis Process 
The study will be analyzed by the sponsor or its agent. 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other study 
information such as subject disposition, demographics and baseline characteristics, IMP 
exposure, and prior and concomitant medications. The SAP will also include a description of 
how missing, unused, and spurious data will be addressed. 
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Statistical issues related to the impact of the COVID-19 pandemic or other unavoidable dire 
circumstances will be more fully developed in the SAP. Unless otherwise specified, the primary 
analyses will include all subjects with usable data in the respective analysis sets, ie, FAS, PPS, 
and safety. Subjects identified as being impacted by the COVID-19 pandemic will be classified 
prior to treatment unblinding. Sensitivity analyses focused on the primary endpoint and possibly 
secondary efficacy endpoints, as well as other secondary CANTAB endpoints, will be performed 
to characterize the potential impact of the pandemic on interpretation of the data. 
The SAP will be finalized before unblinding to preserve the integrity of the statistical analysis 
and study conclusions. 
All statistical analyses, unless otherwise specified, will be performed using SAS® version 9.3 or 
later (SAS Institute, Cary, NC 27513). 
9.5 
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee 
No interim analysis, adaptive design, or data monitoring committee is planned for this study. 
9.6 
Sample Size Calculation and Power Considerations 
In this safety study, a descriptive analysis of TAK-503 and atomoxetine will be performed after 
12 months of double-blinded treatment using results from the CANTAB RTI task. The effect of 
TAK-503 on cognition will be assessed and interpreted on the totality of the data. 
The sample size was estimated using the assumed difference of 0 msec with a noninferiority 
margin of 30 msec and a common standard deviation of 63.4 for the comparison between 
TAK-503 and atomoxetine at Week 49A on the RTI in Study Part A. The assumed common 
standard deviation on RTI is based on a prior study SPD503-206: a randomized, double-blinded, 
placebo-controlled efficacy study of TAK-503 in children and adolescents with ADHD. The 
assumed margin of 30 msec is close to the value (29.3 msec) of change from baseline in reported 
results from an adolescent study with atomoxetine (Shang and Gau 2012). The assumed margin 
was used for sample size only and will not be applied in the noninferiority evaluation. 
A total of 216 subjects, 72 subjects per arm, will be required to provide 80% power for a 2-sided 
95% CI. Expecting a nonevaluable rate of 25%, including postrandomization dropout, during the 
double-blinded period, the randomization target has been set to 288 subjects total or 96 subjects 
per treatment arm. 
As of Amendment 7, TAK-503 and atomoxetine will be evaluated after 12 months of 
double-blinded treatment using results from the CANTAB RTI task via the MMRM; however, 
inferential hypothesis testing via the non-inferiority framework at the Week 49A timepoint will 
no longer be performed due to challenges with retaining an evaluable sample size that would 
allow for sufficient power for this comparison. Superiority to placebo comparisons of TAK-503 
and atomoxetine at the 18-week timepoint, separately, will still be performed, as in the original 
protocol. 
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The number of subjects projected to participate in Study Part B is 120, which will be sufficient to 
have at least 90% power to obtain a 95% confidence interval for the change from baseline RTI 
value that excludes the value 0, given the assumed response values for TAK-503 based on Study 
SPD503-206 (mean=20.7, SD=63.11). 
9.7 
Study Analysis Set 
Study analysis population sets are defined as follows: 
• The randomized set will be defined as all randomized subjects in Study Part A. Any 
subject who is not randomized will be considered a screen failure. 
• The double-blind safety set will be defined as all randomized subjects in Study Part A 
who receive ≥1 IMP dose. The double-blind safety set will be used for safety analysis 
(except for CANTAB domains) for Study Part A. 
• The open-label safety set will be defined as all subjects who receive ≥1 dose of TAK-503 
in Study Part B. All safety and efficacy presentations for Study Part B will be based on 
the open-label safety set.  
• The full analysis set (FAS) will be defined as all subjects in the double-blind safety set 
with ≥1 postbaseline CANTAB assessments. 
• The per-protocol set (PPS) will be defined as all subjects in the FAS who complete the 
study and were deemed protocol-compliant. To be protocol-compliant, a subject will not 
have had any significant protocol deviations during the study that could affect the 
assessment of the primary safety endpoint, the CANTAB RTI task. 
9.8 
Study Analyses 
The analyses of the safety CANTAB domains for Study Part A will be based on the FAS and 
PPS. The analyses of efficacy endpoints will be based on the FAS only. Other safety analyses for 
Study Part A will be based on the safety set; the safety and efficacy analysis for Study Part B 
will be based on the open-label safety set. 
The analyses for the primary safety endpoint and other secondary CANTAB endpoints will be 
performed using the MMRM to handle potential missing data.  
If the severity is missing for an AE during treatment, then a severity of “Severe” will be 
assigned. If the relationship to IP is missing for an AE starting during treatment, a causality of 
“Related” will be assigned. The imputed values for severity and relationship will be used for AE 
summaries. 
The APRS assessment was removed as a secondary efficacy endpoint with Protocol 
Amendment 5, due in large part to the COVID-19 pandemic, since many subjects enrolled prior 
to Amendment 5 are missing APRS data. APRS data that has been collected will be summarized 
descriptively (total and subscale scores) as well as presented in a listing. Unless data permits, no 
inferential analysis of this endpoint will be performed. Missing APRS assessments will not be a 
reason for exclusion from any analysis set. 
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In addition, these endpoints will be summarized using region (Europe vs. US) as a subgroup. As 
stratum size for a few countries will likely be very small, region will be used as a factor for any 
subgroup analysis of these endpoints. If data permit, country level subgrouping may also be 
investigated in a similar manner. 
The SAP will provide additional description of how missing, unused, and spurious data will be 
addressed. The SAP will be finalized before unblinding to preserve the integrity of the statistical 
analysis and study conclusion. 
9.8.1 Study Part A: Double-blinded Evaluation 
The primary safety endpoint will be the change from baseline in the CANTAB RTI task. The 
endpoint will be analyzed over the FAS and PPS with a MMRM with treatment arm, visit, sex 
(male or female), age group (6 to 12 years or 13 to 17 years), region (Europe or US) and the 
interaction of treatment with visit as factors, the corresponding baseline value as a covariate, and 
the interaction between baseline value and visit adjusted in the model. The analysis will be done 
for subjects who complete 18 weeks (Week 18A) and for subjects (TAK-503 and atomoxetine 
treatment arms only) who complete Study Part A Week 49A. The least squares (LS) mean 
difference for each treatment arm will be calculated with the 95% confidence interval (CI) 
reported. 
As suggested by European Medicines Agency (EMA), using data up to 18 weeks, the superiority 
to placebo comparisons including TAK-503 and atomoxetine, separately, will be performed 
using MMRM as specified for the primary endpoint. Statistical tests will be conducted at the 
nominal 2-sided 0.05 level without adjustment for multiplicity. If TAK-503 is superior to 
placebo, then a negative impact on cognition can be excluded. If atomoxetine is superior to 
placebo, then assay sensitivity has been demonstrated. 
Results for the TAK-503 and atomoxetine comparison at Week 49A (Visit 14A), which were 
collected for patients who were enrolled prior to the implementation of Protocol Amendment 7, 
will be evaluated in a descriptive fashion, without the performance of inferential hypothesis 
testing. 
Similarly, the other secondary CANTAB safety endpoints will be analyzed in the same manner 
as the primary CANTAB safety endpoint. CANTAB results for all parameters will be evaluated 
together for totality of the CANTAB data. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Treatment-emergent AEs will be summarized by treatment arm across system organ 
class and preferred term. Treatment-emergent AEs leading to withdrawals and SAEs will be 
summarized similarly. To account for differences in expected exposure durations between 
placebo and active arms, time adjusted event rates (per 100 years) will be presented in the overall 
summary tables, as well. 
Other safety data will be descriptively summarized by period, with details provided in the SAP. 
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The efficacy measurement of ADHD-RS-5 will be assessed based on the FAS using the same 
analysis method (MMRM) as the primary safety endpoint. The CGI-I will be summarized. 
The raw scores for each of the 5 domains, 12 subdomains, and the global score of the  
CHIP-CE:PRF will be summarized by treatment arm. 
The C3PS Total Score and scores for the Learning Problem and Executive Functioning subscales 
will be derived and summarized. These scores will be assessed based on the FAS using the same 
analysis method (MMRM) as the primary safety endpoint. 
9.8.2 Study Part B: Open-label Evaluation 
Safety data for Study Part B will be descriptively summarized. Z-scores for CANTAB measures 
will be calculated using age- and gender-specific normative data if available. Both the values for 
observed and z-scores will be summarized descriptively. 
Efficacy and other endpoints will be summarized by time point. 
9.9 
Study Endpoints 
9.9.1 Safety Endpoints 
• The primary safety endpoint will be the change from baseline in the CANTAB RTI task. 
• Secondary safety endpoints will include the following: 
o CANTAB tasks: RVP, SWM between errors, DMS, and SST 
o Tanner stage, weight, height, BMI 
o Vital signs (BP and pulse) and ECG results, and overall safety events 
o BPRS-C total score and scales for Depression, Anxiety, Psychomotor Excitation, 
Behavior Problems, Withdrawal, Thinking Disturbance, and Organicity 
o C-SSRS 
o Specified UKU side effect rating scale items: Asthenia/Lassitude/Increased 
Fatigability, Sleepiness/Sedation, Increased Duration of Sleep, and Orthostatic 
Dizziness 
o PDSS 
9.9.2 
Efficacy Endpoints 
A primary efficacy endpoint is not applicable for this PASS. 
Secondary efficacy endpoints will include the following: 
• ADHD-RS-5 total score and subscale scores for hyperactivity/impulsivity and inattention 
domains 
• CGI-I, calculated from CGI-S 
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• CHIP-CE:PRF 
• C3PS total score and subscale score for Learning Problems and Executive Functioning 
subscale scores (for subjects enrolled with or after Amendment 5) 
Other endpoints: 
• APRS (for subjects enrolled before Amendment 5 who have a baseline APRS assessment 
in Part A) 
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10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES 
This study will be conducted in accordance with this protocol, the ICH Guideline for Good 
Clinical Practice E6 (Integrated Addendum to ICH E6[R1]: Guideline for Good Clinical Practice 
E6[R2] Current Step 4 version, 9 November 2016), Title 21 of the US Code of Federal 
Regulations (US CFR), the EU Clinical Trial Regulation (EU-CTR, 536/2014), and applicable 
national and local regulatory requirements. The name and address of each third-party vendor (eg, 
CRO) used in this study will be maintained in the investigator’s and sponsor’s files, as 
appropriate. 
10.1 
Sponsor’s Responsibilities 
10.1.1 Good Clinical Practice Compliance 
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6[R2] (2016) and any updates, EU-CTR, 
as well as all applicable national and local laws and regulations. 
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities. 
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of IMP for 
shipment to the site. 
10.1.2 Indemnity/Liability and Insurance 
The sponsor of this research adheres to the recommendations of the Association of British 
Pharmaceutical Industry Guidelines. If appropriate, a copy of the indemnity document is 
supplied to the investigator before study initiation, per local country guidelines. 
The sponsor will ensure that suitable clinical study insurance coverage is in place before the start 
of the study. An insurance certificate will be supplied to the investigator as necessary. 
10.1.3 Public Posting of Study Information 
The sponsor will be responsible for posting appropriate study information on applicable 
websites. Information included in clinical study registries can include participating investigators’ 
names and contact information. 
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10.1.4 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees 
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP.  
This requirement will be fulfilled within 6 months of the end of the study completion date for 
pediatric studies and within 1 year for nonpediatric studies as per guidance. The sponsor will 
provide the ECs with a copy of the same summary. 
10.1.5 Study Suspension, Termination, and Completion 
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly. 
The sponsor will make an end-of-study declaration to the relevant competent authority as 
required by EU-CTR. 
10.2 
Investigator’s Responsibilities 
10.2.1 Good Clinical Practice Compliance 
The investigator must undertake to perform the study in accordance with ICH GCP Guideline 
E6[R2] (2016) and any updates, EU-CTR, and applicable regulatory requirements and 
guidelines. 
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period. 
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and sub-investigators will be provided to the 
study sponsor (or designee) before starting the study. 
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study. 
A coordinating principal investigator will be appointed to review the final clinical study report 
for multicenter studies. Agreement with the final clinical study report will be documented by the 
signed and dated signature of the principal investigator (single-site study) or coordinating 
principal investigator (multicenter study), in compliance with Directive 2001/83/EC as amended 
by Directive 2003/63/EC and ICH Guidance E3 (1995). 
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10.2.2 Protocol Adherence and Investigator Agreement 
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator will be responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators will be required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol. 
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all IMP, containers, and other study materials to the sponsor. Upon 
study completion, the investigator will provide the sponsor, IRB/EC, and regulatory agency with 
final reports and summaries as required by (inter)national regulations. 
Communication with local IRBs/ECs, to ensure accurate and timely information will be provided 
during all study periods, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement. 
10.2.3 
Documentation and Retention of Records 
10.2.3.1 
Case Report Forms 
Case report forms will be supplied by the CRO and should be handled in accordance with 
instructions from the sponsor. 
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log. 
All data sent to the sponsor must be endorsed by the investigator. 
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data. 
All data sent to the sponsor must be endorsed by the investigator. 
10.2.3.2 
Recording, Access, and Retention of Source Data and Study Documents 
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, original clinical laboratory reports, and histology and pathology reports. 
All key data must be recorded in the subject’s medical records. 
The investigator must permit authorized representatives of the sponsor; the respective national, 
local, or foreign regulatory authorities (including those from a third country); the IRB/EC; and 
auditors to inspect facilities or perform trial related monitoring and to have direct access to 
original source records relevant to this study, regardless of media. Additionally, investigators 
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must promptly notify the sponsor of any trial related regulatory agency inspections and will be 
expected to provide the sponsor with a copy of the inspection report. 
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the 
eCRF entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc.). Non-study site personnel will not 
disclose any personal information or personal medical information. 
These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US Food and 
Drug Administration (FDA), EMA, UK Medicines and Healthcare products Regulatory Agency) 
or an auditor. 
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor. 
10.2.3.3 
Audit/Inspection 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site. 
10.2.3.4 
Financial Disclosure 
The investigator will be required to disclose any financial arrangement during the study and for 
1 year after, whereby the outcome of the study could be influenced by the value of the 
compensation for conducting the study, or other payments the investigator received from the 
sponsor. The following information will be collected: any significant payments from the sponsor 
or subsidiaries such as a grant to fund ongoing research, compensation in the form of equipment, 
retainer for ongoing consultation or honoraria; any proprietary interest in IMP; any significant 
equity interest in the sponsor or subsidiaries as defined in Section 21 of the FDA Code of Federal 
Regulations 54 2(b) (1998). 
10.3 
Ethical Considerations 
10.3.1 Informed Consent 
It is the responsibility of the investigator to obtain written and/or electronic (if applicable) 
informed consent and assent from all study subjects prior to any study-related procedures 
including screening assessments. All consent and assent documentation must be in 
accordance with applicable regulations and GCP. Each subject or the subject’s legally 
authorized representative, as applicable, is requested to sign and date the subject informed 
consent form or a certified translation if applicable, after the subject has received and read (or 
been read) the written subject information and received an explanation of what the study 
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involves, including but not limited to: the objectives, potential benefits and risk, inconveniences, 
and the subject’s rights and responsibilities.  
A copy of the informed consent and assent documentation (ie, a complete set of subject 
information sheets and fully executed signature pages) must be given to the subject or the 
subject’s legally authorized representative, as applicable. This document may require translation 
into the local language. Signed consent forms must remain in each subject’s study file and must 
be available for verification at any time. 
At the principal investigator’s discretion, informed consent from a potential or current trial 
participant may be obtained remotely via electronic consent [(e)consent]. Subjects consenting via 
(e)consent, where this is available, will electronically sign the consent form (paper consent will 
be used if required by local regulations). Such exceptional instances should be duly justified and 
documented in the study records. 
The (e)consent provides the same information as in written paper consent, but in an electronic 
format that may include multimedia components. It is important to note that (e)consent is not 
meant to replace the important discussion between the participant and site staff. As with 
traditional consenting, the site will continue to own the consenting process. 
A copy of the informed consent document signed by the investigator (and potential witness) 
should be placed in the subject’s trial source documents, with a notation by the investigator of 
how the consent was obtained (eg, telephone or video call). 
Subjects must be reconsented if they reach the age of legal responsibility during the study, based 
on applicable local and national laws. 
Within the source documents, site personnel should document instruction of and understanding 
by the parent/legally authorized representative/caregiver of the safe, responsible storage and 
administration of IMP to the study subject. 
The principal investigator provides the sponsor with a copy of the consent form (and assent form 
where applicable) that was reviewed by the IRB/EC and received their favorable 
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor. 
10.3.2 Institutional Review Board or Ethics Committee 
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation. 
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The applicant for an EC opinion can be the sponsor or investigator for sites within the EU; for 
multicenter studies, the applicant can be the coordinating principal investigator or sponsor, 
according to national provisions. 
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement. 
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue. 
The IMP and IMP supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents. 
For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of the 
progress of the study and of any changes made to the protocol, but in any case at least once a 
year; this can be done by the sponsor or investigator for sites within the EU, or for multicenter 
studies, it can be done by the coordinating principal investigator, according to national 
provisions. The investigator must also keep the local IRB/EC informed of any serious and 
significant AEs. 
10.3.3 Serious Breach of Protocol for EU Clinical Trial Regulation 
The sponsor will notify the concerned EU Member States of a serious breach of EU-CTR or the 
applicable protocol version through the EU portal not later than 7 days after becoming aware of 
the breach. In this instance a “serious breach” is one likely to affect to a significant degree the 
safety and rights of a participant or the reliability and robustness of trial data. All parties 
involved in the conduct of the clinical trial must immediately report any events they encounter 
that might meet the definition of a serious breach. Reporting by sites will be to the contact point 
designated in the Site Manual; reporting by vendors will be to the contact point provided by the 
sponsor. 
10.4 
Privacy and Confidentiality 
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines. 
After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market TAK-503; national or local regulatory authorities; and the IRB(s)/EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities. 
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Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject).  
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and month and year of birth – will be recorded. They may be transferred to, and used in, 
other countries which may not afford the same level of protection that applies within the 
countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities. 
If a serious data breach affecting personal data is detected, the sponsor or its designee and the 
investigator (as applicable) will take appropriate corrective and preventive actions in response. 
These actions will be documented, and the relevant regulatory agency(ies) will be notified as 
appropriate. Where appropriate, the relevant individuals materially affected by the breach would 
also be notified; in the case of study participants, this would be done through the investigator. 
Takeda applies certain measures to protect participants’ personal data and prevent data breaches, 
detailed in a separate document (Compliance with National Requirements on Data Protection). 
10.5 
Study Results/Publication Policy 
The sponsor will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, the sponsor adheres to external 
guidelines (eg, Good Publication Practices) when forming a publication steering committee, 
which is done for large, multicenter phase 2 to 4 and certain other studies as determined by the 
sponsor. The purpose of the publication steering committee is to act as a non-commercial body 
that advises or decides on dissemination of scientific study data in accordance with the scope of 
this policy. 
All publications relating to the sponsor’s products or projects must undergo appropriate technical 
and intellectual property review, with sponsor agreement to publish prior to release of 
information. The review is aimed at protecting the sponsor’s proprietary information existing 
either at the commencement of the study or generated during the study. To the extent permitted 
by the publisher and copyright law, the principal investigator will own (or share with other 
authors) the copyright on his/her publications. To the extent that the principal investigator has 
such sole, joint or shared rights, the principal investigator grants the sponsor a perpetual, 
irrevocable, royalty-free license to make and distribute copies of such publications. 
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form. 
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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results.  
Notwithstanding the foregoing, no publication that incorporates the sponsor’s confidential 
information shall be submitted for publication without the sponsor’s prior written agreement to 
publish and shall be given to the sponsor for review at least 60 days prior to submission for 
publication. If requested in writing by the sponsor, the institution and principal investigator shall 
withhold submission of such publication for up to an additional 60 days to allow for filing of a 
patent application. 
If the study is part of a multicenter study, the first publication of the study results shall be made 
by the sponsor in conjunction with the sponsor’s presentation of a joint, multicenter publication 
of the compiled and analyzed study results. If such a multicenter publication is not submitted to a 
journal for publication by the sponsor within an 18-month period after conclusion, abandonment, 
or termination of the study at all sites, or after the sponsor confirms there shall be no multicenter 
study publication of the study results, an investigator may individually publish the study results 
from the specific site in accordance with this section. The investigator must, however, 
acknowledge in the publication the limitations of the single-site data being presented. 
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications. 
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11. REFERENCES 
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Brown, K. 2003. Neuroscience. New attention to ADHD genes. Science, 301(5630), 160-1. 
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Guy, W. (ed.) 1976. Clinical Global Impression (CGI). Rockville, MD: US Department of 
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Guanfacine and clonidine, alpha 2-agonists, improve paired associates learning, but not 
delayed matching to sample, in humans. Neuropsychopharmacology, 20(2), 119-30. 
Kahn, R., Khoury, J., Nichols, W. and Lanphear, B. 2003. Role of dopamine transporter 
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Kollins, S., Lopez, F. A., Vince, B., Turnbow, J., Farrand, K., Lyne, A., et al. 2011. Psychomotor 
functioning and alertness with guanfacine extended release in subjects with attention-
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open-label trial of tomoxetine in pediatric attention deficit hyperactivity disorder. J Child 
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Validity of DSM-IV attention-deficit/hyperactivity disorder for younger children. J Am 
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Scahill, L., Chappell, P., Kim, Y., Schultz, R., Katsovich, L., Shepherd, E., et al. 2001. A 
placebo-controlled study of guanfacine in the treatment of children with tic disorders and 
attention deficit hyperactivity disorder. Am J Psychiatry, 158(7), 1067-74. 
Schacht, A., Escobar, R., Wagner, T. and Wehmeier, P. 2011. Psychometric properties of the 
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Shang, C.-Y. and Gau, S. S.-F. 2012. Improving Visual Memory, Attention, and School Function 
with Atomoxetine in Boys with Attention-Deficit/Hyperactivity Disorder. Journal of 
Child and Adolescent Psychopharmacology, 22(5), 353-63. 
The MTA Cooperative Group 1999. A 14-month randomized clinical trial of treatment strategies 
for attention-deficit/hyperactivity disorder. The MTA Cooperative Group. Multimodal 
Treatment Study of Children with ADHD. Arch Gen Psychiatry, 56(12), 1073-86. 
Wang, M., Ramos, B., Paspalas, C., Shu, Y., Duque, A., Vijayraghavan, S., et al. 2007. 
Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN 
channel signaling in prefrontal cortex. Cell, 129(2), 397-410. 
Wilens, T. and Biederman, J. 1992. The stimulants. Psychiatr Clin North Am, 15(1), 191-222. 
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Willcutt, E. G., Doyle, A. E., Nigg, J. T., Faraone, S. V. and Pennington, B. F. 2005. Validity of 
the executive function theory of attention-deficit/hyperactivity disorder: a meta-analytic 
review. Biol Psychiatry, 57(11), 1336-46. 
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Appendix 1 
Table of Evaluation Scales 
Instruments and scales used in protocol SPD503-401 include the following: 
Scale/Assessment 
Versioning/Date (if applicable) 
Diagnostic and Statistical Manual of Mental 
Disorders, Fifth Edition 
See Appendix 2 
ADHD-Rating Scale-5 for Children and Adolescents 
2016 
Clinical Global Impression 
Severity (baseline of Study Parts A and B only)/1976 
Improvement/1976 
Columbia-Suicide Severity Rating Scale 
Baseline/Screening, 1/14/2009 
Since Last Visit, 1/14/2009 
Brief Psychiatric Rating Scale for Children 
See Appendix 3 
Pediatric Daytime Sleepiness Scale 
2003 
Udvalg for Kliniske Undersøgelser Side Effect 
Rating Scale 
1987 
Tanner staging 
See Appendix 7 
Academic Performance Rating Scalea 
1991 
Child Health and Illness Profile: Child Edition: 
Parent Report Form 
2004 
Conners 3 Parent Short Formb 
 
Prior Stimulant Medication Questionnaire 
 
a For subjects enrolled under Appendix 4 and earlier who had a baseline Academic Performance Rating Scale assessment in 
Part A. 
b For subjects enrolled under Appendix 5. 
All scales/assessments will be sent to the site separately. Scales/assessments updated during the 
study will be documented in the table as applicable and the updated scale/assessment will be 
provided to the site. 
Raw data will be stored in the archives at the CRO. 
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Appendix 2 
DSM-5 criteria for Attention Deficit/Hyperactivity Disorder 
A. Either (1) or (2): 
(1) Six (or more) of the following symptoms of inattention have persisted for at least 
6 months to a degree that is inconsistent with developmental level and that negatively 
impacts directly on social and academic/occupational activities: 
 
 
Inattention 
a) 
often fails to give close attention to details or makes careless mistakes in 
schoolwork, work or other activities 
b) 
often has difficulty sustaining attention in tasks or play activities 
c) 
often does not seem to listen when spoken to directly 
d) 
often does not follow through on instructions and fails to finish schoolwork, 
chores, or duties in the workplace (not due to oppositional behavior or failure to 
understand instructions) 
e) 
often has difficulty organizing tasks and activities 
f) 
often avoids, dislikes, or is reluctant to engage in tasks that require sustained 
mental effort (such as schoolwork or homework) 
g) 
often loses things necessary for tasks or activities (eg, toys, school assignments, 
pencils, books, or tools) 
h) 
is often easily distracted by extraneous stimuli 
i) 
is often forgetful in daily activities 
(2) Six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for 
at least 6 months to a degree that is inconsistent with developmental level and that 
negatively impacts directly on social and academic/occupational activities: 
 
 
Hyperactivity 
1. 
often fidgets with hands or feet or squirms in seat 
2. 
often leaves seat in classroom or in other situations in which remaining seated is 
expected 
3. 
often runs about or climbs excessively in situations in which it is inappropriate 
(in adolescents or adults, may be limited to subjective feelings of restlessness) 
4. 
often has difficulty playing or engaging in leisure activities quietly 
5. 
is often “on the go” or often acts as if “driven by a motor” 
6. 
often talks excessively 
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Impulsivity 
7. 
often blurts out answers before questions have been completed 
8. 
often has difficulty awaiting turn 
9. 
often interrupts or intrudes on others (eg, butts into conversations or games) 
B. Several inattentive or hyperactive-impulsive symptoms were present prior to age 12 years. 
C. Several impairments from the symptoms are present in 2 or more settings (e.g., at home, 
school, or work; with friends or relatives; in other activities). 
D. There is clear evidence that the symptoms interfere with, or reduce the quality of, social, 
academic, or occupational functioning  
E. The symptoms do not occur exclusively during the course of Schizophrenia or another 
Psychotic Disorder and are not better explained by another mental disorder (e.g., Mood 
Disorder, Anxiety Disorder, Dissociative Disorder, Personality Disorder, substance 
intoxication or withdrawal). 
Code based on type: 
314.01 Attention-Deficit/Hyperactivity Disorder, Combined Presentation: 
 
 
if both Criteria A1 and A2 are met for the past 6 months 
314.00 Attention-Deficit/Hyperactivity Disorder, Predominately Inattentive Presentation: 
 
 
if Criterion A1 is met but Criterion A2 is not met for the past 6 months 
314.01 Attention-Deficit/Hyperactivity Disorder, Predominately Hyperactive-Impulsive 
Presentation: if Criterion A2 is met but Criterion A1 is not met for the past 6 months 
From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Copyright 2013 
American Psychiatric Association. 
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Appendix 3 
Brief Psychiatric Rating Scale for Children 
From Hughes (2008) 
REVISED BPRS-C WITH DESCRIPTIVE ANCHORS ADDED 
 
Component Code:  
 
Local Case Number: 
  
Client’s Name: 
 
 
Date Completed: 
 
 
Completed By: 
 
 
Not 
Present
Very Mild 
Mild 
Moderate 
Mod. 
Severe
Severe 
Extremely 
Severe
1. 
Uncooperativeness - negative, uncooperative, resistant, difficult 
to manage. 
Not present: Cooperative, pleasant 
Mild: Occasionally refuses to comply with rules and expectations, in only one situation 
or setting. 
Moderate-severe: Persistent failure to comply with rules/expectations in more than one 
setting. Causes frequent impairment in functioning. 
Extremely Severe: Constantly refuses to comply with rules and expectations, 
delinquent behaviors, running away. Causes severe impairment in functioning in 
most situations/settings. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
2. 
Hostility - angry or suspicious affect, belligerence, accusations 
& verbal condemnation of others. 
Not present: Cooperative, pleasant. 
Mild: Occasionally sarcastic, loud, guarded, quarrelsome. Causes mild dysfunction in 
one situation or setting. 
Moderate-severe: Causes frequent impairment in several situations/settings. 
Extremely Severe: Assaultive, destructive. Causes severe impairment in functioning in 
most situations/settings. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
3. 
Manipulativeness - lying, cheating, exploitive of others. 
Not present: Not at all. 
Mild: Occasionally gets in trouble for lying, may cheat on occasions. 
Moderate-severe: Frequently lies/cons/manipulates people he/she knows. Causes 
frequent impairment in functioning in several situation/settings. 
Extremely Severe: Constantly relates to others in an exploitive/manipulative manner, 
cons strangers out of money/situations. Cause severe impairment in functioning in 
most situations/settings. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
4. 
Depressed Mood - sad, tearful, depressive demeanor. 
Not present: Occasionally/quickly disappears. 
Mild: Sustained periods/excessive for event. 
Moderate-severe: Unhappy most of the time/no precipitant. 
Extremely Severe: Unhappy all of the time/psychic pain. Causes severe impairment in 
functioning. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
5. 
Feelings of Inferiority - lacking self-confidence, self-
depreciatory, 
feeling of personal inadequacy. 
Not present: Feels good/positive about self. 
Mild: Occasionally feels not as good as others/deficits in one area. 
Moderate-severe: Feels others are better than they are. Gives negative, bland 
answers, can’t think of anything good about themselves. 
Extremely Severe: Constantly feels others are better. Feels worthless/unlovable. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
6. 
Suicidal Ideation - thoughts, threats, or attempts of suicide. 
Not present: Not at all. 
Mild: Thought when angry. 
Moderate-severe: Recurrent thoughts suicide/plans. 
Extremely Severe: Attempted within last month/actively. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
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Component Code:  
 
Local Case Number: 
  
Client’s Name: 
 
 
Date Completed: 
 
 
Completed By: 
 
 
Not 
Present
Very Mild 
Mild 
Moderate 
Mod. 
Severe
Severe 
Extremely 
Severe
7. 
Peculiar Fantasies - recurrent, odd, unusual, or autistic 
ideations. 
Not present: Not at all. 
Mild: Occasionally has elaborate fantasies, imaginary companions. 
Moderate-severe: Frequently has elaborate fantasies (exclude imaginary friends). 
Interferes occasionally with perception of reality. 
Extremely Severe: Often absorbed in elaborate fantasies, has a difficult time 
distinguishing reality from fantasy. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
8. 
Delusions - ideas of reference, persecutory or grandiose 
delusions. 
Not present: No delusions or ideas of reference. 
Mild: Occasionally feels strangers may be looking/talking/laughing about them. 
Moderate-severe: Frequent distortion of thinking, mistrust, suspicious of others. 
Extremely Severe: Mistrusts/suspicious of everyone/thing. Can’t distinguish from 
reality. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
9. 
Hallucinations - visual, auditory, or other hallucinatory 
perceptions. 
Not present: No visual, auditory, sensory experiences. 
Mild: Hears name called, experiences after an event, active/vivid imagination. 
Moderate-severe: Definite experienced auditory (voices either command or not 
command?), visual (daytime, or several incidences), sensory (specific others). 
Extremely Severe: Constantly experiences auditory (commanding voices), visual 
(images are present during interview), or other experiences or perceptions. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
10. 
Hyperactivity - excessive energy expenditure, frequent changes 
in posture, perpetual motion. 
Not present: Slight restlessness, fidgeting. No impact on functioning. 
Mild: Occasional restlessness, fidgeting, frequent changes of posture. Noticeable, but 
does not cause impairment in functioning. 
Moderate-severe: Excessive energy, movement, cannot stay still or seated. Causes 
dysfunction on numerous occasions/situations. Seeks help for behaviors. 
Extremely Severe: Continuous motor excitement, cannot be stilled. Causes major 
interference in functioning on most occasions/situations. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
11. 
Distractibility - poor concentration, shortened attention span, 
reactivity to peripheral stimuli. 
Not present: Performance consistent with ability. 
Mild: Occasionally daydreams, easily distracted. Is able to focus with prompting. 
Moderate-severe: Frequently has trouble concentrating, avoids mental tasks, 
disruptive. Needs frequent assistance to stay focused. Causes decreased 
performance. 
Extremely Severe: Constant, needs 1:1 assistance to stay focused. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
12. 
Speech or Voice Pressure - loud, excessive, or pressured 
speech. 
Not present: Not at all. 
Mild: Noticeably more verbose than normal, conversation is not strained.  
Moderate-severe: Very verbose or rapid, making conversation strained or difficult to 
maintain. 
Extremely Severe: Talks rapidly, continuously and cannot be interrupted. Conversation 
is extremely difficult or impossible. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
13. Underproductive Speech - minimal, sparse inhibited verbal 
response pattern, or weak low voice. 
Not present: Not at all. 
Mild: Occasionally conveys little information because of minimal speech, vague, 
sparse, low or weak voice.  
Moderate-severe: Persistently the client is vague, low or weak voice, in which at least 
1/4 - 1/2 of the conversation comprehension is impaired. 
Extremely Severe: On numerous occasions/situations conversation is severely 
impaired. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
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Component Code:  
 
Local Case Number: 
  
Client’s Name: 
 
 
Date Completed: 
 
 
Completed By: 
 
 
Not 
Present
Very Mild 
Mild 
Moderate 
Mod. 
Severe
Severe 
Extremely 
Severe
14. Emotional Withdrawal – unspontaneous relations to examiner, 
lack of peer interaction, hypoactivity. 
Not present: Not at all. 
Mild: Occasionally is unresponsive, sometimes refuses peer interactions.  
Moderate-severe: Frequently unresponsive, lacks peer interaction, hypoactive. 
Interferes with relationships. 
Extremely Severe: Constantly oblivious to those around. Preoccupied facial 
expressions, does not respond to questions or look at interviewer. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
15. 
Blunted Affect – deficient emotional expression, blankness, 
flatness of affect.  
Not present: Not at all.  
Mild: Some flattening of affect. Occasionally shows emotional response during 
interview (smiles, laughs, tearful). 
Moderate-severe: Considerable flattening. Frequently the client does not show 
emotional response (does not smile, laugh, look, cry). 
Extremely Severe: Constantly flat. The client does not show emotional response (does 
not smile, laugh, look, cry). 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
16. 
Tension – nervousness, fidgetiness, nervous movements of 
hands or feet. 
Not present: Not at all. 
Mild: Occasionally feels nervous or fidgets. Can be relaxed or reassured. 
Moderate-severe: Most days/time feels nervous/fidgety. Causes mental or physical 
distress. 
Extremely Severe: Pervasive and extreme nervousness, fidgeting, nervous movements 
of hands or feet. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
17. 
Anxiety – clinging behavior, separation anxiety, preoccupation 
with anxiety topics, fears or phobias. 
Not present: Not at all. 
Mild: Occasionally worries (at least 3 times a week) about anticipated/current events, 
separation, fears or phobias. These worries appear excessive for situation. 
Moderate-severe: Most days/time worries about at least 2 life circumstances, or 
anticipated/current events. 
Extremely Severe: Pervasive and extreme worry about most everything, real or 
imagined. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
18.  Sleep Difficulties – inability to fall asleep, intermittent 
awakening, shortened sleep time. 
Not present: Not at all. 
Mild: Some difficulty (at least 1 hour initial, no middle or terminal insomnia). 
Moderate-severe: Definitely has difficulty (at least 2 hours initial insomnia, any middle, 
or terminal lasting up to half an hour). Feelings of unrestorative sleep, evidence of 
mild circadian reversal. 
Extremely Severe: Claims to never sleep, feels exhausted the rest of the day, or severe 
circadian reversal. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
19. 
Disorientation – confusion over persons, places or things. 
Not present: Not at all. 
Mild: Occasionally appears confused or puzzled. Easily reacquainted with surroundings 
when prompted. 
 Moderate-severe: Frequently appears puzzled, confused, baffled regarding familiar 
surroundings, people, or things. 
Extremely Severe: Constantly confused. Perplexed. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
20. 
Speech Deviance – inferior level of speech development, 
underdeveloped vocabulary, mispronunciations. 
Not present: Not at all. 
Mild: Occasionally instances of distorted or idiosyncratic speech. Little impairment of 
understandability. 
 Moderate-severe: Frequent instances with definite impairment in understandability. 
Extremely Severe: Constant speech distortion, almost incomprehensible. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
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Component Code:  
 
Local Case Number: 
  
Client’s Name: 
 
 
Date Completed: 
 
 
Completed By: 
 
 
Not 
Present
Very Mild 
Mild 
Moderate 
Mod. 
Severe
Severe 
Extremely 
Severe
21. 
Stereotypy – rhythmic, repetitive, manneristic movements or 
posture. 
Not present: Not at all. 
Mild: Occasionally displays rhythmic, repetitive, manneristic movements or posture. 
Moderate-severe: Frequent rhythmic, repetitive, manneristic movements or posture. 
Extremely Severe: Most of the time (<50%) displays rhythmic, repetitive, manneristic 
movement or posture. 
0 
□ 
1 
□ 
2 
□ 
3 
□ 
4 
□ 
5 
□ 
6 
□ 
TOTAL SCORE: 
____ 
(add up each item – record on front page as well) 
 
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Appendix 4 
Prior Stimulant Medication Questionnaire  
[The following will be collected for those subjects who have Utaken any stimulantU 
medications prior to this study. This form only needs to be completed for the most 
recent stimulant medication taken. The clinician or study coordinator will complete this 
questionnaire based upon an interview with the parent/caregiver at the Screening visit.] 
--------------------------------------------------------------------------------------------------------------------------------- 
Please record the subject’s/parent’s/caregiver’s responses below (answers A-H). 
Subjects/parents/caregivers may have multiple reasons for stopping stimulant medication. Please record 
UallU the reasons mentioned (mark all that apply in the list below) 
 
Coordinator: Please ask the subject/parent/caregiver “why did you decide to stop taking the last 
stimulant medication?”.  
Name of most recent stimulant medication(s): ______________________________________ 
 
[ ]  
Because the prior medication was not effective. Coordinator: if the reason was lack of 
effectiveness please probe “why did you feel the stimulant was not effective?” and mark the 
subject/parent/caregiver response below: 
[ ] Prior ADHD medication did not work (ie, did not feel the medication did anything for the 
subject). 
[ ]  The prior ADHD medication effect didn’t last long enough 
[ ] The prior ADHD medication wasn’t optimal (the medication worked but not as well as 
expected) per the subject/parent/caregiver 
[ ]  The prior ADHD medication wasn’t optimal (the medication worked but not as well as 
expected) per the subject’s physician 
[ ]  Other, please explain: ___________________________________ 
 
[ ] 
Because the ADHD medication had side effects 
[ ]  
Could not afford paying for the medication 
[ ] 
Wanted to switch to another medication. Specify: 
 
[ ] Methylphenidate hydrochloride short acting/immediate release 
 
  
[ ] Methylphenidate hydrochloride long acting/prolonged release/Modified release 
[ ] Dexamphetamine sulphate short acting/immediate release  
[ ] Dexamphetamine sulphate long acting/prolonged release 
[ ] Mixed amphetamine salts short acting/immediate release  
 
[ ] Mixed amphetamine salts long acting/prolonged release 
[ ] Atomoxetine hydrochloride 
[ ] Guanfacine hydrochloride short acting/immediate release 
[ ] Guanfacine hydrochloride long acting/prolonged release 
[ ] Clonidine short acting/immediate release 
[ ] Clonidine long acting/prolonged release 
[ ] Other, please specify: ____________________________________ 
 
[ ]  
Wanted to stop taking a stimulant ADHD medication 
[ ]  
Wanted to stop taking any medication for ADHD  
[ ]  
Wanted to switch to non-pharmacological interventions to treat ADHD 
[ ]  
Other, please specify: ________________________________________ 
 
 
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Appendix 5.1 
Boys’ Stature-for-age and Weight-for-age Percentiles 
 
 
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Appendix 6.1 
Girls’ Stature-for-age and Weight-for-age Percentiles 
 
 
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Appendix 7 
Tanner Staging Self-assessment 
Self-assessment in this study is defined as subjects or parents indicating which drawing of the 
scale corresponds to the subject’s sexual maturation stage at the time of the specific visit. For 
this purpose, site staff (the principal investigator or a designee) reads the guidance and the text 
corresponding to each drawing and asks the subject or parent to choose the applicable drawing. 
The response from the subject or the parent will be documented in the Tanner Staging Form by 
the site staff. 
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Appendix 7.1 
Tanner stage for males 
 
 
 
 
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Appendix 7.2 
Tanner stage for females 
 
 
 
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Appendix 8 
Examples of Clinically relevant CYP3A4 Inhibitors and Inducers 
CYP3A4/5 Inhibitors 
CYP3A4/5 Inducers 
Macrolide Antibiotics 
Carbamazepine 
Clarithromycin 
Barbiturates (eg, phenobarbital) 
Erythromycin 
Phenytoin 
Troleandomycin 
Rifabutin 
Telithromycin 
Oxcarbazepine 
HIV Protease Inhibitors 
Rifampin 
Indinavir 
St. John’s Wort 
Nelfinavir 
Troglitazone (redrawn due to liver AE) 
Ritonavir, saquinavir 
HIV Antivirals 
Calcium Channel Blockers 
Efavirenz 
Diltiazem 
Nevirapine 
Verapamil 
Other 
Miscellaneous 
Glucocorticoids 
Amiodarone 
Modafinil 
Cimetidine 
Miscellaneous 
Fluvoxamine 
Fluconazole 
Itraconazole 
Aprepitant 
Ketoconazole 
Boceprevir 
Mibefradil 
Ciprofloxacin 
Nefazodone 
Delaviridine 
Grapefruit juice or fresh grapefruit 
Fluvoxamine 
Gestodene 
Imatinib 
Mifepristone 
Norfloxacin 
Norfluoxetine 
Telaprevir 
Voriconazole 
Starfruit 
Flockart D. Drug Interactions. DRUG-INTERACTION TABLE (CYTOCHROME P450 SYSTEM) 
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