Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Keywords: ADHD SHP465 Hyperactivity
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 141
Healthy volunteers: no

Brief summary:
The purpose of the study is to evaluate the long-term safety and tolerability of SHP465 at 6.25 milligram (mg) in children aged 4 to 12 years diagnosed with Attention-Deficit/Hyperactivity Disorder (ADHD).

Detailed description:

Arms:
arm 1: Group A participants who have been rolled-over from antecedent SHP465 studies and Group B participants who will be newly enrolled into the study will receive SHP465 capsule 6.25 mg orally once daily for 360 days.

Interventions: intervention 1: SHP465
Intervention descriptions: intervention 1: SHP465 capsule will be administered in a dose of 6.25 mg orally once daily for 360 days.

Protocol document:
Prot_000.pdf: 
PROTOCOL: SHP465-308
TITLE:
A Phase 3, Open-label, Multicenter, 12-Month Safety and Tolerability 
Study of SHP465 in Children Aged 4 to 12 Years Diagnosed with 
Attention-deficit/Hyperactivity Disorder
DRUG:
SHP465, mixed salts of a single-entity amphetamine
IND:
66,329
EUDRACT NO.:
Non-EUDRACT
SPONSOR:
Shire Development LLC
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR:
, MD
PROTOCOL 
HISTORY:
Version 2.0: 18 May 2018
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure 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 Shire.
 




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EMERGENCY CONTACT INFORMATION
In the event of an SAE, the investigator must fax or e-mail the Shire Clinical Trial Serious 
Adverse Event Form within 24 hours to the Shire Global Drug Safety Department.  Applicable 
fax numbers and e-mail address can be found on the form (sent under separate cover).  A copy of 
the Shire Clinical Trial Serious Adverse Event Form must also be sent to the CRO/Shire medical 
monitor by e-mail using the details below.
E-mail address: 
 (electronic query submission site)
For protocol- or safety-related issues during normal business hours 8AM-5PM eastern 
standard time, the investigator must contact the PPD medical monitor:
, MD
Phone: 
Mobile: 
 (callers will be transferred to the medical monitor’s cell phone)
For protocol- or safety-related issues outside of normal business hours, the investigator must 
contact the PPD medical monitor:
Phone:  


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PRODUCT QUALITY COMPLAINTS
Investigators are required to report investigational product quality complaints to Shire within 
24 hours. This includes any instances wherein the quality or performance of a Shire product 
(marketed or investigational) does not meet expectations (eg, inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (eg, wrong product such that the label and contents are different 
products). For instructions on reporting AEs related to product complaints, see Section 8.
Please use the information as follows as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
Email Address
North and South America
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)




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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
AMENDMENT SUMMARY AND RATIONALE ........................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
ABBREVIATIONS .......................................................................................................................11
STUDY SYNOPSIS ......................................................................................................................12
STUDY SCHEDULES..................................................................................................................17
1
BACKGROUND INFORMATION.......................................................................................23
1.1
Indication and Current Treatment Options...............................................................23
1.2
Product Background and Clinical Information ........................................................24
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................25
2.1
Rationale for the Study.............................................................................................25
2.2
Study Objectives ......................................................................................................25
2.2.1
Primary Objective..................................................................................................25
2.2.2
Secondary Objectives.............................................................................................25
3
STUDY DESIGN ...................................................................................................................26
3.1
Study Design and Flow Chart ..................................................................................26
3.2
Duration and Study Completion Definition .............................................................27
3.3
Sites and Regions .....................................................................................................27
4
STUDY POPULATION.........................................................................................................28
4.1
Inclusion Criteria......................................................................................................28
4.2
Exclusion Criteria.....................................................................................................29
4.2.1
Female Contraception............................................................................................31
4.2.2
Male Contraception................................................................................................31
4.3
Discontinuation of Subjects .....................................................................................31
4.3.1
Management of Blood Pressure and Pulse During the Study................................32
4.3.1.1
Systolic and Diastolic Blood Pressure ...................................................32
4.3.1.2
Pulse .......................................................................................................32
4.3.2
Reasons for Discontinuation..................................................................................33
4.3.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit.................................33
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................34
5.1
Prior Treatment ........................................................................................................34
5.2
Concomitant Treatment............................................................................................34


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5.2.1
Permitted Treatment...............................................................................................34
5.2.2
Prohibited Treatment .............................................................................................34
6
INVESTIGATIONAL PRODUCT ........................................................................................36
6.1
Identity of Investigational Product...........................................................................36
6.1.1
Blinding the Treatment Assignment......................................................................36
6.2
Administration of Investigational Product(s)...........................................................36
6.2.1
Interactive Response Technology for Investigational Product Management ........36
6.2.2
Allocation of Subjects to Treatment ......................................................................36
6.2.3
Dosing....................................................................................................................36
6.2.4
Unblinding the Treatment Assignment..................................................................37
6.3
Labeling, Packaging, Storage, and Handling ...........................................................37
6.3.1
Labeling .................................................................................................................37
6.3.2
Packaging...............................................................................................................38
6.3.3
Storage ...................................................................................................................38
6.4
Drug Accountability.................................................................................................39
6.5
Subject Compliance..................................................................................................40
7
STUDY PROCEDURES........................................................................................................41
7.1
Study Schedule.........................................................................................................41
7.1.1
Screening and Washout Period (Group A and Group B).......................................41
7.1.1.1
Screening Visit (Visit 1) for Group B ....................................................42
7.1.1.2
Washout Telephone Call (Group B).......................................................43
7.1.1.3
Baseline Visit (Visit 2) Group A............................................................43
7.1.1.4
Baseline Visit (Visit 2) Group B............................................................44
7.1.2
Treatment Period (Group A and Group B) ............................................................45
7.1.2.1
Treatment Period (Visits 5 to 16/Early Termination) ............................45
7.1.3
Safety Follow-up Period (Group A and Group B).................................................46
7.1.4
Additional Care of Subjects After the Study .........................................................47
7.2
Study Evaluations and Procedures ...........................................................................47
7.2.1
Demographic and Other Baseline Characteristics .................................................47
7.2.1.1
Mini International Neuropsychiatric Interview for Children and 
Adolescents ............................................................................................47
7.2.2
Efficacy..................................................................................................................48
7.2.2.1
The ADHD-Rating Scale-5 ....................................................................48
7.2.2.2
Clinical Global Impression.....................................................................48
7.2.3
Safety .....................................................................................................................49
7.2.3.1
Medical and Medication History............................................................49
7.2.3.2
Physical Examination (Including Height and Weight) ..........................49
7.2.3.3
Adverse Event Collection.......................................................................50


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7.2.3.4
Vital Signs..............................................................................................50
7.2.3.5
Height and Weight .................................................................................51
7.2.3.6
Clinical Laboratory Evaluations.............................................................51
7.2.3.7
Pregnancy Test .......................................................................................53
7.2.3.8
Electrocardiogram ..................................................................................55
7.2.3.9
Post Sleep Questionnaire........................................................................55
7.2.3.10
Children’s Sleep Habits Questionnaire ..................................................55
7.2.3.11
Columbia-Suicide Severity Rating Scale-Baseline Version ..................56
7.2.3.12
Suitability of the Subject to Remain in the Study..................................56
7.2.4
Volume of Blood to Be Drawn From Each Subject ..............................................57
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................58
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................58
8.1.1
Severity Categorization..........................................................................................58
8.1.2
Relationship Categorization...................................................................................59
8.1.3
Outcome Categorization ........................................................................................59
8.1.4
Symptoms of the Disease Under Study .................................................................59
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................59
8.1.6
Pregnancy...............................................................................................................60
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................60
8.2
Serious Adverse Event Procedures ..........................................................................61
8.2.1
Reference Safety Information................................................................................61
8.2.2
Reporting Procedures.............................................................................................61
8.2.3
Serious Adverse Event Definition .........................................................................62
8.2.4
Serious Adverse Event Collection Time Frame.....................................................62
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................63
8.2.6
Fatal Outcome........................................................................................................63
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................63
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................64
9.1
Data Collection.........................................................................................................64
9.2
Clinical Data Management.......................................................................................64
9.3
Data Handling Considerations..................................................................................64
9.4
Statistical Analysis Process......................................................................................64
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......65
9.5.1
Interim Analysis.....................................................................................................65
9.5.2
Data Monitoring Committee..................................................................................65
9.6
Sample Size Calculation and Power Considerations................................................65


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9.7
Study Population ......................................................................................................65
9.8
Efficacy Analyses.....................................................................................................65
9.9
Safety Analyses........................................................................................................66
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................68
10.1
Sponsor’s Responsibilities .......................................................................................68
10.1.1 Good Clinical Practice Compliance.......................................................................68
10.1.2 Public Posting of Study Information......................................................................68
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................68
10.1.4 Study Suspension, Termination, and Completion..................................................68
10.2
Investigator’s Responsibilities .................................................................................69
10.2.1 Good Clinical Practice Compliance.......................................................................69
10.2.2 Protocol Adherence and Investigator Agreement..................................................69
10.2.3 Documentation and Retention of Records.............................................................70
10.2.3.1
Case Report Forms.................................................................................70
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................70
10.2.3.3
Audit/Inspection.....................................................................................70
10.2.3.4
Financial Disclosure...............................................................................71
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation............................71
10.3
Ethical Considerations..............................................................................................71
10.3.1 Informed Consent...................................................................................................71
10.3.2 Institutional Review Board or Ethics Committee..................................................72
10.4
Privacy and Confidentiality......................................................................................72
10.5
Study Results/Publication Policy .............................................................................73
11 REFERENCES .......................................................................................................................75
12 APPENDICES ........................................................................................................................77
APPENDIX 1
PROTOCOL HISTORY ........................................................................78
APPENDIX 2
DIAGNOSTIC CRITERIA/DISEASE CLASSIFICATION.................79
Appendix 2.1
DSM-5 Criteria.......................................................................................80
Appendix 2.2
Boys’ Stature-for-Age and Weight-for-Age Percentiles........................82
Appendix 2.3
Blood Pressure Levels for Boys by Age and Height Percentile.............83
Appendix 2.4
Girls’ Stature-for-Age and Weight-for-Age Percentiles ........................85
Appendix 2.5
Blood Pressure Levels for Girls by Age and Height Percentile.............86
APPENDIX 3
SCALES AND ASSESSMENTS...........................................................88


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LIST OF TABLES
Table 1:
Schedule of Assessments for Group A..........................................................17
Table 2:
Schedule of Assessments for Group B ..........................................................20
Table 3:
Common Excluded Treatments and Associated Washout 
Period - Relative to Baseline Visit (Visit 2)..................................................35
Table 4:
Volume of Blood to Be Drawn From Each Subject......................................57
LIST OF FIGURES
Figure 1:
Study Design Flow Chart for Group A..........................................................26
Figure 2:
Study Design Flow Chart for Group B..........................................................27


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ABBREVIATIONS
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS-5
Attention-deficit/Hyperactivity Disorder Rating Scale 5
AE
adverse event
BMI
body mass index
CGI
Clinical Global Impressions
CGI-I
Clinical Global Impressions – Improvement
CGI-S
Clinical Global Impressions – Severity of Illness
CRF
case report form
CRO
contract research organization
CSHQ
Children’s Sleep Habits Questionnaire
C-SSRS
Columbia-Suicide Severity Rating Scale
DMC
data monitoring committee
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
EC
Ethics Committee
ECG
electrocardiogram
ET
early termination
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
IRB
Institutional Review Board
IWRS
interactive web response system
LAR
legally authorized representative
MINI-KID
Mini International Neuropsychiatric Interview for Children and 
Adolescents
PSQ
Post Sleep Questionnaire
PK
pharmacokinetic(s)
SAE
serious adverse event
SAP
statistical analysis plan
TEAE
treatment-emergent adverse event
US
United States


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STUDY SYNOPSIS
Protocol number: SHP465-308
Drug: SHP465, mixed salts of a single-entity amphetamine
Title of the study: A Phase 3, Open-label, Multicenter, 12-Month, Safety and Tolerability Study of SHP465 in 
Children Aged 4 to 12 Years Diagnosed with Attention-deficit/Hyperactivity Disorder
Number of subjects (total and for each treatment arm):
Approximately 145 subjects will be enrolled into this study to ensure 60 subjects complete at least 6 months of study 
treatment. Subjects will enroll into this study either directly or from antecedent studies SHP465-112 or SHP465-309. 
The sample size was established to provide long term safety data in this population and will include at least 
40 subjects aged 4-5 years at the time of informed consent in the antecedent trial or this trial, if directly enrolled.
Investigators: Multicenter study
Sites and region: Approximately 50 sites in the United States (US)
Study period (planned): 2017-2019
Clinical phase:
3
Objectives:
Primary: To evaluate the long-term safety and tolerability of SHP465 at 6.25 mg administered as a daily morning 
dose in children aged 4-12 years, inclusive, diagnosed with Attention-deficit/Hyperactivity Disorder (ADHD).
The evaluation of safety and tolerability will be based on the occurrence of treatment-emergent adverse events 
(TEAEs), evaluation of vital signs (systolic and diastolic blood pressure and pulse), weight, height, body mass index 
(BMI); clinical laboratory and electrocardiogram (ECG) results; sleep assessment (Post Sleep Questionnaire [PSQ] 
and Children’s Sleep Habits Questionnaire [CSHQ]); and responses to the Columbia-Suicide Severity Rating Scale 
(C-SSRS).
Secondary: 
1.
To describe the long-term efficacy of SHP465 using the clinician-administered ADHD Rating Scale 5 
(ADHD-RS-5) Child, Home Version.
2.
To describe the long-term efficacy of SHP465 using the Clinical Global Impressions–Improvement (CGI-I) 
scale.
Rationale:
The purpose of the study is to evaluate the long-term safety of SHP465 in children aged 4 to 12 years diagnosed 
with ADHD. Results from this study will provide important information on the long-term safety, tolerability, and 
efficacy of SHP465 at lower doses in the preschool/pediatric ADHD population. 
Investigational product, dose, and mode of administration:
SHP465 will be provided as 6.25 mg capsules.
The parent/legally authorized representative (LAR) will be instructed to dispense 1 capsule to the subject daily 
throughout the study at 7:00 AM (±2 hours). SHP465 will be administered in 1 of the following ways:

Swallow SHP465 capsules whole, or

Open capsule and sprinkle the entire contents on applesauce.
The sprinkled applesauce should be consumed immediately; it should not be stored. Subjects should take the 
sprinkled applesauce in its entirety without chewing.
 
 


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Methodology:
This study is a Phase 3 long-term, open-label, multicenter, safety and tolerability study in children (aged 4-12 years, 
inclusive, at the time of consent was obtained in the antecedent study [SHP465-112 or SHP465-309] or at the time 
of consent into this study if directly enrolled) with ADHD.
Subjects enrolled in this study will be divided into 2 groups based on participation in antecedent studies as follows:

Subjects in Group A are those who have been rolled-over from antecedent studies (SHP465-112 or 
SHP465-309). These subjects do not need additional screening and washout procedures. 

Subjects in Group B will be newly enrolled subjects who will be required to undergo full screening and 
washout before enrollment.
Subjects in Group A will participate in the following 2 study periods: (1) treatment period and (2) safety follow-up. 
Subjects in Group B will participate in the following 3 study periods: (1) screening and washout, (2) treatment 
period, and (3) safety follow-up.
For subjects in Group A, the last visit of the antecedent study, SHP465-112 or SHP465-309, will serve as the 
baseline visit (Visit 2) for this study. For subjects in Group B, a screening visit will precede a washout period. 
Subjects aged 4-12 years will receive SHP465 at a fixed dose of 6.25 mg.
Subjects in both groups will be treated and evaluated for 12 months, and visit the site up to 15 times for subjects in 
Group A and up to 16 times for subjects in Group B.
The investigator or designee must obtain written informed consent from the subject's parent/LAR and 
documentation of assent (if applicable) by the subject before any protocol-related procedure is performed. 
Procedures performed at each visit for all subjects are defined in the Study Schedules: Table 1 (Group A) and 
Table 2 (Group B).
Inclusion and exclusion criteria:
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the following criteria (including test 
results):
1.
Subject is male or female aged 4 to 12 years, inclusive, at the time of consent for antecedent SHP465 trials 
(SHP465 112 or SHP465-309) in the ADHD population or at the time of consent for directly enrolled subjects 
into this study.
2.
Subject’s parent or legally authorized representative (LAR) must provide signature of informed consent, and 
there must be documentation of assent (if applicable) by the subject in accordance with the International 
Council on Harmonization (ICH) Good Clinical Practice (GCP) Guideline E6 (1996) and any updates and 
applicable regulations, before completing any study-related procedures. 
3.
Subject and parent/LAR are willing and able to comply with all of the testing and requirements defined in the 
protocol, including oversight of morning dosing. Specifically, the same parent/LAR should be available daily to 
dispense the dose of investigational product for the duration of the study.
4.
For subjects in Group A:

Subject enrolled in the antecedent study SHP465-112 must have completed treatment period and the 
pharmacokinetic (PK) sample collection (at the dose of 6.25 mg) without incidence of a clinically 
significant TEAE.

Subject enrolled in the antecedent study SHP465-309 must have completed the treatment period 
without reporting a clinically significant TEAE that would preclude subsequent exposure to SHP465. 
5.
For subjects in Group B (directly enrolled subjects), the following criteria must be met:

Subject meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 
criteria for a primary diagnosis of ADHD (any subtype) based on a detailed psychiatric evaluation 
using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID)


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
Subject aged 4 to 5 years has an ADHD-RS-5 Child Version Total score of ≥28 (boys) or ≥24 (girls) at 
baseline (Visit 2)

Subject aged 6 to 12 years has an ADHD-RS-5 Child, Home Version Total score of ≥28 at baseline 
(Visit 2)

Subject has a Clinical Global Impression–Severity of Illness score (CGI-S) ≥4 at baseline (Visit 2)

Subject has previously undergone an adequate course of nonpharmacological treatment based on 
investigator judgment (aged 4-5 year olds) OR the subject is not completely satisfied with current 
adequate course of ADHD therapy (aged 6-12 year olds), OR the subject has a severe enough 
condition to consider enrollment without undergoing prior nonpharmacological treatment, based on 
investigator judgment.

Subject functions as an age-appropriate level intellectually, based on investigator judgment.
6.
Subject who is a female and of child-bearing potential must not have a positive serum beta human chorionic 
gonadotropin pregnancy test at the screening visit (Visit 1) and must have a negative urine pregnancy test at the 
baseline visit (Visit 2) and agree to comply with any applicable contraceptive requirements of the protocol.
7.
Subject has lived with the same parent/LAR for at least 6 months.
Exclusion Criteria:
Subjects will be excluded from the study if any of the following exclusion criteria are met at baseline (Visit 2) for 
Group A or at screening (Visit 1) and/or baseline (Visit 2) for Group B. These criteria apply to all subjects 
regardless of participation in an antecedent trial:
1.
Subject was terminated from an antecedent SHP465 trial for noncompliance and/or had a serious TEAE during 
any previous SHP465 trial.
2.
Subject is required to or is anticipated to take any medication that has central nervous system effects or affects 
performance, such as sedating antihistamines and decongestant sympathomimetics, or is a monoamine oxidase 
inhibitor. Stable use of bronchodilator inhalers is not exclusionary.
3.
Subject has a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious process 
requiring antibiotics), disability, or other condition that might confound the results of safety assessments 
conducted in the study or that might increase risk to the subject. Similarly, the subject will be excluded if he or 
she has any additional condition(s) that, in the investigator’s opinion, would prohibit the subject from 
completing the study or would not be in the best interest of the subject. The additional condition(s) would 
include any significant illness or unstable medical condition that could lead to difficulty complying with the 
protocol. Mild, stable asthma is not exclusionary.
4.
Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in the 
investigational product.
5.
Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
6.
Subject has a blood pressure measurement 95th percentile for age, sex, and height at screening (Visit 1) and/or 
baseline (Visit 2).
7.
Subject has a height ≤5th percentile for age and sex at screening (Visit 1) and/or baseline (Visit 2).
8.
Subject has a weight ≤5th percentile for age and sex at screening (Visit 1) and/or baseline (Visit 2).
9.
Subject has a known history of symptomatic cardiovascular disease, structural cardiac abnormality, 
cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac conditions placing them at 
increased vulnerability to the sympathomimetic effects of a stimulant drug.
10. Subject has a history of seizures (other than infantile febrile seizures).
11. Subject has failed to fully respond, based on investigator judgment, to an adequate course of amphetamine 
therapy.
12. Subject is taking any medication that is excluded per the protocol.


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13. Subject had any clinically significant ECG or clinical laboratory abnormalities at the screening (Visit 1) and/or 
baseline visit (Visit 2).
14. Subject has current abnormal thyroid function, defined as abnormal thyroid-stimulating hormone and thyroxine 
at the screening (Visit 1) and/or baseline visit (Visit 2). Treatment with a stable dose of thyroid medication for 
at least 3 months is permitted.
15. Subject has a current, controlled (requiring medication or therapy) or uncontrolled, comorbid psychiatric 
disorder including, but not limited to, any of the following comorbid Axis I disorders and Axis II disorders:

Post-traumatic stress disorder or adjustment disorder

Bipolar disorder, psychosis, schizophrenia or family history of these disorders

Pervasive developmental disorder

Obsessive-compulsive disorder

Serious tic disorder, or a family history of Tourette disorder

Any other disorder that in the opinion of the investigator contraindicates SHP465 or amphetamine 
treatment or confounds efficacy or safety assessments 
16. Subject has a primary sleep disorder (eg, sleep apnea, narcolepsy)
17. Subject has a history or is currently diagnosed with an eating disorder
18. Subject is currently considered a suicide risk in the opinion of the investigator, has previously made a suicide 
attempt, or has a prior history of or currently demonstrating suicidal ideation.
19. Subject has a history of physical, sexual, or emotional abuse.
20. Subject has initiated behavioral therapy within 1 month before baseline (Visit 2). Subject may not initiate 
behavioral therapy during the study.
21. 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 1) or baseline (Visit 2).
22. Subject is female and pregnant or lactating.
23. Subject cannot swallow a pill and/or applesauce or has an allergy to applesauce.
Maximum duration of subject involvement in the study:
Planned duration of screening/washout:

For Group A (subjects from antecedent studies): None

For Group B (directly enrolled subjects): up to 32 days
Planned duration of treatment: 

For Group A (subjects from antecedent studies): 12 months, baseline visit procedures will be used to 
confirm subject eligibility for this study

For Group B (directly enrolled subjects): 12 months
Planned duration of safety follow-up:

For Group A (subjects from antecedent studies): 7 days

For Group B (directly enrolled subjects): 7 days


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Endpoints and statistical analysis:
Analysis Sets

Screened Set: all subjects who have provided informed consent.

Enrolled Set: all subjects who have been assigned a subject identification number.

Safety Set: all enrolled subjects who have taken at least 1 dose of study drug.

Full Analysis Set (FAS): all subjects in the safety set who completed at least 1 postdose efficacy 
assessment using ADHD-RS-5 Total score.
Safety Endpoints
Safety assessments include the occurrence of TEAEs and evaluations of blood pressure, pulse, weight, height, BMI; 
results of clinical laboratory, ECG, and sleep questionnaires (PSQ and CSHQ).
Additionally, the C-SSRS scale will capture the safety of SHP465 related to suicidality.
Efficacy Endpoints
The efficacy endpoint is defined as the change from baseline in the clinician-administered ADHD-RS-5 Total score.
The CGI-I will be a second efficacy and used to determine the proportion of subjects with an “improved” 
measurement based on the CGI-S measured at baseline. The CGI-I categories of “very much improved” and “much 
improved” will be classified as “improved” and all other assessed categories are grouped together as “not 
improved.”
Statistical Methodology for Safety Endpoints
Safety analyses will be summarized using the safety set, and presented by antecedent study treatment group and 
overall for TEAEs, clinical laboratory results, weight, height, BMI, vital signs, ECGs, PSQ, and CSHQ. The 
C-SSRS results will be summarized and listings of the C-SSRS data will be provided for subjects with a positive 
response.
Statistical Methodology for Efficacy Endpoints
The FAS will be used to report the efficacy data. Descriptive summary statistics will be presented by antecedent 
study treatment group and overall for the observed efficacy variables. Change from baseline for the ADHD-RS-5 
Total score at each on-therapy treatment visit will be summarized.
The number and proportion of subjects with an “improved” measurement in CGI-I will be reported at each 
applicable postdose visit. CGI-I scores will also be summarized.


Shire
CONFIDENTIAL
Page 17
Study Protocol Amendment 2
SHP465-308
18 May 2018
STUDY SCHEDULES
Table 1:
Schedule of Assessments for Group A
Period
Baseline
Treatment Period
1-Week Safety
Follow-up
Visita
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ETb
Telephone
Call
Assessment 
Week/Month
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Day
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
Informed 
consent/assent

Inclusion/exclusion 
criteriac

Subject demographics

Medical and medication 
history d

Physical examination


Vital signse, f















Heightg















Weightg















Clinical laboratory 
testsh



Electrocardiogram 
(12-lead)i








Serum pregnancy testl

Urine pregnancy testl












ADHD-RS-5k















CGI-Ij














PSQj















CSHQj

















Shire
CONFIDENTIAL
Page 18
Study Protocol Amendment 2
SHP465-308
18 May 2018
Table 1:
Schedule of Assessments for Group A
Period
Baseline
Treatment Period
1-Week Safety
Follow-up
Visita
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ETb
Telephone
Call
Assessment 
Week/Month
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Day
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
C-SSRS Since Last 
Visit versionk















Suitability of subject to 
remain in studyj














Concomitant 
medications
















Adverse Events
















Access IWRS















Investigational product 
distributed














Investigational product 
returned














Investigational product 
compliance














ADHD-RS-5=Attention-deficit/Hyperactivity Disorder Rating Scale 5, Child, Home Version; BMI=body mass index; CGI-I=Clinician’s Global Impression − Improvement; CGI-
S=Clinician’s Global Impression – Severity of Illness; CSHQ=Children’s Sleep Habits Questionnaire; C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; 
ET=early termination; IWRS=interactive web response system; M=month; MINI-KID=Mini International Neuropsychiatric Interview for Children and Adolescents; PSQ=Post 
Sleep Questionnaire; TEAEs=treatment-emergent adverse events; W=week.
a Visit windows are with respect to baseline (Visit 2): ±2 days for Visit 3-4 and ±5 days for Visit 5-16 during treatment period, and +2 days for the safety follow up telephone call.
b Subjects who terminate early will undergo the evaluations listed for Visit 16.
c Inclusion/exclusion criteria will be reviewed at baseline (Visit 2).
d Medical history will include all lifetime psychiatric and nonpsychiatric medications and procedures.
e Vital signs include oral or tympanic temperature, pulse, sitting blood pressure, and respiratory rate. The subject will have been seated for a minimum of 3 minutes before blood 
pressure, pulse, and respiratory rate measurements are taken. Measurement of blood pressure and pulse will be collected 3 times (with at least 2 minutes in between each 
collection) using the provided age-appropriate cuff. The average of each set of 3 measurements will be used to determine continued participation in the study. 
f Blood pressure and pulse rate will be measured at each study visit. Temperature and respiratory rate will be measured at baseline (Visit 2). 
g Height and weight will be measured without shoes and with light clothing using a stadiometer for height and calibrated scale for weight.
h Clinical laboratory evaluations will include hematology, biochemistry, endocrinology, and urinalysis.
i Electrocardiograms will be recorded in triplicate with at least 3 minutes in between each collection at baseline only.


Shire
CONFIDENTIAL
Page 19
Study Protocol Amendment 2
SHP465-308
18 May 2018
Table 1:
Schedule of Assessments for Group A
Period
Baseline
Treatment Period
1-Week Safety
Follow-up
Visita
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ETb
Telephone
Call
Assessment 
Week/Month
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Day
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
j Whenever possible, the same individual should complete/rate consistently the following scales and questionnaires as appropriate: ADHD-RS-5, CGI-I, and subject check to 
remain in the study; PSQ, and CSHQ. Include assessment of decreased appetite.
k C-SSRS Pediatric/Cognitively impaired “Since Last Visit” version is completed for all visits. The scale will be compared with the C-SSRS Pediatric/Cognitively impaired 
“Baseline” from the antecedent study.
l For females of child-bearing potential only.


Shire
CONFIDENTIAL
Page 20
Study Protocol Amendment 2
SHP465-308
18 May 2018
Table 2:
Schedule of Assessments for Group B
Period
Screening/ 
Washouta
Baseline
Treatment Period 
1-Week 
Safety
Follow-up
Visit Numberb
1
Phone 
call
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ETc
Telephone 
Call
Assessment 
Week/Month 
-5 to -1
-1
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Dayb
–32 to –3
-7
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
Informed 
consent/assent

Inclusion/exclusion 
criteriad



Subject 
demographics

MINI-KID

Medical and 
medication history 
includes prior 
medications and 
procedurese

Urine drug screen

g
Serum pregnancy 
testi 

g
Urine pregnancy
testi













ADHD-RS-5f















CGI-Sf

CGI-If














Physical 
examination

g

Heighth
















Weighth
















Vital signsj, k

g














Clinical laboratory 
testsl

g




Shire
CONFIDENTIAL
Page 21
Study Protocol Amendment 2
SHP465-308
18 May 2018
Table 2:
Schedule of Assessments for Group B
Period
Screening/ 
Washouta
Baseline
Treatment Period 
1-Week 
Safety
Follow-up
Visit Numberb
1
Phone 
call
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ETc
Telephone 
Call
Assessment 
Week/Month 
-5 to -1
-1
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Dayb
–32 to –3
-7
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
Electrocardiogram 
(12-lead)m
m
g, m







C-SSRS baseline 
versionf

C-SSRS since last 
visit versionf















PSQf















CSHQf















Adverse Events


















Concomitant 
medications


















Suitability of 
subject to remain 
in studyf














IWRS
















Study drug 
dispensed














Study drug 
capsules returned














ADHD-RS-5 =Attention-deficit/Hyperactivity Disorder-Rating Scale 5, Child, Home Version; BMI=body mass index; CGI-I=Clinician’s Global Impressions − Improvement; 
CGI--S=Clinician’s Global Impressions – Severity of Illness; CSHQ=Children’s Sleep Habits Questionnaire; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; ET=early termination; IWRS=interactive web response system; M=month; MINI-KID=Mini International Neuropsychiatric Interview for Children and 
Adolescents; PSQ=Post Sleep Questionnaire; W=week.
a Following successful screening, a site representative will contact the subject's parent/LAR to instruct the subject on discontinuing any prohibited medication for the washout 
period.
b Visit windows are with respect to baseline (Visit 2): ±2 days for Visit 3-4 and ±5 days for Visit 5-16 during treatment period, and +2 days for the safety follow-up telephone call.
c Subjects who terminate early will undergo the evaluations listed for Visit 16.
d Inclusion/exclusion criteria will be reviewed during the washout telephone call and at baseline (Visit 2).


Shire
CONFIDENTIAL
Page 22
Study Protocol Amendment 2
SHP465-308
18 May 2018
Table 2:
Schedule of Assessments for Group B
Period
Screening/ 
Washouta
Baseline
Treatment Period 
1-Week 
Safety
Follow-up
Visit Numberb
1
Phone 
call
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ETc
Telephone 
Call
Assessment 
Week/Month 
-5 to -1
-1
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Dayb
–32 to –3
-7
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
e Medical history will include all lifetime psychiatric and nonpsychiatric medications and procedures.
f Whenever possible, the same individual should complete/rate consistently the following scales and questionnaires as appropriate: ADHD-RS-5, CGI-S/I, and subject check to 
remain in the study; PSQ and CSHQ. Include assessment of decreased appetite.
g If >32 days have elapsed since the screening evaluation was completed at Visit 1, then the following evaluations must be repeated at baseline (Visit 2): vital signs, clinical 
laboratory evaluations, and ECGs in triplicate. The physical examination will be abbreviated with a review of the following body systems: general appearance, respiratory, and 
cardiovascular.
h Height and weight will be measured without shoes and with light clothing using a stadiometer for height and calibrated scale for weight.
i For females of child-bearing potential only
j Vital signs include oral or tympanic temperature, pulse, sitting blood pressure, and respiratory rate. The subject will have been seated for a minimum of 3 minutes before blood 
pressure, pulse, and respiratory rate measurements are taken. Measurement of blood pressure and pulse will be collected 3 times (with at least 2 minutes in between each 
collection) using the age-appropriate cuff.
k Blood pressure and pulse rate will be measured at each study visit. Temperature and respiratory rate will be measured at screening (Visit 1) only.
l Clinical laboratory evaluations will include hematology, biochemistry, endocrinology, and urinalysis.
m ECGs will be recorded in triplicate with at least 3 minutes in between each collection at screening only and at baseline only if >32 days have elapsed since the screening 
evaluation was completed at Visit 1.


Shire
CONFIDENTIAL
Page 23
Study Protocol Amendment 2
SHP465-308
18 May 2018
1
BACKGROUND INFORMATION
SHP465 extended-release capsules contain mixed salts of a single-entity amphetamine, a central 
nervous system (CNS) stimulant. The product was previously referred to as SPD465 however it 
is now being studied under the code of SHP465. SHP465 contains equal amounts (by weight) of 
4 salts: dextroamphetamine sulfate and amphetamine sulfate, dextroamphetamine saccharate 
and amphetamine aspartate monohydrate. This results in a 3:1 mixture of dextro- to 
levo- amphetamine base equivalent.
SHP465 capsules are for oral administration. They contain 3 types of drug-releasing beads, an 
immediate release and 2 different types of delayed release (DR) beads. The first DR bead 
releases amphetamine at pH 5.5 and the other DR bead releases amphetamine at pH 7.0.
Amphetamines are noncatecholamine sympathomimetic amines with central nervous system 
stimulant activity. Amphetamine increases the availability of biogenic amines (primarily 
dopamine and norepinephrine) in central nerve terminals through multiple actions, including 
stimulating neurotransmitter release into the nerve terminal and inhibiting reuptake from the 
synapse. These actions may be the basis of its therapeutic actions in 
attention-deficit/hyperactivity disorder (ADHD); however, the mode of therapeutic action in 
ADHD is not known.
1.1
Indication and Current Treatment Options
The exact etiology of ADHD is unknown. Extensive research has suggested that neurotransmitter 
deficits (Arnsten, 2001), genetics (Arnsten, 2001; Brown, 2003), environment (Kahn et al., 
2003), and perinatal complications (Bhutta and Anand, 2002) may all be contributing factors. 
The hypothesized mechanism of action of effective medications in ADHD is to raise 
neurotransmitter levels (specifically norepinephrine and/or dopamine, or their precursors) at the 
synapse either by facilitating neurotransmitter release from the synapse or by decreasing 
neurotransmitter reuptake by binding or activating the postsynaptic receptor (Kratochvil et al., 
2003; Wang et al., 2007).
According to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5), 
ADHD has 3 subtypes: hyperactive/impulsive, inattentive, and combined and individuals with 
ADHD may manifest considerably different symptomology depending on sex, disorder subtype, 
and the presence of comorbid disorders.
Compared with nonstimulants, stimulant medications (ie, amphetamine or methylphenidate) 
produce the most robust improvements in symptom expression across all age ranges (Spencer et 
al., 2001). Furthermore, stimulant medications have a rapid onset of action, within 1 to 2 hours 
of dosing, compared with nonstimulants (eg, atomoxetine), which can require dosing for up to 
4 to 6 weeks to achieve maximal therapeutic benefit (Wilens et al., 2002).
Nonpharmacological measures (psychological, educational, and social) can also be beneficial 
and psychosocial treatments for adults with ADHD have been studied (Safren et al., 2004; 
Greenfield and Hechman, 2005). 


Shire
CONFIDENTIAL
Page 24
Study Protocol Amendment 2
SHP465-308
18 May 2018
Comorbid psychiatric and learning disorders are common in adults with ADHD and appropriate 
evaluation, diagnosis, and treatment are recommended (Weiss and Murray, 2003).
Importantly, symptoms may not only manifest throughout the day. Many patients continue to 
have residual symptoms lasting into the evening hours (Greenfield and Hechman, 2005). Adult 
patients may benefit from symptom relief into the evening hours for such activities as planning 
and organizing, or professional activities (eg, professional work at night), spousal/parental 
responsibilities, and driving. Similarly, impairments in nighttime activities are recognized in the 
pediatric population, which may need coverage all day and into the evening as well (eg, to do 
homework and to participate in family/social activities).
The impairments in psychosocial academic and occupational functioning associated with ADHD 
may arise from underlying chronic deficiencies in executive function (Brown, 1996). In general, 
the term executive function is used to describe a set of cognitive abilities that control and 
regulate judgments and behaviors which are necessary for goal-directed behavior; however, the 
specific definition of executive functioning varies and is debated. Understanding and treating 
executive functioning deficits is increasingly considered an unmet medical need in ADHD.
1.2
Product Background and Clinical Information
SHP465 and its prototypes have been evaluated in 1641 subjects in 16 clinical studies, of which 
13 clinical studies were in adult subjects aged 18 to 55 years and 3 clinical studies were in 
pediatric subjects aged 6 to 17 years. The SHP465 clinical development program has shown that 
doses of 12.5 to 50 mg in adult subjects and 12.5 to 25 mg in pediatric subjects demonstrate a 
safety and efficacy comparable to the profile reflected in class labeling for stimulant products 
approved in the United States (US).
The pharmacokinetic (PK) profile of SHP465 is not affected if the capsule is consumed intact or 
if capsule contents are sprinkled onto a small amount of food (ie, 1 tablespoon of applesauce) 
and then ingested. The PK properties of SHP465 are not affected by sex or race. The PK 
properties between d- and l-amphetamine are similar.
Acceptable safety and tolerability profiles observed were consistent with the types of side effect 
specified in stimulant class labeling in the US. Specifically, administration of SHP465 was 
associated with increases in blood pressure (mean increase approximately 2-4 mmHg) and heart 
rate (mean increase approximately 3-6 bpm), and treatment-emergent adverse events (TEAEs) of 
insomnia, decreased appetite, decreased weight, heart rate increased, and anxiety, as well as 
psychiatric events (eg, mania, suicidality).
Always refer to the latest version of the SHP465 Investigator’s Brochure (IB) for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, PK, efficacy, and safety of SHP465.


Shire
CONFIDENTIAL
Page 25
Study Protocol Amendment 2
SHP465-308
18 May 2018
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The purpose of the study is to evaluate the long-term safety of SHP465 at 6.25 mg in children 
aged 4 to 12 years diagnosed with ADHD. Results from this study will provide important 
information on the long-term safety, tolerability, and efficacy of SHP465 at lower doses in the 
preschool/pediatric ADHD population.
2.2
Study Objectives
2.2.1
Primary Objective
The primary objective of this study is to evaluate the long-term safety and tolerability of SHP465 
at 6.25 mg administered as a daily morning dose in children aged 4-12 years (inclusive at the 
time of consent) diagnosed with ADHD.
The evaluation of safety and tolerability will be based on the occurrence of treatment-emergent 
adverse events (TEAEs), evaluation of vital signs (systolic and diastolic blood pressure and 
pulse), weight, height, body mass index (BMI); clinical laboratory and electrocardiogram (ECG) 
results; sleep assessment (Post Sleep Questionnaire [PSQ], and Children’s Sleep Habits 
Questionnaire [CSHQ]); and responses to the Columbia-Suicide Severity Rating Scale (C-
SSRS).
2.2.2
Secondary Objectives
The secondary objectives of this study are as follows:
1. To describe the long-term efficacy of SHP465 using the clinician-administered ADHD 
Rating Scale 5 (ADHD-RS-5) Child, Home Version.
2. To describe the long-term efficacy of SHP465 using the Clinical Global 
Impressions-Improvement (CGI-I) scale.






Shire
CONFIDENTIAL
Page 28
Study Protocol Amendment 2
SHP465-308
18 May 2018
4
STUDY POPULATION
Each subject must participate in the informed consent process and provide written informed 
consent/assent before any procedures specified in the protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the following 
criteria (including test results):
1. Subject is male or female aged 4 to 12 years, inclusive, at the time of consent for 
antecedent SHP465 trials (SHP465-112 or SHP465-309) in the ADHD population or at 
the time of consent for directly enrolled subjects into this study.
2. Subject’s parent or legally authorized representative (LAR) must provide signature of 
informed consent, and there must be documentation of assent (if applicable) by the 
subject in accordance with the International Council on Harmonization (ICH) Good 
Clinical Practice (GCP) Guideline E6 (1996) and any updates and applicable regulations, 
before completing any study-related procedures. 
3. Subject and parent/LAR are willing and able to comply with all of the testing and 
requirements defined in the protocol, including oversight of morning dosing. Specifically, 
the same parent/LAR should be available daily to dispense the dose of investigational 
product for the duration of the study.
4. For subjects in Group A:

Subject enrolled in the antecedent study SHP465-112 must have completed the    
treatment period and the pharmacokinetic (PK) sample collection (at the dose of 6.25 
mg) without incidence of a clinically significant TEAE.

Subject enrolled in the antecedent study SHP465-309 must have completed  the 
treatment period without reporting a clinically significant TEAE that would preclude 
subsequent exposure to SHP465. 
5. For subjects in Group B (directly enrolled subjects), the following criteria must be met:

Subject meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition (DSM-5) criteria for a primary diagnosis of ADHD (any subtype) based on a 
detailed psychiatric evaluation using the Mini International Neuropsychiatric 
Interview for Children and Adolescents (MINI-KID)

Subject aged 4 to 5 years has an ADHD-RS-5 Child Version Total score of 
≥28 (boys) or ≥24 (girls) at baseline (Visit 2)

Subject aged 6 to 12 years has an ADHD-RS-5 Child Version Total score of ≥28 at 
baseline (Visit 2)

Subject has a Clinical Global Impression–Severity of Illness score (CGI-S) ≥4 at 
baseline (Visit 2)

Subject has previously undergone an adequate course of nonpharmacological 


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treatment based on investigator judgment (aged 4-5 year olds) OR the subject is not 
completely satisfied with current adequate course of ADHD therapy (aged 6-12 year 
olds), OR the subject has a severe enough condition to consider enrollment without 
undergoing prior nonpharmacological treatment, based on investigator judgment.

Subject functions as an age-appropriate level intellectually, based on investigator 
judgment.
6. Subject who is a female and of child-bearing potential must not have a positive serum 
beta human chorionic gonadotropin pregnancy test at the screening visit (Visit 1) and 
must have a negative urine pregnancy test at the baseline visit (Visit 2) and agree to 
comply with any applicable contraceptive requirements of the protocol.
7. Subject has lived with the same parent/LAR for at least 6 months.
4.2
Exclusion Criteria
Subjects will be excluded from the study if any of the following exclusion criteria are met at 
baseline (Visit 2) for Group A or at screening (Visit 1) and/or baseline (Visit 2) for Group B. 
These criteria apply to all subjects regardless of participation in an antecedent trial:
1. Subject was terminated from an antecedent SHP465 trial for noncompliance and/or had a 
serious TEAE during any previous SHP465 trial.
2. Subject is required to or is anticipated to take any medication that has central nervous 
system effects or affects performance, such as sedating antihistamines and decongestant 
sympathomimetics, or is a monoamine oxidase inhibitor. Stable use of bronchodilator 
inhalers is not exclusionary.
3. Subject has a concurrent chronic or acute illness (such as severe allergic rhinitis or an 
infectious process requiring antibiotics), disability, or other condition that might 
confound the results of safety assessments conducted in the study or that might increase 
risk to the subject. Similarly, the subject will be excluded if he or she has any additional 
condition(s) that, in the investigator’s opinion, would prohibit the subject from 
completing the study or would not be in the best interest of the subject. The additional 
condition(s) would include any significant illness or unstable medical condition that 
could lead to difficulty complying with the protocol. Mild, stable asthma is not 
exclusionary.
4. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to 
any excipients in the investigational product.
5. Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
6. Subject has a blood pressure measurement ≥95th percentile for age, sex, and height at 
screening (Visit 1) and/or baseline (Visit 2).
7. Subject has a height ≤5th percentile for age and sex at screening (Visit 1) and/or baseline 
(Visit 2).


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8. Subject has a weight ≤5th percentile for age and sex at screening (Visit 1) and/or baseline 
(Visit 2).
9. Subject has a known history of symptomatic cardiovascular disease, structural cardiac 
abnormality, cardiomyopathy, serious heart rhythm abnormalities, or other serious 
cardiac conditions placing them at increased vulnerability to the sympathomimetic effects 
of a stimulant drug.
10. Subject has a history of seizures (other than infantile febrile seizures).
11. Subject has failed to fully respond, based on investigator judgment, to an adequate course 
of amphetamine therapy.
12. Subject is taking any medication that is excluded per the protocol.
13. Subject had any clinically significant ECG or clinical laboratory abnormalities at the 
screening (Visit 1) and/or baseline visit (Visit 2).
14. Subject has current abnormal thyroid function, defined as abnormal thyroid-stimulating 
hormone and thyroxine at the screening (Visit 1) and/or baseline visit (Visit 2). Treatment 
with a stable dose of thyroid medication for at least 3 months is permitted.
15. Subject has a current, controlled (requiring medication or therapy) or uncontrolled, 
comorbid psychiatric disorder including, but not limited to, any of the following 
comorbid Axis I disorders and Axis II disorders:

Post-traumatic stress disorder or adjustment disorder

Bipolar disorder, psychosis, schizophrenia or family history of these disorders

Pervasive developmental disorder

Obsessive-compulsive disorder

Serious tic disorder, or a family history of Tourette disorder

Any other disorder that in the opinion of the investigator contraindicates SHP465 or 
amphetamine treatment or confounds efficacy or safety assessments 
16. Subject has a primary sleep disorder (eg, sleep apnea, narcolepsy)
17. Subject has a history or is currently diagnosed with an eating disorder
18. Subject is currently considered a suicide risk in the opinion of the investigator, has 
previously made a suicide attempt, or has a prior history of or currently demonstrating 
suicidal ideation.
19. Subject has a history of physical, sexual, or emotional abuse.
20. Subject has initiated behavioral therapy within 1 month before baseline (Visit 2). Subject 
may not initiate behavioral therapy during the study.
21. 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 1) or 
baseline (Visit 2).
22. Subject is female and pregnant or lactating.
23. Subject cannot swallow a pill and/or applesauce or has an allergy to applesauce.


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4.2.1
Female Contraception 
Sexually active females of childbearing potential 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 dose of IMP. If 
hormonal contraceptives are used they should be administered according to the package insert. 
Females of childbearing potential who are not currently sexually active must agree to use 
acceptable contraception, as defined below, if they become sexually active during the period of 
the study and 30 days following the last dose of IMP.
Female children and adolescent subjects should be either:

Premenarchal and either Tanner Stage 1 or <9 years, or

Females of childbearing potential with a negative urine and/or serum beta-human 
chorionic gonadotropin (-hCG) pregnancy test at screening and/or baseline (Group 
A and Group B subjects) and a negative urine pregnancy test at the baseline visit 
(Visit 2). Females of childbearing potential must agree to abstain from sexual activity 
that could result in pregnancy or agree to use acceptable methods of contraception.
Acceptable methods of contraception are:

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: If subject becomes sexually active 
during the study, they should use 1 of the other acceptable methods noted above in 
addition to the hormonal contraceptive until it has been stabilized for 30 days.
4.2.2
Male Contraception
Male subjects must agree to either abstain from sex or to use condoms if they become sexually 
active during the period of the study and for 30 days following the last dose of investigational 
product.
4.3
Discontinuation of Subjects
A subject may withdraw from the study, or the parent/LAR may withdraw the subject 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 
investigational product with the medical monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Visit 16/early termination (ET) are to be performed as completely as possible. Whenever 
possible, all discontinued subjects should also undergo the protocol-specified follow-up. 
Comments (spontaneous or elicited) or complaints made by the subject must be recorded in the 


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source documents. The reason for termination, date of stopping investigational product, and the 
total amount of investigational product taken must also be recorded in the source documents and 
the most clinically relevant reason should be entered on the CRF.
Subjects who discontinue will not be replaced.
4.3.1
Management of Blood Pressure and Pulse During the Study 
To ensure that potential blood pressure and pulse increases associated with the use of SHP465 in 
this population are carefully monitored and appropriately managed, all subjects must be further 
evaluated if they meet any of the criteria defined in Sections 4.3.1.1 and 4.3.1.2.
4.3.1.1
Systolic and Diastolic Blood Pressure
Blood pressure criteria for further evaluation have been developed based on the normative data 
presented in the National Institutes of Health Fourth Report on the Diagnosis, Evaluation, and 
Treatment of High Blood Pressure in Children and Adolescents (NIH, 2004).
Prior to obtaining vital signs (blood pressure and pulse) the subjects should be at rest for at least 
3 minutes.
If any subject’s blood pressure measurements meet either criterion below, the investigator will 
notify the medical monitor. If any subject’s blood pressure measurements meet either criterion 
below on 3 consecutive visits, the subject should be considered for potential discontinuation 
based upon the clinical judgment of the investigator and in conjunction with the medical 
monitor. 

Elevations in the average (of 3 readings) sitting systolic blood pressure defined as an 
increase of >15 mmHg from the baseline visit (Visit 2) OR a value >95th percentile for 
age, sex, and height.

Elevations in average (of 3 readings) sitting diastolic blood pressure defined as an 
increase of >15 mmHg from the baseline visit (Visit 2) OR an average (of 3 readings) 
sitting diastolic blood pressure value >95th percentile for age, sex, and height.
Any subject with a systolic or diastolic blood pressure measurement <95th percentile for age, sex, 
and height percentile may be discontinued from the study based upon the clinical judgment of
the investigator regarding the subject’s safety.
4.3.1.2
Pulse
The resting pulse rate criterion for further evaluation has been defined based on the normative 
data presented in the National Health Statistics Report’s “Resting Pulse Rate Reference Data for 
Children, Adolescents, and Adults: United States, 1999-2008” (Ostchega et al., 2011).
Any subject that has a resting, sitting pulse rate >126 bpm for age 4-5 years or >116 bpm for age 
6-12 years based on the average of 3 readings or is symptomatic requires further assessment. In 
this case an unscheduled visit needs to be conducted within 1 business day. At the unscheduled 
visit, if the subject’s pulse rate remains above the criteria based on the average of 3 readings or if 


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the subject is symptomatic then the subject’s investigator will discuss the findings with the 
medical monitor. In careful consideration of the subject's pulse value, magnitude of increase 
from baseline and symptoms, a joint decision between the investigator and the medical monitor 
will be made regarding continued participation in the study. If a visit cannot be scheduled the 
next day, the subject may be discontinued from the study.
Any subject with a pulse rate equal or lower than the number for age defined above may be 
discontinued from the study based upon the clinical judgment of the investigator regarding the 
subject’s safety.
4.3.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and source documents. If a subject is withdrawn for more than 1 reason, each 
reason should be documented in the source documents.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol violation

Withdrawal by subject or parent/LAR

Lost to follow-up

Lack of efficacy

Blood pressure and/or pulse criteria met

Other (must be specified)
4.3.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent/LAR of 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 they return to the site for final safety evaluations and return any unused 
investigational product.


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5
PRIOR AND CONCOMITANT TREATMENT
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
behavioral treatment, nonpharmacological treatment such as psychotherapy) received within 
30 days (or PK equivalent of 5 half-lives, whichever is longer) prior to the date of first dose of 
investigational product. Prior treatment information must be recorded in the subject’s source 
documents.
Washout for all prior medications must be a minimum of 5 times the half-life of the medication.
5.2
Concomitant Treatment
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded in the appropriate source document.
5.2.1
Permitted Treatment
Medications permitted during the study are listed as follows:

Stable (ie, for at least 3 months before the baseline visit [Visit 2] for subjects in 
Group A and the screening/washout visit [Visit 1] for subjects in Group B) dose of 
thyroid medication is permitted

Stable (ie, for at least 1 month before the baseline visit [Visit 2] for subjects in 
Group A and the screening/washout visit [Visit 1] for subjects in Group B) dose of 
bronchodilator inhalers (however, beta-agonists and chronic use of oral 
corticosteroids are prohibited)

Any medications that do not affect blood pressure, heart rate, or the central nervous 
system, and which are considered necessary for the subject’s welfare, may be 
administered at the discretion of the investigator

Nonsedating antihistamines such as fexofenadine (eg, Allegra, Sanofi), loratadine 
(eg, Claritin, Schering-Plough), and cetirizine hydrochloride (eg, Zyrtec, 
McNeil-PPC)

Over-the-counter nonstimulant cold remedies
Concomitant psychotherapy must also be recorded in the appropriate section of the source 
documents.
5.2.2
Prohibited Treatment
Table 3 details the washout period, relative to the baseline visit (Visit 2), for treatments that are 
excluded during this study. Subjects can only be instructed to discontinue a medication for this 
study after informed consent has been obtained.


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Table 3:
Common Excluded Treatments and Associated Washout Period - Relative to 
Baseline Visit (Visit 2)
Minimum 
Number of Days 
Before Baseline 
Visit
Treatment
7
14
30
Psychostimulants, amphetamines, and amphetamine-like agents
X
Antihypertensivesa
X
Antihistamines (centrally and peripherally active)
X
Herbal preparations (including melatonin)
X
Sedatives, anxiolytics, antipsychoticsa
X
Monoamine oxidase inhibitorsa
X
Antidepressantsa
X
Clonidine and guanfacine
X
Selective noradrenaline reuptake inhibitors and noradrenaline reuptake inhibitorsa
X
CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine, ritonavir)
X
Alkalinizing agents (eg, sodium bicarbonate, acetazolamide, some thiazides)
X
Acidifying agents (eg, guanethidine, reserpine, glutamic acid HCl, ascorbic acid, ammonium 
chloride, sodium acid phosphate, methenamine salts)
X
a These medications may signal that an exclusionary diagnosis is present. The medical monitor should be consulted before 
instructing a subject to discontinue 1 of these medications for this study.


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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is SHP465, which will be provided in 6.25 mg capsule form. The product was 
previously referred to as SPD465 and is registered with the Drug Enforcement Agency (DEA) as 
SPD465; however, it is now being studied under the code of SHP465. The drug will be labeled 
with SHP465 (SPD465).
6.1.1
Blinding the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology for Investigational Product Management
An interactive web response system (IWRS) will be employed in this study to manage the 
tracking and confirmation of shipments, supply, inventory, ordering, expiration, site assignments, 
and dosing of the investigational products.
The IWRS provider will provide a user manual and training to each site, with detailed instruction 
on the use of the IWRS.
6.2.2
Allocation of Subjects to Treatment
All subjects will receive open-label SHP465 during this study.
Subject numbers are assigned to all subjects as they consent to take part in the antecedent study 
or this study if directly enrolled. Within each site (numbered uniquely within a protocol), the 
subject number is assigned to subjects according to the sequence of presentation for study 
participation.
6.2.3
Dosing
Dosing should begin at 7:00 AM (±2 hours) on the morning after the baseline visit (Visit 2). The 
parent/LAR responsible for dosing will be instructed to dispense 1 capsule to the subject daily in 
the morning throughout the study, at approximately the same time each day. The same 
parent/LAR should be available daily to dispense the dose of investigational product for the 
study duration.
SHP465 may be administered in 1 of the following ways:

Swallow SHP465 capsule whole, or

Open capsule and sprinkle the entire contents on applesauce
The sprinkled applesauce should be consumed immediately; it should not be stored. Subjects 
should take the sprinkled applesauce in its entirety without chewing. The dose of a single capsule 
should not be divided. The empty capsule shells should be discarded.


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Subjects will be treated with SHP465 at 6.25 mg.
The investigator will categorize subject response into 1 of the following 3 conditions, along with 
the associated actions:

Intolerable response (ie, subject experiences intolerable side effects): If this lower 
dose also produces an intolerable effect, the subject should be discontinued from the 
study.

Ineffective response (ie, subject has not achieved at least a 30% reduction in 
ADHD-RS-5 Child, Home Version  total score from the baseline visit [Visit 2] and a 
CGI-I score of 1 or 2).

Acceptable response (ie, subject has achieved at least a 30% reduction in 
ADHD-RS-5 Child, Home Version total score from the baseline visit [Visit 2] and a 
CGI-I score of 1 or 2 with tolerable side effects): This response suggests that an 
optimal dose has been achieved and the subject should maintain this dose for the 
remainder of the study.
If the subject experiences unacceptable tolerability, in the opinion of the clinician, the subject 
will be discontinued.
6.2.4
Unblinding the Treatment Assignment
Not applicable.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
products container.
All investigational product is labeled with a minimum of the protocol number, medication 
identification number (if applicable), dosage form (including product name and quantity in 
pack), directions for use, storage conditions, expiry date (if applicable), batch number and/or 
packaging reference, the statement “CAUTION: New Drug - Limited by Federal (or United 
States) Law to Investigational Use”, “Keep out of reach of children”, and the sponsor's name and 
address. Any additional labeling requirements for participating countries and/or controlled 
substances will also be included on the label.
Space is allocated on the label so that the site representative can record a unique subject 
identifier and initials.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label


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
Obscure the clinical study label

Identify the study subject by name
Additional labels may not be added without the sponsor’s prior full agreement.
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
SHP465 capsules are packaged in 9-count high-density polyethylene bottles with child-resistant 
closures.
Changes to sponsor-supplied packaging before dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that the investigational product is stored 
in a secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier and initials on the investigational product 
bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is 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 range. Temperature 
excursions will require site investigation as to cause and remediation. The sponsor will determine 
the ultimate impact of excursions on the investigational product 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 for use by the 
sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
All controlled-substance investigational product for the sponsor’s studies must be stored in a 
securely locked, substantially constructed room or cabinet according to all applicable local, state, 
and/or national laws. Limited, controlled access to these investigational products must be 
maintained, as well as chain of custody, for all investigational product movement.


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6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has the overall responsibility for administering/dispensing the investigational 
product. Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) 
who is adequately trained in 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 designee will be required to have a valid DEA Form 223 certificate of 
registration for 2N Controlled Substances for the duration of the study and be able to order and 
distribute 2N Controlled Substances via a valid DEA Form 222.
The investigator or designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to the parent/LAR of 
subjects included in this study following the procedures set out in the study protocol. The 
parent/LAR of each subject will be given only the investigational product carrying the subject’s 
treatment assignment. All dispensed medication will be documented on the source documents 
and/or other investigational product record. 
The investigator is responsible for ensuring the retrieval of all study supplies from each subject’s 
parent/LAR.
No investigational product stock or returned inventory from a Shire-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, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock, subject-returned 
investigational product, and empty/used investigational product packaging are to be sent to a 
nominated contractor on behalf of the sponsor. Investigational products being returned to the 
sponsor’s designated contractors must be counted and verified by clinical site personnel and the 
sponsor (or designated contract research organization [CRO]). For unused supplies where the 
original supplied tamper-evident feature is verified as intact, the tamper-evident feature must not 
be broken and the labeled amount is to be documented in lieu of counting. Shipment return 
forms, when used, must be signed before shipment from the site. Validated electronic return 
systems (ie, interactive response technology) do not require a shipment form. Returned 
investigational products must be packed in a tamper-evident manner to ensure product integrity. 
Contact the sponsor for authorization to return any investigational product before shipment. 
Shipment of all returned investigational product must comply with local, state, and national laws. 
As this is a controlled substance, investigational product cannot be destroyed at site, and must be 


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returned to the depot. All DEA Form 222s will be required to accompany any site shipments and 
site returns back to the depot. Accountability must be performed at the capsule level.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
The parent/LAR of each subject must be instructed to bring their unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed at the container/packaging level for unused investigational product 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 schedules of assessments (Table 1 [Group A] and Table 2 [Group B]) detail all procedures to 
be completed at each visit and should serve as the primary section of the protocol regarding 
visit-specific study procedures.
Clinician-completed rating scales and assessments conducted by the site, ie, ADHD-RS-5, 
CGI-S, CGI-I, and C-SSRS must be completed by the same rater whenever possible. The 
parent/LAR completed PSQ and CSHQ should be completed by the same individual whenever 
possible.
For both groups throughout the treatment period, visits should be scheduled as outlined (±2 days 
for Visit 3-4 and ±5 days for Visit 5-16), with reference to the baseline visit (Visit 2). The safety 
follow-up call should be scheduled 7 days after the final dose with a +2-day visit window.
For Group A, the subjects will be required to visit the site up to 15 times and for Group B, the 
subjects will be required to visit the site up to 16 times over a 12-month period.
Additional unscheduled visits and/or assessments may occur as needed for safety (eg, 
unscheduled visits for blood pressure and/or pulse measurements).
7.1.1
Screening and Washout Period (Group A and Group B)
For subjects in Group A, the last visit of the antecedent study, SHP465-112 or SHP465-309, will 
serve as the baseline visit (Visit 2) for this study. The investigator or designee must obtain 
written informed consent from the subject's parent/LAR prior to any procedures related to this 
protocol being performed.
Subjects in Group B are directly enrolled subjects and will be required to undergo full screening 
and washout before enrollment. A separate screening visit will be conducted followed by a 
washout period for subjects in Group B.
The principal investigator or designee must obtain written informed consent from the subject’s 
parent/LAR before any SHP465-308 study-related procedures are conducted during the 
screening visit (Visit 1). There must also be documentation of assent (if required by the 
Institutional Review Board [IRB]), indicating that the subject is aware of the investigational 
nature of the study and the required procedures and restrictions, before the performance of any 
SHP465-308 study-related procedures.
A subject cannot be instructed to washout any medication for this study until after informed 
consent is obtained.
Screening procedures may take place across multiple days to allow enough time to complete all 
procedures and confirm initial subject eligibility. Screening procedures and dates should be well 
documented in the source documents. The date of the screening visit (Visit 1) is the date the 
subject and parent/LAR has signed informed consent for this study. Subjects requiring washout 


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must have an abbreviated physical examination, clinical laboratory tests, and 12-lead ECG 
repeated if >32 days have elapsed since the safety measurements at the screening visit (Visit 1) 
were collected.
7.1.1.1
Screening Visit (Visit 1) for Group B
Subjects in Group B will be screened at Visit 1 to establish eligibility for study participation.
Table 2 (Group B) details all procedures to be completed at the screening visit (Visit 1) and 
should serve as the primary point of reference regarding study procedures. Additional 
clarification on the procedures performed during the screening visit (Visit 1) is as follows:

Eligibility will be established per inclusion and exclusion criteria, including 
documentation of any prior nonpharmacological treatment, specified MINI-KID, and 
C-SSRS criteria. Areas of impairment will be recorded for all subjects for assessing 
the severity of the subject’s condition.

All adverse events (AEs) occurring after signature of informed consent must be 
recorded in the source documents.

Three 12-lead ECGs will be taken, with approximately 3 minutes in between each 
one, to ensure that appropriate baseline intervals are established. The investigator will 
perform the initial interpretation of the ECG immediately after collection to ensure 
the safety of each subject. The ECG tracing will be sent to the central reader for 
analysis. Upon review of the report from the central reader, the investigator will 
re-evaluate the clinical significance of the ECG in light of other safety data for the 
subject. If abnormal and significant results are observed following assessment by the 
central reader, the investigator, in consultation with the appointed CRO medical 
monitor, will confirm the subject’s eligibility to participate in this study.

Vitals will include oral or tympanic temperature, pulse, sitting blood pressure, and 
respiratory rate. Also, blood pressure and pulse will be collected 3 times (with at least 
2 minutes in between each collection) using the age-appropriate cuff during the visit. 
The average of each set of 3 measurements will be used to determine continued 
participation in the study (see Section 4.3.1).

Height and weight will be measured without shoes. 

The “baseline” version of the Pediatric/Cognitively Impaired Version C-SSRS should 
be completed.

Clinical lab tests will include hematology, biochemistry, endocrinology, and 
urinalysis. 

Historical/concomitant medications will be recorded as follows:

All lifetime psychoactive medications and lifetime nonpharmacological 
interventions (behavioral therapy) for ADHD

Other medications used during the 30 days before the screening visit (Visit 1)


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A screen failure is a subject who has given informed consent and failed to meet the inclusion 
and/or met at least 1 of the exclusion criteria and has not been randomized or administered 
investigational products. Subjects cannot be rescreened once they have been designated as a 
screen failure.
7.1.1.2
Washout Telephone Call (Group B)
The washout period will be initiated after clinical laboratory test results and 12-lead ECG results 
have been received and reviewed by the investigator.
Eligible subjects will be contacted by a member of the site staff and provided with instructions 
on discontinuing any protocol-prohibited medications. During washout, a subject’s current 
prohibited medications (if applicable) will be discontinued for a period of up to 32 days or 
5 times the half-life of the medication, whichever is longer. Washout periods for prohibited 
medications are defined in Table 3.
As part of the washout telephone call, site personnel will perform the following procedures:

Schedule the baseline visit (Visit 2)

Review the inclusion/exclusion criteria

Ask about any concomitant medications that the subject is taking. If new concomitant 
medications that require washout are noted, instructions for appropriate washout will 
be provided

Provide instructions on discontinuing any medication requiring washout

Determine if any AEs have occurred since the screening visit (Visit 1)
If a medication washout is not necessary, the washout telephone call will include all the above 
procedures except providing instructions on discontinuing any current medications.
7.1.1.3
Baseline Visit (Visit 2) Group A
Visit 2 for subjects in Group A will be the same day as the final on-site visit for the antecedent 
study. During this visit, subjects will be screened for eligibility into study SHP465-308.
The investigator or designee must obtain written informed consent from the subject’s 
parent/LAR before any SHP465-308 study-related procedures conducted during the baseline visit 
(Visit 2). There must also be documentation of assent (if required by IRB), indicating that the 
subject is aware of the investigational nature of the study and the required procedures and 
restrictions, before the performance of any SHP465-308 study-related procedures.
Inclusion/exclusion criteria must be reviewed during this visit to ensure subjects continue to 
meet all eligibility criteria.
Table 1 (Group A) outlines all procedures to be conducted during Visit 2 and should serve as the 
primary point of reference regarding study procedures. Additional clarification on the procedures 
performed during the baseline visit (Visit 2) is provided as follows:


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
Vitals will include oral or tympanic temperature, pulse, sitting blood pressure, and 
respiratory rate. Also, blood pressure and pulse will be collected 3 times (with at least 
2 minutes in between each collection) using the age-appropriate cuff during the visit. 
The average of each set of 3 measurements will be used to determine continued 
participation in the study (Section 4.3.1).

For eligible subjects, the investigator or assigned site staff designee will access the 
IWRS to enroll the subject and obtain an investigational product bottle number to 
dispense to the subject’s parent/LAR. Sufficient investigational product will be 
dispensed to last until the next regularly scheduled visit. The parent/LAR responsible 
for dosing will be instructed to dispense 1 capsule each day to the subject. Dosing 
will begin the morning after the baseline visit (Visit 2).

The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired 
Version should be completed.
7.1.1.4
Baseline Visit (Visit 2) Group B
Once the screening central clinical laboratory tests and 12-lead ECG results have been obtained, 
in addition to repeat assessments (if required), and the subject has completed the required 
washout period (if applicable), the subject will return to the site for the baseline visit (Visit 2).
Inclusion/exclusion criteria must also be reviewed during this visit to ensure that the subject 
continues to meet all eligibility criteria.
Table 2 (Group B) outlines all procedures to be conducted during the baseline visit (Visit 2) and 
should serve as the primary point of reference regarding study procedures. Additional 
clarification on the procedures performed during the baseline visit (Visit 2) is provided as 
follows:

For subjects with >32 days since the safety measurements at the screening visit 
(Visit 1) were collected, an abbreviated physical examination, vital signs, clinical 
laboratory tests, and 12-lead ECG in triplicate must be repeated, and the results 
reviewed by the investigator before the subject is enrolled.

Blood pressure and pulse will be collected 3 times (with at least 2 minutes in between 
each collection) using the age-appropriate cuff during the visit. The average of each 
set of 3 measurements will be used to determine continued participation in the study 
(see Section 4.3.1).

If >32 days since the screening visit (Visit 1), 3 ECGs will be taken, with 
approximately 3 minutes in between each one, to ensure that appropriate baseline 
intervals are established. The investigator will perform the initial interpretation of the 
ECG immediately after collection to ensure the safety of each subject to continue 
with the study. The ECG tracing will be sent to the central reader for analysis. 
Upon review of the report from the central reader, the investigator will re-evaluate the 
clinical significance of the ECG in light of other safety data for the subject. If 
abnormal and significant results are observed following assessment by the central 
reader, the investigator, in consultation with the appointed CRO medical monitor, will 


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confirm the subject’s continued participation in this study.

The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired 
Version should be completed.

For eligible subjects, the investigator or assigned site staff designee will access the 
IWRS to enroll the subject and obtain an investigational product bottle number to 
dispense to the subject’s parent/LAR. Sufficient investigational product will be 
dispensed to last until the next regularly scheduled visit. The parent/LAR responsible 
for dosing will be instructed to dispense 1 capsule each day to the subject. Dosing 
will begin the morning after the baseline visit (Visit 2).
7.1.2
Treatment Period (Group A and Group B)
At each visit during the treatment period up to and including Visit 16, sufficient investigational 
product will be dispensed to last until the next regularly scheduled visit. The parent/LAR 
responsible for dosing will be instructed to dispense 1 capsule each day to the subject. At each 
visit, the subject’s parent/LAR must return any empty or unused bottles to permit drug 
accountability and compliance to be assessed.
Throughout the treatment period, subjects may attend the clinic for unscheduled visits to address 
any medical needs that arise between scheduled visits.
Table 1 (Group A) and Table 2 (Group B) outline all procedures to be conducted during Visits 3 
and 4 and should serve as the primary point of reference regarding study procedures. Further 
clarification for these visits is outlined as follows:

At Visits 3 and 4, subjects must return any empty or unused bottles to permit drug 
accountability and compliance to be assessed.

Subjects will be dispensed a 9-count bottle of investigational product to cover them 
until their next regularly scheduled visit. Subjects will be instructed to take 1 capsule 
each day. Dosing will begin the morning after each visit.

Blood pressure and pulse will be collected 3 times (with at least 2 minutes in between 
each collection) using the age-appropriate cuff during the visit. The average of each 
set of 3 measurements will be used to determine continued participation in the study 
(see Section 4.3.1).

Scales should be completed by the same rater with input from the same parent/LAR 
whenever possible.

The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired 
Version should be completed during Visits 3 and 4.
7.1.2.1
Treatment Period (Visits 5 to 16/Early Termination)
Subjects will continue daily morning treatment for an additional 12 months.  
Throughout the treatment period, subjects may attend the clinic for unscheduled visits to address 
any medical needs that arise between scheduled visits.


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Table 1 (Group A) and Table 2 (Group B) outline the procedures to be completed at each visit 
during the treatment period and should serve as the primary point of reference regarding study 
procedures. Additional clarification on the procedures to be performed during the treatment 
period Visits 5 to 16 is provided as follows:

Scales are to be completed by the same rater with input from the same parent/LAR 
whenever possible

At each visit during the treatment period, subjects must return any empty or unused 
bottles to permit drug accountability and compliance to be assessed

Subjects will be dispensed a 9-count bottle of investigational product to cover them 
until their next regularly scheduled visit. Subjects will be instructed to take 1 capsule 
each day. Dosing will begin the morning after each visit.

The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired 
Version should be completed during the treatment period.

Blood pressure and pulse will be collected 3 times (with at least 2 minutes in between 
each collection) using the age-appropriate cuff during the visit. The average of each 
set of 3 measurements will be used to determine continued participation in the study 
(see Section 4.3.1).
All subjects who complete the study or discontinue early will complete Visit 16/ET.
Table 1 (Group A) and Table 2 (Group B) outline all procedures to be conducted during 
Visit 16/ET and should serve as the primary point of reference regarding study procedures.
Further clarification on the procedures performed during Visit 16/ET is provided as follows:

Unused investigational product and empty containers will be collected to calculate 
medication compliance.

Blood pressure and pulse will be collected 3 times (with at least 2 minutes in between 
each collection) using the age-appropriate cuff during the visit. The average of each 
set of 3 measurements will be used to determine continued participation in the study 
(see Section 4.3.1).
7.1.3
Safety Follow-up Period (Group A and Group B)
The follow-up period for this protocol is 7 days (+2 days) from the final dose of investigational 
product.
At the end of this period, there will be a telephone call initiated by the site staff to query for 
serious adverse events (SAEs), TEAEs, and concomitant treatments. All TEAEs and SAEs that 
are not resolved at the time of this contact will be followed to closure (see Section 8.1).


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7.1.4
Additional Care of Subjects After the Study
No aftercare is planned for this study. The investigator will discuss the available ADHD 
treatment options for subjects.
7.2
Study Evaluations and Procedures
The individual indicated in each scale description will perform all assessments listed as follows. 
Assessments are to be performed according to the schedule shown in Table 1 (Group A) and
Table 2 (Group B). Care must be taken by the site personnel or the investigator to fully explain 
the scale before completion.
If the subject terminates treatment early, all assessments listed in Table 1 (Group A) and Table 2
(Group B) for Visit 16/ET and the safety follow-up call should be completed. Whenever 
possible, raters (including parent/LAR, and the investigator or site designee) observing the 
subject’s behavior should be consistent from visit to visit throughout the study.
7.2.1
Demographic and Other Baseline Characteristics
Demographic characteristics such as age, sex, weight, height, and BMI will be collected 
throughout the study according to Table 1 (Group A) and Table 2 (Group B).
7.2.1.1
Mini International Neuropsychiatric Interview for Children and 
Adolescents
The MINI-KID is a structured clinical diagnostic interview designed to assess the presence of 
psychiatric disorders in children and adolescents in a way that is comprehensive and concise. It 
follows the structure and format of the adult version of the interview and is organized in 
diagnostic sections or modules. Using branching tree logic, the instrument asks 2 to 4 screening 
questions for each disorder. Additional symptom questions within each disorder section are 
asked only if the screen questions are positively endorsed. The MINI-KID is the structured 
psychiatric interview of choice for psychiatric evaluation and outcome tracking in clinical 
psychopharmacology trials and epidemiological studies. In a validation study (Sheehan et al., 
2010), the MINI-KID generated reliable and valid psychiatric diagnoses for children and 
adolescents and does so in one-third of the time as the Kiddie Schedule for Affective Disorders 
and Schizophrenia Present and Lifetime Version. The standard MINI-KID Version 7.0.2 for 
DSM-5 assesses the 30 most common and clinically relevant disorders or disorder subtypes in 
pediatric mental health. With this version the child and parent are interviewed together. The 
MINI-KID should be completed by an individual who has experience in the evaluation of 
pediatric patients with ADHD and the scale, and may include physicians, or licensed 
psychologists/clinicians. All individuals performing this assessment must be preapproved by the 
sponsor or designee.


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7.2.2
Efficacy
7.2.2.1
The ADHD-Rating Scale-5
The ADHD-RS-5 (DuPaul et al., 2016), the primary efficacy measure, is completed by the 
clinician and will be administered at baseline and each subsequent visit up to and including 
Visit 16/ET to capture the ADHD symptoms within each study period. 
The ADHD-RS rating scale was developed to measure the behaviors of children with ADHD and 
is commonly used in clinical studies of ADHD (Buitelaar et al., 2007; Döpfner et al., 2006; 
Kratochvil et al., 2001; Michelson et al., 2001; Spencer et al., 2001). The ADHD-RS-5 consists 
of 18 items designed to reflect current symptomatology of ADHD based on DSM-5 criteria. 
Each item is scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting 
severe symptoms) with total scores ranging from 0-54. The 18 items may be grouped into 
2 subscales: hyperactivity/impulsivity (9 items) and inattentiveness (9 items).
The ADHD-RS-5 should be completed by a clinician experienced in the evaluation of children 
with ADHD. Since the ADHD-RS-5 is an important measure for guidance in dosing decisions, 
the ADHD-RS-5 must be performed by an individual who is experienced with the scale. All 
individuals performing this assessment must be pre-approved by the sponsor or designee.
The title, version, and date of the ADHD-RS-5 used in this study are included in Table 1.
7.2.2.2
Clinical Global Impression
The Clinical Global Impression Scale (Guy, 1976) permits a global evaluation of the subject’s 
severity and improvement over time. 
The Clinical Global Impression has been used extensively in clinical studies of ADHD 
(Michelson et al., 2001; Weiss et al., 2005; Wilens et al., 2001).
For Group B, the investigator will perform the CGI-S to rate the severity of a subject’s condition 
on a 7-point scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill 
subjects) at the baseline visit (Visit 2). Additionally at the baseline visit, the investigator should 
establish 3 target areas of improvement with the subject and the subject’s parent/LAR. To 
generate the targets, an open-ended question such as “If this program of treatment works for your 
child, what things do you hope he/she will be doing better?” should be asked. Ratings will be 
completed with respect to ADHD symptoms.
For Group A and Group B, at each visit from Visit 3 up to and including Visit 16/ET, the 
investigator will assess the subject’s improvement relative to the 3 target areas of improvement 
recorded at the baseline visit (Visit 2), on the CGI-I, a 7-point scale ranging from 1 (very much 
improved) to 7 (very much worse).
The CGI-S and CGI-I should be completed by a clinician experienced in the evaluation of 
children with ADHD. Since the CGI-I is an important measure for guidance in dosing decisions, 
the CGI-I must be performed by a principal investigator or subinvestigator who is 


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medically/clinically responsible for the subject and experienced with the scale. All individuals 
performing this assessment must be pre-approved by the sponsor or designee
The title, version, and date of the CGI-S and the CGI-I used in this study are included 
in Appendix 3.
7.2.3
Safety
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.
7.2.3.1
Medical and Medication History
For subjects in Group A, any new medical history, ie, medical conditions that arose after the 
recording of the medical history in the antecedent study will be recorded at baseline (Visit 2).
For subjects in Group B, the investigator will take a complete medical history at the screening 
visit (Visit 1), including a medication history, and record all information gathered. The 
investigator must record all clinically or medically relevant information regardless of how much 
time has elapsed since the date of diagnosis.
With the consent of the subject and subject’s parent/LAR, medical records from other treatment 
providers should be requested.
7.2.3.2
Physical Examination (Including Height and Weight)
For subjects in Group A, a full physical examination will be performed at the baseline visit 
(Visit 2) and at the end of treatment visit (Visit 16).
For subjects in Group B, a full physical examination will be performed at the screening visit 
(Visit 1) and at the end of treatment visit (Visit 16). Additionally, an abbreviated physical 
examination is required at the baseline visit (Visit 2) if >32 days have elapsed since the physical 
examination completed as part of the screening visit (Visit 1) was performed.
A physical examination will be performed by a qualified, licensed individual per local 
requirements (eg, physician, physician assistant, or nurse practitioner).
A full physical examination is composed of a review of the following body systems:

General appearance

Skin

Head, eyes, ears, nose, and throat

Spine/Neck/Thyroid

Respiratory

Cardiovascular

Abdomen (including liver and kidneys)


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
Musculoskeletal

Neurological
If an abbreviated physical examination is required at the baseline visit (Visit 2), a review of the 
body systems will include the following:

General appearance

Respiratory

Cardiovascular
For subjects in Group A, abnormalities identified at the baseline visit (Visit 2) will be 
documented in the subject’s source documents. Changes after the baseline visit (Visit 2) will be 
captured as TEAEs, as determined by the investigator.
For subjects in Group B, abnormalities identified at the screening visit (Visit 1) will be 
documented in the subject’s source documents. Changes after the screening visit (Visit 1) will be 
captured as TEAEs, as determined by the investigator.
7.2.3.3
Adverse Event Collection
At each study visit, parent/LAR and/or subject will be questioned in a general way to ascertain if 
AEs 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. (Refer to 
Section 8.) This information should be collected prior to the completion of assessments at all 
study visits. In addition, any symptoms/conditions reported during assessments and deemed to be 
clinically significant by the investigator will be assessed as AEs. 
7.2.3.4
Vital Signs
For subjects in Group A, measurements of oral or tympanic temperature, pulse, sitting blood 
pressure, and respiratory rate will be performed according to the schedule shown in Table 1. 
Measurement of temperature and respiratory rate will be performed as part of the last dose 
maintenance visit of the antecedent study.
For subjects in Group B, measurements of oral or tympanic temperature and sitting respiratory 
rate will be performed at the screening visit (Visit 1) only (Table 2). Measurements of sitting 
systolic and diastolic blood pressure and pulse will be performed at each visit to the site. Blood 
pressure, pulse, and respiratory rate will be determined after subjects have remained seated for a 
minimum of 3 minutes.
Blood pressure will be determined by age-appropriate cuff (the same equipment and the same 
arm should be used throughout the study). A blood pressure cuff appropriate for the subject’s 
arm length and girth should be used for all blood pressure measurements. The age-appropriate 
cuff should be approximately two-thirds the length/width of the subject’s arm (from elbow to 
shoulder). All blood pressure measurements should be performed throughout the study using the 
age-appropriate cuff and should be performed by the same study center personnel (if possible) 


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throughout the study. Three measurements should be obtained using the age-appropriate cuff 
with at least 2 minutes in between each collection for blood pressure and pulse and report the 
average of the 3 measurements for each parameter. The 3 individual measurements and the 
averaged reading should be recorded in the source documents.
Any clinically significant deviations from baseline (Visit 2) in vital signs that are deemed 
clinically significant in the opinion of the investigator are to be recorded as a TEAE.
7.2.3.5
Height and Weight
Height will be captured at baseline and each monthly treatment visit for all subjects. A calibrated 
stadiometer must be used for all height measurements. Height should be measured in inches or 
centimeters without shoes with the subject standing on a flat surface and with chin parallel to the 
floor. The body should be straight but not rigid. The subject’s height should be recorded as 
accurately as possible and should be recorded to the nearest centimeter.
Weight will be captured at each visit to the site. The same calibrated scale must be used for all 
weight measurements. Weight should be measured in pounds or kilograms without shoes and 
with light clothing. Weight should be recorded as accurately as possible and should be recorded 
to the nearest 0.1 pound or 0.1 kilogram. 
7.2.3.6
Clinical Laboratory Evaluations
All clinical laboratory assays will be performed according to the laboratory’s normal procedures. 
Reference ranges are to be supplied by the laboratory and will be 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, indicating if the 
value(s) is/are not clinically significant or clinically significant. Abnormal clinical laboratory 
values, which 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.
Clinical laboratory evaluations will be performed as per schedule of assessments Table 1
(Group A) and Table 2 (Group B). Additionally, for subjects in Group B, clinical laboratory tests 
are required to be repeated before the baseline visit (Visit 2), and the results reviewed before 
enrolling the subject in the study, if >32 days have elapsed since the clinical laboratory 
evaluations completed as part of the screening visit (Visit 1) were performed.
*Note: Blood and urine samples may be stored for up to but not longer than 25 years.


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The following clinical laboratory evaluations will be performed:
Biochemistry and Endocrinology
A blood sample (~3 mL) for biochemistry will be taken to assess the following parameters:
Total cholesterol
Calcium
Aspartate aminotransferase 
Urate
Phosphorus
Blood urea nitrogen
Alanine aminotransferase
Total bilirubin
Sodium
Creatinine
Alkaline phosphatase
Glucose
Potassium
Albumin
Gamma-glutamyl transferase 
Total protein
Thyroid-stimulating hormone
Lactate dehydrogenase
Thyroxine, Free
Hematology
A blood sample (~2 mL) for hematology will be taken to assess the following parameters:
Hemoglobin
Neutrophils
Hematocrit
Lymphocytes
Red blood cells
Monocytes
Platelet count
Eosinophils
White blood cell count – total and differential 
Basophils
Mean corpuscular hemoglobin 
Neutrophils Band Forms
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume


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Urinalysis
A urine sample (~10 mL) for urinalysis will be collected to assess the following parameters:
Glucose
pH
Specific gravity
Urobilinogen
Blood
Color
Ketones
Leukocyte esterase
Protein
Nitrite
Bilirubin
If urinalysis detects protein and/or blood, a microscopic examination will be conducted. The 
microscopic examination will consist of red blood cell, white blood cell, casts, and bacteria.
For Group B subjects, a urine drug and alcohol screen will be conducted at the screening visit 
(Visit 1). As a reminder, a urine drug screen should be repeated at the baseline visit (Visit 2) if 
more than 32 days have elapsed since the screening visit (Visit 1). The following drugs/drug 
classes will be tested:
Urine Drug Screen
Cocaine
Cannabinoids
Phencyclidine
d-amphetamine
Benzodiazepines class
Barbiturates class
Opiates class
Propoxyphene
Methaqualone
Methadone
Methamphetamine
The urine drug screen must be negative at the screening visit (Visit 1) for the subject to be 
eligible to enroll in the study.
If the subject has a positive urine drug screen at the screening visit (Visit 1) that the investigator 
is able to attribute to a medication that has been prescribed to the subject, the urine drug screen 
must be repeated at the baseline visit (Visit 2) and must be negative so the investigator can verify 
that the disallowed medication which caused a positive result at the screening visit (Visit 1) has 
been discontinued prior to the baseline visit (Visit 2). 
7.2.3.7
Pregnancy Test
For Group A subjects, a serum -HCG pregnancy test is performed on all females of 
child-bearing potential at the baseline visit (Visit 2). For Group B subjects, a serum -HCG 


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pregnancy test is performed on all females of child-bearing potential at the screening visit 
(Visit 1).
Additionally, the serum pregnancy test must be repeated at the baseline visit (Visit 2) if greater 
than 32 days have elapsed since the screening visit (Visit 1). The results must be reviewed by the 
investigator before the subject can be randomized. 
For Group A subjects, a urine pregnancy test is performed on all females of child-bearing 
potential at Visit 5, and all subsequent visits until Visit 16/ET. For Group B subjects, a urine 
pregnancy test is performed on all females of child-bearing potential at the baseline visit 
(Visit 2), and all subsequent visits from Visit 5 to Visit 16/ET.


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7.2.3.8
Electrocardiogram
A 12-lead ECG will be performed as per schedule of assessments Table 1 (Group A) and Table 2
(Group B). Additionally, for subjects in Group B, a 12-lead ECG is required to be repeated 
before the baseline visit (Visit 2), and the results reviewed before enrolling the subject in the 
study, if >32 days have elapsed since the 12-lead ECG completed as part of the screening visit 
(Visit 1) was performed. Additional ECGs may be performed during the study at the 
investigator’s discretion. Electrocardiograms will be recorded in triplicate with approximately 
3 minutes apart at the screening visit or baseline visit for Group B.
All ECGs will be performed after 3 minutes of rest using the central ECG provider’s equipment 
and will be sent to the central ECG provider electronically.
The initial interpretation of the ECG, normal or abnormal and clinical significance, will be 
performed immediately after collection to ensure the safety of each subject. An ECG tracing will 
then be evaluated by a cardiologist at a central ECG reading vendor and returned to the site with 
a determination of normal or abnormal. Upon review of the report from this vendor, the 
investigator will re-evaluate the clinical significance of the ECG while taking into consideration 
all other safety data available for the subject.
Although a central ECG reader is being used for this study, the eligibility of the subject is based 
on the investigator’s assessment of the ECG. If abnormal and significant results are observed 
following assessment by the central reader, the investigator, in consultation with the appointed 
CRO medical monitor, reconfirms subject eligibility to continue.
All ECGs transmitted to the central ECG reader will be analyzed. If the central ECG reader 
receives multiple ECGs, the first readable ECGs will be analyzed as the scheduled ECG. Every 
ECG transmitted to the central ECG reader will have corresponding source document data 
collected. No ECG should be deleted by study site personnel. All ECGs must be transmitted to 
the central provider regardless of quality, results, or number of ECGs taken at a respective visit.
7.2.3.9
Post Sleep Questionnaire
The PSQ is a 7-item questionnaire typically used to assess sleep quality with pharmacologic 
treatment. The questionnaire collects data on average time to sleep, sleep latency, frequency of 
interrupted sleep, duration of interrupted sleep, total sleep time and sleep quality over the last 
week. The PSQ will be completed by the parent/LAR with the subject and the responses will be 
reviewed by the clinician during the study visit. 
The PSQ will be conducted at each visit to the site starting with the baseline visit (Visit 2) and 
will be completed by the subject’s parent/LAR. The title, version, and date of the PSQ version 
used in this study are included in Appendix 3.
7.2.3.10
Children’s Sleep Habits Questionnaire 
The CSHQ is a tool designed to screen for the most common sleep problems in children and 
consists of 33 items for scoring and several extra items intended to provide administrators with 
other potentially useful information about respondents. The instrument evaluates the child’s 


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sleep based on behavior within 8 different subscales: bedtime resistance, sleep-onset delay, sleep 
duration, sleep anxiety, night wakings, parasomnias, sleep-disordered breathing, and daytime 
sleepiness. 
The CSHQ will be conducted at each visit to the site starting with the baseline visit (Visit 2) and 
will be completed by the subject’s parent/LAR.
7.2.3.11
Columbia-Suicide Severity Rating Scale-Baseline Version
The C-SSRS (Posner, 2007) is a semistructured interview that captures the occurrence, severity, 
and frequency of suicide related thoughts and behaviors during the assessment period. The 
interview includes definitions and suggested questions to solicit the type of information needed 
to determine if a suicide-related thought or behavior occurred.
The C-SSRS contains 2 required items pertaining to suicidal ideation, 4 required items pertaining 
to suicidal behavior, and 1 required item pertaining to nonsuicidal but self-injurious behavior. In 
situations where there is a positive response to the screening questions, there are 8 additional 
suicidal ideation items and 4 additional suicidal behavior items which are completed. Thus, there 
is a maximum of 19 items to be completed.
The C-SSRS must be performed by an individual who is medically responsible for the subject. 
All individuals performing this assessment must be preapproved by the sponsor or delegated 
vendor.
The Pediatric/Cognitively Impaired Version of the scale will be used in the study. Two time 
point versions of the C-SSRS are used in this study as follows:

For Group B subjects only, the “baseline” version will be administered at the 
screening visit (Visit 1).

For Group A and B subjects, the “since last visit” version will be completed at the 
baseline visit (Visit 2) and all visits afterwards.
The title, version, and date of the C-SSRS “baseline” version and the C-SSRS “since last visit” 
version used in this study are included in Appendix 3.
7.2.3.12
Suitability of the Subject to Remain in the Study
At each visit (except for Visit 16/ET) starting with the baseline visit (Visit 2), the investigator 
will assess the subject’s ability to continue in the study. The investigator or a medically qualified
designee will review all available safety information (including sleep behavior, weight and BMI) 
and will evaluate for the presence of insomnia or decreased appetite potentially leading to weight 
loss. In cases where the subject has clinically significant decreases in appetite or insomnia, the 
investigator should intervene as necessary based on clinical judgment (eg, diet, behavioral 
interventions, sleep hygiene) and consider discontinuation of treatment if necessary. In any cases 
where a subject has clinically significant and persistent sleep difficulties (eg, the CSHQ score of 
≥41 for 2 consecutive weeks since the beginning of treatment) or has had ≥7% weight loss the 
investigator must discuss the case with the medical monitor and assess whether it’s in the best 


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interest for the subject to remain in the study. The evaluation and decision should also be clearly 
documented in the subject’s source notes.
As part of the assessment of the subject’s suitability to remain in the study the investigator 
should also assess the subject’s current potential for suicide, suicidal ideation, self-harm, or harm 
to others, as well as psychiatric disorders. The investigator should make this assessment by 
conducting a clinical interview with the subject and by reviewing of all other relevant sources 
available, including results of the C-SSRS. Any subject who has 1 or more positive responses 
must undergo further evaluation to ensure that they are not in any way at risk. 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 investigator should pay particular attention to:

Any ‘yes’ response to Items 2, 3, 4, or 5 on the C-SSRS or any suicidal behavior
The subject’s source notes should clearly document that the assessment of continued suitability 
including assessment of the subject’s appetite, weight loss, insomnia and 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.
7.2.4
Volume of Blood to Be Drawn From Each Subject
Table 4:
Volume of Blood to Be Drawn From Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Safety
Biochemistry
3
3
9
Hematology
2
3
6
Total
15
During this study, it is expected that approximately 15 mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 15 mL. When >1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments may be combined. If a 
catheter is used, the first 1 mL of blood from each sampling will be discarded. For subjects in 
Group B, biochemistry and hematology clinical laboratory tests will be repeated at the baseline 
visit (Visit 2) if >32 days have elapsed since the screening visit (Visit 1).


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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 and 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 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is 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 in the source 
documents. In addition to untoward AEs, unexpected benefits outside the investigational product 
indication should also be captured.
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 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 are performed so that resolution of 
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 pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia before 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate source documents).
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 investigational product 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 investigational product. 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 investigational product and the occurrence 
of the AE, then the AE should be considered “related.” The causality assessment must be 
documented in the source documents.
The following additional guidance may be helpful:
Term
Relationship Definition
Related
The temporal relationship between the event and the administration of the 
investigational product 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 investigational product and the event.
8.1.3
Outcome Categorization
The outcome of AEs must be recorded during the course of the study on the source documents. 
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 investigational product, a shift 


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of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. 
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 investigational product, 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 phase, there are abnormal clinical laboratory, vital sign, or ECG 
values that were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is 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 informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant or the partner of a male study 
participant must be reported within 24 hours to the Shire Global Drug Safety Department using 
the Shire Investigational and Marketed Products Pregnancy Report Form. A copy of the Shire 
Investigational and Marketed Products Pregnancy Report Form (and any applicable follow-up 
reports) must also be sent to the CRO/Shire Medical Monitor using the details specified in the 
emergency contact information section of the protocol. The pregnant female study participant 
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 post partum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Trial Serious Adverse Event 
Form. Note:  An elective abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Trial Serious Adverse Event Form as well 
as the Shire Investigational and Marketed Products Pregnancy Report Form. The test date of the 
first positive serum/urine -HCG test or ultrasound result will determine the pregnancy onset 
date.
8.1.7
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined as follows) must be reported to the 
sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 


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described in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE.
The following categories are not mutually exclusive; the event can meet >1 category:

Abuse – Persistent or sporadic intentional intake of investigational product 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 investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose of 1 capsule of the product.

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined as follows.
Cases of subjects missing doses of the investigational product 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 investigational product should be considered as a 
reportable medication error.
All investigational product provided to pediatric subjects should be supervised by the 
parent/LAR.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the investigator’s brochure, which the 
sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Drug Safety Department and the CRO/Shire medical monitor within 24 hours of the first 
awareness of the event. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors (see Section 8.1.7) unless they result in 
an SAE.


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The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Nonserious AEs Required by the Protocol 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 Shire Global Drug Safety 
Department. 
A copy of the Shire Clinical Study Serious Adverse Event and Nonserious AEs Required by the 
Protocol Form (and any applicable follow-up reports) must also be sent to the CRO/Shire 
medical monitor using the details specified in the emergency contact information section of the 
protocol.
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product 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.
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 7.1.3 and must be reported 
to the Shire Global Drug Safety Department and the CRO/Shire medical monitor within 24 hours 
of the first awareness of the event.


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In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire 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 investigational product action was previously taken (eg, drug interrupted, reduced, 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the 
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and clinical CRO are responsible for notifying the relevant regulatory authorities 
and US central IRBs of related, unexpected SAEs.
In addition the sponsor and clinical CRO are responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the SHP465 program.
The investigator is responsible for notifying the local IRB, local Ethics Committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.


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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 source documents. A study monitor will visit each site in accordance with the monitoring 
plan and review the CRF data against the source data for completeness and accuracy. 
Discrepancies between source data and data entered on the CRF 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 source documents entry as soon as possible to ensure data 
accuracy and completeness.
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
Not applicable.
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The statistical analysis plan (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, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized before database lock.
All statistical analyses will be performed using SAS(SAS Institute, Inc, Cary, NC 27513).


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9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
9.5.1
Interim Analysis
After approximately 50 subjects have completed 6 months of study treatment, the database will 
be archived and all available safety and efficacy data will be analyzed for regulatory reporting 
reasons. After the 6-month data cut additional analyses will be performed, where applicable, for 
regulatory purposes such as subsequent safety updates and final report.
9.5.2
Data Monitoring Committee
An external independent data monitoring committee (DMC) was set up to review the data 
pertaining to safety and tolerability of the study therapy for the duration of this program, which 
includes studies SHP465-112, SHP465-308, and SHP465-309. The DMC will review the data 
pertaining to safety and tolerability of the study therapy. Confidentiality of the unblinded DMC 
analyses is a critical concern and to address this, an unblinded independent reporting team will 
be identified within a CRO. The independent reporting team will have no involvement in the 
conduct of the study. Further details regarding the DMC can be found in the DMC charter, which 
will be available before the administration of investigational product. 
Further details regarding the DMC can be found in the DMC charter, which will be available 
before the administration of investigational product.
9.6
Sample Size Calculation and Power Considerations
Approximately 145 subjects will be enrolled into this study to ensure 60 subjects complete at 
least 6 months of study treatment. Subjects will enroll into this study from antecedent studies, 
SHP465-112 or SHP465-309 as well as de novo subjects who can be directly enrolled into this 
study. The sample size was established to provide long term safety data in children aged 4 to 12 
years and will include at least 40 subjects aged 4-5 years at the time of informed consent in the 
antecedent trial or this trial, if directly enrolled.
The sample size for this study is not based on statistical considerations.
9.7
Study Population

The screened set will include all subjects who have provided informed consent.

The enrolled Set will consist of all subjects who have been assigned a subject 
identification number.

The safety set will consist of all subjects who have taken at least 1 dose of 
investigational product.

The full analysis set (FAS) will include all subjects in the safety set who completed at 
least 1 postdose efficacy assessment using ADHD-RS-5 total score.
9.8
Efficacy Analyses
The FAS will be used to report the efficacy data. 


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The efficacy endpoint is defined as the change from baseline in the clinician-administered 
ADHD-RS-5 total score.
The CGI-I will be a second efficacy and used to determine the proportion of subjects with an 
“improved” measurement based on the CGI-S measured at baseline. The CGI-I categories of 
“very much improved” and “much improved” will be classified as “improved” and all other 
assessed categories are grouped together as “not improved.”
Descriptive summary statistics will be presented by treatment group of the antecedent studies 
and overall for the observed efficacy variables. Observed and change from baseline in total score 
for the ADHD-RS-5 total score at each on-therapy treatment visit will be summarized using the 
number of subjects, mean, standard deviation, median, minimum, and maximum values.
The CGI-I categories of “very much improved” and “much improved” will be classified as 
“improved” and all other assessed categories are grouped together as “not improved.”
The number and proportion of subjects with an “improved” measurement in CGI-I will be 
reported at each applicable postdose visit. CGI-I scores will also be summarized.
The efficacy data will be descriptively summarized for each age (4-5 years and 6-12 years), sex, 
race (white and non-white), and ethnicity sub-groups.
Rules for handling of missing data will be described in the SAP.
9.9
Safety Analyses
Safety assessments include the occurrence of TEAEs and evaluations of blood pressure, pulse, 
height, weight, BMI, results of clinical laboratory evaluations and ECG, sleep questionnaires 
(PSQ and CSHQ), and C-SSRS.
The safety set will be used to report the safety data. Safety analyses will be presented by 
treatment group of the antecedent studies and overall.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. Treatment 
emergent AEs are defined as AEs that started or deteriorated on or after the date of the first dose 
of investigational product, and no later than 3 days following the last dose of investigational 
product. The number of events, incidence, and percentage of TEAEs will be calculated overall, 
by system organ class, by preferred term, and by treatment group. Treatment emergent AEs will 
be further summarized by severity and relationship to investigational product. Adverse events 
related to investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed.
Clinical laboratory tests, vital signs, and ECG findings will be summarized by visit. Potentially 
clinically important findings will also be summarized or listed.
The PSQ and CSHQ will be summarized using appropriate descriptive statistics at each visit.


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The C-SSRS results will be summarized and listings of the C-SSRS data will be provided for 
subjects with a positive response.
In addition, the safety data on TEAEs will also be descriptively summarized by treatment within 
each age (4-5 years and 6-12 years), sex, race (white and non-white), and ethnicity subgroup.


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10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, and local ethical 
and legal 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 (1996) and any updates, and 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 source documents 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 before release of 
investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.3
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.
10.1.4
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 


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registered clinical study which has been posted to a designated public website will be updated 
accordingly.
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 
(1996) and any updates, 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 before 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. Curricula vitae for investigators and subinvestigators are 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 the physician of the subject’s participation in the study.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any coinvestigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are 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 investigational product, 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 is provided at 
all phases during the study, 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.


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10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are 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 the 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 will have separate source documentation; no data will be recorded directly onto the 
CRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate/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.
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 electronic diary.
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; the IRB/EC; and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The clinical research associate/study monitor (and auditors, IRB/EC, or regulatory inspectors) 
may check the CRF 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).
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]) 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 


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national and local regulatory authorities), other regulatory authorities, the sponsor or its 
representatives, and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is 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 is 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 investigational product; and any 
significant equity interest in the sponsor or subsidiaries as defined in US FDA 21 Code of 
Federal Regulations 54 2(b) (1998).
10.2.4
Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation
When using controlled substances, biohazardous material, or substances for infectious diseases, 
the investigator must at all times comply with all local, state, and national laws pertaining to 
registration and reporting with the appropriate regulatory body and control and handling of such 
substances.
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent from all 
study subjects before any SHP465-308 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 parent/LAR, 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 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 parent/LAR, 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.
Within the source documents, site personnel should document instruction of and understanding 
by the parent/LAR of the safe, responsible storage, and administration of investigational product 
to the study subject.
The principal investigator provides the sponsor with a copy of the consent form and assent form 
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 before the start of the study unless it is agreed to and documented (abiding by regulatory 
guidelines and national provisions) before study start that another party (ie, sponsor or 


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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
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 before site 
initiation.
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.
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents.
The investigator is responsible for keeping the IRB/EC appraised of the progress of the study and 
of any changes made to the protocol, but in any case at least once a year. For multicenter studies, 
this 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.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with Health Insurance Portability and Accountability Act (HIPAA) of 1996. 
A site that is not a covered entity as defined by HIPAA must provide documentation of this fact 
to the CRO.
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 SHP465; 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.
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).


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The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates 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.
10.5
Study Results/Publication Policy
Shire 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, Shire adheres to external guidelines (eg, Good Publication Practices 2) when 
forming a publication steering committee, which is done for large, multicenter Phase 2 through 
4 and certain other studies as determined by Shire. The purpose of the publication steering 
committee is to act as a noncommercial body that advises or decides on dissemination of 
scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish before 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.
Subject to the terms of the paragraph as follows, 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 before 
submission for publication. If requested in writing by Shire, 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, 


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or termination of the study at all sites, or after the sponsor confirms that 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 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.


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11
REFERENCES
Arnsten, A. F. 2001. Modulation of prefrontal cortical-striatal circuits: relevance to therapeutic 
treatments for Tourette syndrome and attention-deficit hyperactivity disorder. Adv 
Neurol, 85, 333-41.
Bhutta, A. T. & Anand, K. J. 2002. Vulnerability of the developing brain. Neuronal mechanisms. 
Clin Perinatol, 29, 357-72.
Brown, K. 2003. Neuroscience. New attention to ADHD genes. Science, 301, 160-1.
Brown, T. 1996. Attention-Deficit Disorder Scales For Adolescents and Adults. The 
Psychological Corporation.
Buitelaar, J. K., Michelson, D., Danckaerts, M., Gillberg, C., Spencer, T. J., Zuddas, A., Faries, 
D. E., Zhang, S. & Biederman, J. 2007. A randomized, double-blind study of 
continuation treatment for attention-deficit/hyperactivity disorder after 1 year. Biol 
Psychiatry, 61, 694-9.
Döpfner, M., Steinhausen, H. C., Coghill, D., Dalsgaard, S., Poole, L., Ralston, S. J. & ADORE 
Study Group 2006. Crosscultural reliability and validity of ADHD assessed by the 
ADHD Rating Scale in a pan-European study. Eur Child Adolesc Psychiatry, 15, 146-
145.
DuPaul, G. J., Reid, R., Anastopoulos, A. D., Lambert, M., Watkins, M. & Power, T. 2016. 
Parent and teacher ratings of attention-deficit/hyperactivity disorder symptoms: Factor 
structure and normative data. Psychol Assess, 28, 214-25.
Greenfield, B. & Hechman, L. 2005. Treatment of attention deficit hyperactivity disorder in 
adults. Expert Rev Neurother, 5, 107-21.
Guy, W. (ed.) 1976. Clinical Global Impression (CGI), Rockville, MD: US Department of 
Health, Education, and Welfare.
Kahn, R. S., Khoury, J., Nichols, W. C. & Lanphear, B. P. 2003. Role of dopamine transporter 
genotype and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, 
and oppositional behaviors. J Pediatr, 143, 104-10.
Kratochvil, C. J., Bohac, D., Harrington, M., Baker, N., May, D. & Burke, W. J. 2001. An open-
label trial of tomoxetine in pediatric attention deficit hyperactivity disorder. J Child 
Adolesc Psychopharmacol, 11, 167-70.
Kratochvil, C. J., Vaughan, B. S., Harrington, M. J. & Burke, W. J. 2003. Atomoxetine: a 
selective noradrenaline reuptake inhibitor for the treatment of attention-
deficit/hyperactivity disorder. Expert Opin Pharmacother, 4, 1165-74.
Michelson, D., Faries, D., Wernicke, J., Kelsey, D., Kendrick, K., Sallee, F. R. & Spencer, T. 
2001. Atomoxetine in the treatment of children and adolescents with attention-
deficit/hyperactivity disorder: a randomized, placebo-controlled, dose-response study. 
Pediatrics, 108, E83.
NIH 2004. The fourth report on the diagnosis, evaluation, and treatment of high blood pressure 
in children and adolescents. Pediatrics, 114, 555-76.


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Ostchega, Y., Porter, K. S., Hughes, J., Dillon, C. F. & Nwankwo, T. 2011. Resting pulse rate 
reference data for children, adolescents, and adults: United States, 1999-2008. Natl 
Health Stat Report, 1-16.
Posner, K. Suicidality Issues in Clinical Trials: Columbia Suicidal Adverse Event Identification 
in FDA Safety Analyses Division of Metabolism and Endocrinology Products Advisory 
Committee Meeting, Food and Drug Administration, 2007.
Safren, S. A., Sprich, S., Chulvick, S. & Otto, M. W. 2004. Psychosocial treatments for adults 
with attention-deficit/hyperactivity disorder. Psychiatr Clin North Am, 27, 349-60.
Sheehan, D. V., Sheehan, K. H., Shytle, R. D., Janavs, J., Bannon, Y., Rogers, J. E., Milo, K. M., 
Stock, S. L. & Wilkinson, B. 2010. Reliability and validity of the Mini International 
Neuropsychiatric Interview for Children and Adolescents (MINI-KID). Journal of 
Clinical Psychiatry, 71, 313-26.
Spencer, T., Biederman, J., Heiligenstein, J., Wilens, T., Faries, D., Prince, J., Faraone, S. V., 
Rea, J., Witcher, J. & Zervas, S. 2001. An open-label, dose-ranging study of atomoxetine 
in children with attention deficit hyperactivity disorder. J Child Adolesc 
Psychopharmacol, 11, 251-65.
Wang, Y., Zheng, Y., Du, Y., Song, D. H., Shin, Y. J., Cho, S. C., Kim, B. N., Ahn, D. H., 
Marquez-Caraveo, M. E., Gao, H., Williams, D. W. & Levine, L. R. 2007. Atomoxetine 
versus methylphenidate in paediatric outpatients with attention deficit hyperactivity 
disorder: a randomized, double-blind comparison trial. Aust N Z J Psychiatry, 41, 222-30.
Weiss, M. & Murray, C. 2003. Assessment and management of attention-deficit hyperactivity 
disorder in adults. CMAJ, 168, 715-22.
Weiss, M., Tannock, R., Kratochvil, C., Dunn, D., Velez-Borras, J., Thomason, C., Tamura, R., 
Kelsey, D., Stevens, L. & Allen, A. J. 2005. A randomized, placebo-controlled study of 
once-daily atomoxetine in the school setting in children with ADHD. J Am Acad Child 
Adolesc Psychiatry, 44, 647-55.
Wilens, T. E., Spencer, T. J. & Biederman, J. 2002. A review of the pharmacotherapy of adults 
with attention-deficit/hyperactivity disorder. J Atten Disord, 5, 189-202.
Wilens, T. E., Spencer, T. J., Biederman, J., Girard, K., Doyle, R., Prince, J., Polisner, D., 
Solhkhah, R., Comeau, S., Monuteaux, M. C. & Parekh, A. 2001. A controlled clinical 
trial of bupropion for attention deficit hyperactivity disorder in adults. Am J Psychiatry,
158, 282-8.


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12
APPENDICES




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APPENDIX 2
DIAGNOSTIC CRITERIA/DISEASE CLASSIFICATION


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Appendix 2.1
DSM-5 Criteria
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 maladaptive and inconsistent with developmental level:
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 maladaptive and inconsistent with 
developmental level:
Hyperactivity
(a)
often fidgets with hands or feet or squirms in seat
(b)
often leaves seat in classroom or in other situations in which remaining seated is 
expected
(c)
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)
(d)
often has difficulty playing or engaging in leisure activities quietly
(e)
is often “on the go” or often acts as if “driven by a motor”
(f)
often talks excessively


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Impulsivity
(g)
often blurts out answers before questions have been completed
(h)
often has difficulty awaiting turn
(i)
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 (eg, at school 
[or work] and at home).
D. 
There is clear evidence of clinically significant impairment in social, academic, or 
occupational functioning.
E.
The symptoms do not occur exclusively during the course of a Pervasive Development 
Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for 
by another mental disorder (eg, Mood Disorder, Anxiety Disorder, Dissociative 
Disorder, or a Personality Disorder).
Code based on type:
314.01 Attention-Deficit/Hyperactivity Disorder, Combined Type:
if both Criteria A1 and A2 are met for the past 6 months
314.00 Attention-Deficit/Hyperactivity Disorder, Predominately Inattentive Type:
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 
Type: 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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Source: National Heart Lung and Blood Institute; May 2004
http://www nhlbi nih.gov/guidelines/hypertension/child_tbl.htm 
Note: To determine the eligibility of a male subject for entry in the study (based on the study 
inclusion criteria), first determine the percentile of height for the subject based on their age (as a 
whole number based on the subject’s last birthday; see the Boys’ Stature-for-age and Weight-for-
age Percentiles). For subjects who fall between 2 height percentiles, use the lower of the 2 
percentiles. Once the subject’s age and height percentile for age are determined, use the table 
above to determine eligibility. The subject’s systolic and diastolic blood pressure readings at the 
screening visit (Visit 1) and the baseline visit (Visit 2) must not exceed the corresponding table 
value (90th blood pressure percentile) for their age and height percentile.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
   
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
  




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Appendix 2.5
Blood Pressure Levels for Girls by Age and Height Percentile
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Source: National Heart Lung and Blood Institute; May 2004
http://www nhlbi nih.gov/guidelines/hypertension/child_tbl.htm 
Note: To determine the eligibility of a female subject for entry in the study (based on study 
inclusion criteria), first determine the percentile of height for the subject based on their age (as a 
whole number based on the subject’s last birthday; see the Girls’ Stature-for-age and Weight 
Percentiles). For subjects who fall between 2 height percentiles, use the lower of the 2 
percentiles. Once the subject’s age and height percentile for age are determined, use the table 
above to determine eligibility. The subject’s systolic and diastolic blood pressure readings at the 
screening visit (Visit 1) and the baseline visit (Visit 2) must not exceed the corresponding table 
value (90th blood pressure percentile) for their age and height percentile.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
  
 
 
 
  
 
 
  
 
 
 
 
 
 
  
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
 
   
 
 
 
  
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


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APPENDIX 3
SCALES AND ASSESSMENTS
The following scales/assessments will be utilized in this study:
Full Title of Scale/Assessment
Version Number
Date Issued
ADHD-RS-5 Child, Home Version 
N/A
2016
CGI-I and CGI-S
N/A
1976
C-SSRS
Baseline
Since Last Visit
Baseline 23 Jun 2010
Since Last Visit 23 Jun 2010
CSHQ
N/A
2009
MINI-KID
7.0.2
08 Aug 2016
PSQ
N/A
N/A
ADHD-RS-5= Attention-deficit/Hyperactivity Disorder Rating Scale 5; CGI-I= Clinical Global Impressions – Improvement; 
CGI-S= Clinical Global Impressions – Severity of Illness; CSHQ=Children’s Sleep Habits Questionnaire; C-SSRS= Columbia-
Suicide Severity Rating Scale MINI-KID=Mini International Neuropsychiatric Interview for Children and Adolescents; N/A=not 
applicable; PSQ=Post Sleep Questionnaire.
A separate master file containing each scale/assessment listed above will be provided to the site. 
Updates to scales/assessments during the study (if applicable) will be documented in the table 
above and a new master file containing the revised scale/assessment will be provided to the site.

SAP_001.pdf: 


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Protocol SHP465-308
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TABLE OF CONTENTS
LIST OF IN-TEXT TABLES ..........................................................................................................4
LIST OF IN-TEXT FIGURES.........................................................................................................4
ABBREVIATIONS .........................................................................................................................5
1.
INTRODUCTION ...................................................................................................................6
2.
STUDY DESIGN.....................................................................................................................7
2.1
General Study Design.................................................................................................7
2.2
Randomization ...........................................................................................................9
2.3
Blinding......................................................................................................................9
2.4
Schedule of Assessments ...........................................................................................9
2.5
Determination of Sample Size..................................................................................16
2.6
Multiplicity Adjustments for Type I Error Control..................................................16
3.
OBJECTIVES........................................................................................................................17
3.1
Primary Objective ....................................................................................................17
3.2
Secondary Objectives...............................................................................................17
4.
SUBJECT POPULATION SETS ..........................................................................................18
4.1
Screened Set .............................................................................................................18
4.2
Enrolled Set..............................................................................................................18
4.3
Safety Set..................................................................................................................18
4.4
Full Analysis Set ......................................................................................................18
5.
SUBJECT DISPOSITION.....................................................................................................19
6.
PROTOCOL DEVIATIONS .................................................................................................20
7.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................21
7.1
Demographic and Other Baseline Characteristics....................................................21
7.2
Medical History........................................................................................................22
8.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ......................................23
8.1
Exposure to Investigational Product ........................................................................23
8.2
Measurement of Treatment Compliance..................................................................23
9.
PRIOR AND CONCOMITANT MEDICATION .................................................................25
10. EFFICACY ANALYSES ......................................................................................................26
10.1
Primary Efficacy Endpoint and Analysis.................................................................26
10.2
Key Secondary Efficacy Endpoint(s) and Analysis .................................................26
10.2.1 ADHD-RS-5 Child, Home Version.......................................................................26
10.2.2 CGI-I scores...........................................................................................................26
10.3
Exploratory Efficacy Endpoint(s) and Analysis.......................................................27
11. SAFETY ANALYSES...........................................................................................................28
11.1
Adverse Events.........................................................................................................28


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Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
11.1.1 Adverse Events of Special Interest ........................................................................29
11.2
Clinical Laboratory Variables ..................................................................................31
11.3
Vital Signs (Including Height and Weight)..............................................................36
11.4
Electrocardiogram (ECG).........................................................................................42
11.5
Other Safety Variables .............................................................................................44
11.5.1 Columbia-Suicide Severity Rating Scale (C-SSRS)..............................................44
11.5.2 Post Sleep Questionnaire (PSQ) ............................................................................45
11.5.3 Children’s Sleep Habit Questionnaire (CSHQ).....................................................45
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES...........47
13. OTHER ANALYSES ............................................................................................................48
14. INTERIM ANALYSIS ..........................................................................................................49
15. DATA MONITORING/REVIEW COMMITTEE ................................................................50
16. COMPUTER METHODS .....................................................................................................51
17. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ................................................52
18. DATA HANDLING CONVENTIONS.................................................................................53
18.1
General Data Reporting Conventions ......................................................................53
18.2
Derived Efficacy Endpoints .....................................................................................53
18.3
Association of Early Termination Assessments to Scheduled Visits.......................53
18.4
Repeated or Unscheduled Assessments of Safety Parameters.................................54
18.5
Missing Dispensed or Returned Date or Number of Capsules of 
Investigational Product.............................................................................................54
18.6
Missing Date Information for Prior or Concomitant Medications...........................54
18.6.1 Incomplete Start Date ............................................................................................54
18.6.2 Incomplete Stop Date.............................................................................................55
18.7
Missing Date Information for Adverse Events ........................................................56
18.8
Missing Severity Assessment for Adverse Events...................................................56
18.9
Missing Relationship to Investigational Product for Adverse Events......................56
18.10
Character Values of Clinical Laboratory Variables .................................................56
19. REFERENCES ......................................................................................................................57
20. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS..............................58


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Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
LIST OF IN-TEXT TABLES
Table 1
Schedule of Assessments for Group A..........................................................10
Table 2
Schedule of Assessments for Group B ..........................................................13
Table 3
Psychiatric Events .........................................................................................29
Table 4
Criteria for Potentially Clinically Important Laboratory Tests for 
Subjects Aged 4-5 Years ...............................................................................33
Table 5
Criteria for Potentially Clinically Important Laboratory Tests for 
Subjects Aged 6-12 Years .............................................................................35
Table 6
Criteria for Potentially Clinically Significant Vital Sign Findings in 
Subjects Aged 4-5 Years ...............................................................................38
Table 7
Criteria for Potentially Clinically Significant Vital Sign Findings for 
Subjects Aged 6-12 Years .............................................................................38
Table 8
Normal Range of Pulse Rate (beats/min) ......................................................39
Table 9
95th Percentile Cut-off Values of Blood Pressure Norms by Sex, Age, 
and Height Percentiles...................................................................................41
Table 10
Criteria for Potentially Clinically Important ECG Values for Age 4-5 
Years..............................................................................................................43
Table 11
Criteria for Potentially Clinically Important ECG Values for Age 6-12 
Years..............................................................................................................43
LIST OF IN-TEXT FIGURES
Figure 1:
Study Design Flow Chart for Group A............................................................8
Figure 2:
Study Design Flow Chart for Group B............................................................8


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CONFIDENTIAL
Page 5
Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
ABBREVIATIONS
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS-5
Attention-deficit/Hyperactivity Disorder Rating Scale 5
AE
adverse event
BMI
body mass index
CGI
Clinical Global Impressions
CGI-I
Clinical Global Impressions – Improvement
CGI-S
Clinical Global Impressions – Severity of Illness
CRF
case report form
CRO
contract research organization
CSHQ
Children’s Sleep Habits Questionnaire
C-SSRS
Columbia-Suicide Severity Rating Scale
DMC
data monitoring committee
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th edition
EC
Ethics Committee
ECG
electrocardiogram
ET
early termination
FAS
full analysis set
FoTA
Final on-Treatment Assessment
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
ICH
International Council for Harmonisation
IRB
Institutional Review Board
IWRS
interactive web response system
LAR
legally authorized representative
MINI-KID
Mini International Neuropsychiatric Interview for Children and 
Adolescents
PSQ
Post Sleep Questionnaire
PK
pharmacokinetic(s)
RBC
red blood cells
REML
restricted maximum likelihood
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
TEAE
treatment-emergent adverse event
US
United States
WBC
white blood cells
WHO
World Health Organization


Shire
CONFIDENTIAL
Page 6
Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
1.
INTRODUCTION
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of safety and efficacy data as described in the SHP465-308 study protocol 
Amendment version 2.0 dated 18 May 2018, the protocol administrative change #1 dated 17 Oct 
2017, the protocol administrative change #2 dated 27 Nov 2017, the protocol administrative 
change #3 dated 22 Mar 2018, and the protocol administrative change #4 dated 21 Sep 2018. 
Specifications for tables, figures, and listings are contained in a separate document.
Final results of the SHP465-309 study have confirmed that the dose of 6.25 mg was safe and 
well-tolerated but was not efficacious in the treatment of ADHD in children 6-12 years old. Shire 
decided to terminate the ongoing open-label SHP465-308 study on 14 Dec 2018. All data 
collected will be used in the analyses and the analysis results will be reported.


Shire
CONFIDENTIAL
Page 7
Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
2.
STUDY DESIGN
2.1
General Study Design
Study SHP465-308 is a Phase 3, open-label, multicenter, 12-month safety and tolerability study 
of SHP465 in children (aged 4-12 years, inclusive, at the time of consent was obtained in the 
antecedent study [SHP465-112 or SHP465-309] or at the time of consent into this study if 
directly enrolled) with ADHD.
Approximately 80 subjects will be enrolled into this study. Subjects enrolled in this study will be 
divided into 2 groups based on participation in antecedent studies as follows: 

Subjects in Group A are those who have been rolled over from antecedent studies 
(SHP465-112 or SHP465-309). These subjects do not need additional screening and 
washout procedures. 

Subjects in Group B will be directly enrolled subjects who will be required to undergo full 
screening and washout procedures before first dose.
Antecedent study SHP465-112 is a Phase 1 study in subjects aged 4-5 years who were 
administered 6.25 mg SHP465. Antecedent study SHP465-309 is a Phase 3 study in subjects 
aged 6-12 years who were randomized to either 6.25 mg SHP465 or placebo.
For subjects in Group A, the baseline defined in the antecedent study, SHP465-112 or SHP465-
309, will serve as the baseline visit (Visit 2) for analyses of this study. For subjects in Group B, a 
screening visit will precede a washout period. Data will be summarized using the following 
layouts:

For full analysis, data will be summarized using the following 5 columns:
o
Antecedent Study:
•
Group A 112 SHP465 6.25mg
•
Group A 309 Placebo
•
Group A 309 SHP465 6.25mg
o
Direct Enrollment: Group B SHP465 6.25mg
o
Total

For full analysis by-age group summaries, data will be summarized using the following 3 
columns:
o
Group A Antecedent Study
o
Group B Direct Enrollment
o
Total
For all subjects in Group A and Group B, SHP465 will be administered as a daily morning dose 
of 6.25 mg in the treatment of ADHD.




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CONFIDENTIAL
Page 9
Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
2.2
Randomization
No randomization will be conducted for this study.
2.3
Blinding
This is an open-label study. No blinding is needed.
2.4
Schedule of Assessments
Table 1 and Table 2 below present a schedule of study assessments.


Shire
CONFIDENTIAL
Page 10
Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
Table 1
Schedule of Assessments for Group A
Period
Baseline
Treatment Period
1-Week 
Safety
Follow-up
Visita
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ 
ETb
Telephone 
Call
Assessment 
Week/Month 
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Day
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
Informed consent/assent
Inclusion/exclusion 
criteriac

Subject demographics

Medical and medication 
history d

Physical examination


Vital signse, f















Heightg















Weightg















Clinical laboratory testsh



Electrocardiogram 
(12-lead)i








Serum pregnancy testl 

Urine pregnancy testl












ADHD-RS-5k















CGI-Ij














PSQj















CSHQj















C-SSRS since last visit 
versionk















Suitability of subject to 
remain in studyj
















Shire
CONFIDENTIAL
Page 11
Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
Table 1
Schedule of Assessments for Group A
Period
Baseline
Treatment Period
1-Week 
Safety
Follow-up
Visita
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ 
ETb
Telephone 
Call
Assessment 
Week/Month 
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Day
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
Concomitant 
medications
















Adverse Events
















Access IWRS















Investigational product 
dispensed














Investigational product 
returned














Investigational product 
compliance














ADHD-RS-5 =Attention-deficit/Hyperactivity Disorder-Rating Scale 5, Child, Home Version; BMI=body mass index; CGI-I=Clinician’s Global Impressions − Improvement; 
CGI--S=Clinician’s Global Impressions – Severity of Illness; CSHQ=Children’s Sleep Habits Questionnaire; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; ET=early termination; IWRS=interactive web response system; M=month; MINI-KID=Mini International Neuropsychiatric Interview for Children and 
Adolescents; PSQ=Post Sleep Questionnaire; W=week.
a Visit windows are with respect to baseline (Visit 2): ±2 days for Visit 3-4 and ±5 days for Visit 5-16 during treatment period, and +2 days for the safety follow up telephone call.
b Subjects who terminate early will undergo the evaluations listed for Visit 16.
c Inclusion/exclusion criteria will be reviewed at baseline (Visit 2).
d Medical history will include all lifetime psychiatric and nonpsychiatric medications and procedures.
e Vital signs include oral or tympanic temperature, pulse, sitting blood pressure, and respiratory rate. The subject will have been seated for a minimum of 3 minutes before blood 
pressure, pulse, and respiratory rate measurements are taken. Measurement of blood pressure and pulse will be collected 3 times (with at least 2 minutes in between each 
collection) using the provided age-appropriate cuff. The average of each set of 3 measurements will be used to determine continued participation in the study.
f Blood pressure and pulse rate will be measured at each study visit. Temperature and respiratory rate will be measured at baseline (Visit 2).
g Height and weight will be measured without shoes and with light clothing using a stadiometer for height and calibrated scale for weight.
h Clinical laboratory evaluations will include hematology, biochemistry, endocrinology, and urinalysis.
i Electrocardiograms will be recorded in triplicate with at least 3 minutes in between each collection at baseline only.
j Whenever possible, the same individual should complete/rate consistently the following scales and questionnaires as appropriate: ADHD-RS-5, CGI-I, and subject check to 
remain in the study; PSQ, and CSHQ. Include assessment of decreased appetite.
k C-SSRS Pediatric/Cognitively impaired “Since Last Visit” version is completed for all visits. The scale will be compared with the C-SSRS Pediatric/Cognitively impaired 


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CONFIDENTIAL
Page 12
Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
Table 1
Schedule of Assessments for Group A
Period
Baseline
Treatment Period
1-Week 
Safety
Follow-up
Visita
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ 
ETb
Telephone 
Call
Assessment 
Week/Month 
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Day
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
“Baseline” from the antecedent study.
l For females of child-bearing potential only.


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Page 13
Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
Table 2
Schedule of Assessments for Group B
Period
Screening/
Washouta
Baseline
Treatment Period
1-Week 
Safety
Follow-
up
Visit Numberb
1
Phone
call
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ 
ETc
Telephon
e Call
Assessment 
Week/Month 
-5 to -1
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Dayb
–32 to –
3
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
Informed 
consent/assent

Inclusion/exclusion 
criteriad



Subject 
demographics

MINI-KID

Medical and 
medication history 
includes prior 
medications and 
procedurese

Urine drug screen

g
Serum pregnancy 
testi 

g
Urine pregnancy testi













ADHD-RS-5f















CGI-Sf

CGI-If














Physical examination

g

Heighth
















Weighth
















Vital signsj, k

g
















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CONFIDENTIAL
Page 14
Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
Table 2
Schedule of Assessments for Group B
Period
Screening/
Washouta
Baseline
Treatment Period
1-Week 
Safety
Follow-
up
Visit Numberb
1
Phone
call
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ 
ETc
Telephon
e Call
Assessment 
Week/Month 
-5 to -1
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Dayb
–32 to –
3
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
Clinical laboratory 
testsl

g


Electrocardiogram 
(12-lead)m
m
g, m







C-SSRS baseline 
versionf

C-SSRS since last 
visit versionf















PSQf















CSHQf















Adverse Events


















Concomitant 
medications


















Suitability of subject 
to remain in studyf














IWRS
















Study drug 
dispensed














Study drug capsules 
returned
















Shire
CONFIDENTIAL
Page 15
Statistical Analysis Plan Version 2.0
Protocol SHP465-308
14 Feb 2019
Table 2
Schedule of Assessments for Group B
Period
Screening/
Washouta
Baseline
Treatment Period
1-Week 
Safety
Follow-
up
Visit Numberb
1
Phone
call
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16/ 
ETc
Telephon
e Call
Assessment 
Week/Month 
-5 to -1
0
W1
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12
W53
Assessment Dayb
–32 to –
3
0
7
14
30
60
90
120
150
180
210
240
270
300
330
360
367
ADHD-RS-5 =Attention-deficit/Hyperactivity Disorder-Rating Scale 5, Child, Home Version; BMI=body mass index; CGI-I=Clinician’s Global Impressions − Improvement; 
CGI--S=Clinician’s Global Impressions – Severity of Illness; CSHQ=Children’s Sleep Habits Questionnaire; C-SSRS=Columbia-Suicide Severity Rating Scale; 
ECG=electrocardiogram; ET=early termination; IWRS=interactive web response system; M=month; MINI-KID=Mini International Neuropsychiatric Interview for Children and 
Adolescents; PSQ=Post Sleep Questionnaire; W=week.
a Following successful screening, a site representative will contact the subject's parent/LAR to instruct the subject on discontinuing any prohibited medication for the washout 
period.
b Visit windows are with respect to baseline (Visit 2): ±2 days for Visit 3-4 and ±5 days for Visit 5-16 during treatment period, and +2 days for the safety follow-up telephone call.
c Subjects who terminate early will undergo the evaluations listed for Visit 16.
d Inclusion/exclusion criteria will be reviewed during the washout telephone call and at baseline (Visit 2).
e Medical history will include all lifetime psychiatric and nonpsychiatric medications and procedures.
f Whenever possible, the same individual should complete/rate consistently the following scales and questionnaires as appropriate: ADHD-RS-5, CGI-S/I, and subject check to 
remain in the study; PSQ and CSHQ. Include assessment of decreased appetite.
g If >32 days have elapsed since the screening evaluation was completed at Visit 1, then the following evaluations must be repeated at baseline (Visit 2): vital signs, clinical 
laboratory evaluations, and ECGs in triplicate. The physical examination will be abbreviated with a review of the following body systems: general appearance, respiratory, and 
cardiovascular.
h Height and weight will be measured without shoes and with light clothing using a stadiometer for height and calibrated scale for weight
i For females of child-bearing potential only
j Vital signs include oral or tympanic temperature, pulse, sitting blood pressure, and respiratory rate. The subject will have been seated for a minimum of 3 minutes before blood 
pressure, pulse, and respiratory rate measurements are taken. Measurement of blood pressure and pulse will be collected 3 times (with at least 2 minutes in between each 
collection) using the age-appropriate cuff.
k Blood pressure and pulse rate will be measured at each study visit. Temperature and respiratory rate will be measured at screening (Visit 1) only.
l Clinical laboratory evaluations will include hematology, biochemistry, endocrinology, and urinalysis.
m ECGs will be recorded in triplicate with at least 3 minutes in between each collection at screening only and at baseline only if >32 days have elapsed since the screening 
evaluation was completed at Visit 1.


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2.5
Determination of Sample Size
Approximately 80 subjects will be enrolled into this study to ensure 60 subjects complete at least 
6 months of study treatment. Subjects will enroll into this study from antecedent studies, 
SHP465-112 or SHP465-309 as well as de novo subjects who will be enrolled directly. The 
sample size was established to provide long-term safety data in children aged 4 to 12 years and 
will include at least 40 subjects aged 4-5 years at the time of informed consent in the antecedent 
study or this study, if directly enrolled. The sample size for this study is not based on statistical 
considerations.
2.6
Multiplicity Adjustments for Type I Error Control
Efficacy and safety data will be summarized descriptively for this study. No formal statistical 
tests will be done and multiplicity adjustment is not needed.


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3.
OBJECTIVES
3.1
Primary Objective
The primary objective is to evaluate the long-term safety and tolerability of SHP465 at 6.25mg 
administered as a daily morning dose in children aged 4-12 years (inclusive at the time of 
consent) diagnosed with Attention-deficit/Hyperactivity Disorder (ADHD).
The evaluation of safety and tolerability will be based on the occurrence of treatment-emergent 
adverse events (TEAEs), evaluation of vital signs (systolic and diastolic blood pressure and 
pulse), weight, height, body mass index (BMI); clinical laboratory and electrocardiogram 
(ECG) results; sleep assessment (Post Sleep Questionnaire [PSQ], and Children’s Sleep Habits 
Questionnaire [CSHQ]); and responses to the Columbia-Suicide Severity Rating Scale (C-
SSRS).
3.2
Secondary Objectives
The secondary objectives are:

To describe the long-term efficacy of SHP465 using the clinician administered ADHD 
Rating Scale 5 (ADHD-RS-5) Child, Home Version.

To describe the long-term efficacy of SHP465 using the Clinical Global Impressions–
Improvement (CGI-I) scale.


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4.
SUBJECT POPULATION SETS
The following subject sets are applicable to this study:
4.1
Screened Set
The Screened Set will consist of all subjects who have provided informed consent.
4.2
Enrolled Set
The Enrolled Set will consist of all subjects who been assigned a subject identification number 
and enrolled at the Baseline Visit (Visit 2).
4.3
Safety Set
The Safety Set will consist of all subjects who have taken at least 1 dose of investigational 
product.
4.4
Full Analysis Set
The Full Analysis Set (FAS) will consist of all subjects in the Safety Set who have completed at 
least 1 post-dose efficacy assessment using ADHD-RS-5 Total Score.


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5.
SUBJECT DISPOSITION
A listing of all screen failures (ie, subjects who were screened but not enrolled) will be presented 
along with reasons for the failing the screening assessments and details of any reported adverse 
events (AEs).
All disposition data will be summarized for the Safety Set by treatment group in the antecedent 
studies (SHP465 or Placebo), current treatment (SHP465) for each enrollment type (rolled-over or 
directly enrolled), and current treatment (SHP465) for overall.
The number of subjects included in each analysis set (ie, Screened, Enrolled, Safety, and Full 
Analysis) will be summarized.
The number and percentage of subjects who completed and discontinued during the treatment 
period will be presented. The reasons for discontinuation from the treatment period, as recorded
on the Study Completion page of the electronic case report form (eCRF), will be summarized
(number and percentage). A subject who completes the final assessments and procedures 
specified at the final scheduled visit at the end of the treatment period (i.e., Visit 16) will have 
completed the study.
In addition, the number and percentage of subjects who completed the study visits will be
presented.
Any subject who discontinued during the treatment period will be listed by discontinuation 
reason for the Safety Set.
Follow-up information, new (post-treatment) AEs and new (post-treatment) medication, will be 
listed for the Safety Set.


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6.
PROTOCOL DEVIATIONS
Protocol deviations and violations will be recorded by the site separately  from the 
clinical database. The CRO/Shire will classify the protocol deviations and violations per the
agreed protocol violation and deviation management plan. The Shire study team will review
the protocol deviations and their classification throughout the study and before database lock.
Decisions of the review will include:

Accuracy of protocol deviations and violations categorization.

For any criteria for protocol deviations that can be completely implemented by a computer 
program, the detailed algorithm will be agreed upon. Details of such algorithms will be
included in the derived dataset specifications and finalized before database lock.
Confirmed protocol violations and protocol deviations will be documented in the Protocol 
Violation/Deviation tracker tool for the study. Protocol deviations/violations will be summarized
by category and site for each treatment group of the antecedent studies, current treatment 
(SHP465) for each enrollment type, and overall for the Safety Set. Protocol deviations/violations 
will be listed for the Safety Set.


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7.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
7.1
Demographic and Other Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented for the 
Safety Set and FAS by treatment group of the antecedent studies (SHP465 or Placebo), current 
treatment of SHP465 for each enrollment type (rolled over or direct enrollment), and current 
treatment of SHP465 for overall.
The following demographic characteristics will be summarized in the following order in the 
tables: age, age group (4-5 years, 6-12 years), sex, ethnicity, race, weight, height, and body mass 
index (BMI). In addition, other baseline characteristics such as years since diagnosis of ADHD, 
baseline ADHD-RS-5 Child, Home Version total score for children aged 4-5 years and for 
children aged 6-12 years, and baseline Clinical Global Impressions-Severity (CGI-S) will be 
summarized. Baseline is defined as the last assessment before the first administration of the 
investigational product for Group B and as the non-missing assessment for the last visit of the 
antecedent study for Group A.
Age, weight, height, BMI, years since diagnosis of ADHD, ADHD-RS-5 Child, Home Version 
total score for children aged 4-5 years and for children aged 6-12 years will be summarized as 
continuous variables using number of subjects, mean and SD, median, and minimum and 
maximum values. Sex, ethnicity, race, and baseline CGI-S will be summarized as categorical 
variables using number of subjects and percentages for each category. For Group A, all 
summarized values will be taken from the baseline value from antecedent studies, while for 
Group B, summarized values will be taken from the Screening Visit (Visit 1), except for baseline 
ADHD-RS-5 Child, Home version Total Score and baseline CGI-S, which will be taken from the 
Baseline Visit (Visit 2). In addition, baseline weight and baseline height will be summarized in 
both conventional and international system of units.
Age will be calculated as the difference between date of birth (DOB) and earliest date of 
informed consent (DINFC) (i.e., consent date from antecedent studies for Group A and consent 
date from SHP465-308 for Group B), truncated to months, using the following:

Age = floor((intck('month',DOB,DINFC) - (day(DINFC) < day(DOB))) / 12)
BMI will be calculated using one of the following:

Weight in pounds * 703 / (Height in inches)2

Weight in kilograms / (Height in meters)2
Number of years since diagnosis of ADHD will be based on the date of the earliest informed 
consent (i.e., consent date from antecedent studies for Group A and consent date from SHP465-
308 for Group B). Demographics and baseline characteristics will be listed for the Safety Set.


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7.2
Medical History
Medical history will be collected at the Screening visit from antecedent studies for subjects in 
Group A and at the Screening Visit (Visit 1) for subjects in Group B. Medical history will be 
listed for the Safety Set.
The psychiatric diagnosis will be established using the Mini-International Neuropsychiatric
Interview for Children and Adolescents (MINI-KID) Version 7.0.2 for DSM-5 Disorder at the
Screening visit (Visit 1) for subjects in Group B only and will be listed for the Safety Set.
ADHD non-medication treatment history, behavioral therapy history, collected at the
Screening Visit of antecedent studies for subjects in Group A and at the Screening Visit 
(Visit 1) for subjects in Group B, will be listed for the Safety Set.
For ADHD medication history collected at Screening Visits, version WHODRUG March 2017
of the World Health Organization (WHO) drug dictionary will be used to classify ADHD
medications by preferred term. ADHD medication history will be summarized separately by the
number and percentage of subjects receiving each medication within each preferred term by 
treatment group of the antecedent studies, current treatment (SHP465) for each enrollment type, 
and overall for the Safety Set. ADHD medication history will be listed for the Safety Set.


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8.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
8.1
Exposure to Investigational Product
Exposure to the investigational product (SHP465) will be summarized for the Safety Set by 
treatment group of the antecedent studies, current treatment (SHP465) for each enrollment type, 
and overall. The following statistics will be calculated by visit for the investigational product:

Days of dosing: number of days on which dose information was available and non-zero

Total dose (mg) for SHP465: total number of capsules taken × dose level

Average daily dose (mg/day) for SHP465: the total dose / total days of dosing

Cumulative dose (mg) for SHP465: sum of total dose since start of treatment
The following statistics will be calculated for the investigational product for the whole 
treatment period:

Total days of dosing = sum of the number of days dosed for each visit during that period

Duration of exposure in weeks = the total number of days dosed / 7 days per week

Total dose (mg) for SHP465 = total number of capsules taken × dose level

Average daily dose (mg/day) for SHP465 = the total dose / total number of days of dosed
An appropriate statistical summary will be applied to each of the above statistical quantities.
Subjects will be categorized in 4 week increments by overall duration of exposure in days and 
will be presented by subject counts and percentages.
In addition, person-time (overall total exposure in days) will be derived for SHP465. It is 
calculated as the total number of days in which SHP465 was taken for each subject (total days of 
dosing for the Treatment period), and then sum over all subjects for the Treatment period.
All dosing information, for example, total dose, average daily dose and cumulative dose, will be 
listed.
If a bottle has missing start and end dates then the subject’s dose information from this bottle
will be treated as missing. In particular, for the subjects who are lost in the follow up after the
Baseline Visit (Visit 2), it will not be assumed that any of the investigational product has been
ingested unless there is a post-baseline safety assessment. The days, from which there are no 
records showing that subjects have taken investigational product, will be excluded from the 
calculation of exposure. Subjects that do not return the investigational product but return to
the site for the following visit will have the dose return information entered into the database on 
the scheduled visit.
8.2
Measurement of Treatment Compliance
Investigational product dosing compliance during the whole treatment period, are defined as the 
total number of capsules actually taken by a subject during that period divided by the total number 
of capsules expected to be taken during the same period multiplied by 100. The total number of 


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capsules actually taken is calculated by the total number of capsules dispensed minus the number of 
capsules returned. If a bottle is not returned, the number of capsules returned for that bottle will be 
imputed to zero, unless it is the last visit during study. If a subject is early terminated from the study 
without returning any bottles or providing number of capsules returned on any bottles that are 
dispensed at the visit before early termination, the number of capsules taken from these bottles will 
be treated as missing. The number of capsules expected to be taken is calculated as the number of 
days the subject was in the particular period multiplied by the number of capsules to be taken per 
day during that period.
Summary statistics for investigational product compliance will be presented by treatment group of 
the antecedent studies, current treatment (SHP465), and overall for and the whole treatment period 
for the Safety Set. The investigational product treatment compliance will be categorized as <80%, 
80-120%, or >120% for and the whole treatment period. The category 80-120% is considered 
compliant for analysis purpose. The categorical data will be presented for the Safety Set.
Calculated compliance data for each subject will be listed.


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9.
PRIOR AND CONCOMITANT MEDICATION
Version WHODRUG March 2017 of the WHO drug dictionary will be used to classify prior and 
concomitant medications by preferred term.
Prior medication is defined as any medication taken prior to the date of first dose of 
investigational product in this study.
Concomitant medication is defined as any medication with a start date prior to the date of the
first dose of investigational product and continuing after the first dose of investigational
product or with a start date between the dates of the first dose and last dose of investigational
product, inclusive.
Any medication with a start date after the date of the last dose of investigational product (post-
treatment) will not be considered a concomitant medication
Both prior and concomitant medication usage will be summarized separately by the number and 
percentage of subjects receiving each medication within each preferred term by treatment group 
of the antecedent studies, current treatment (SHP465) for each enrollment type, and overall for
the Safety Set. Medications can be counted both as prior and concomitant medication. Multiple
medication usage by a subject in the same category will be counted only once for the purpose
of the summaries.
All prior, concomitant and post-treatment medications will be listed for the Safety Set.


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10.
EFFICACY ANALYSES
All efficacy analyses will be performed using the FAS. Efficacy data will be summarized 
descriptively and no formal statistical tests will be performed. Only post-baseline assessments 
from Visit 3 (Week 1) up to Visit 16 (Month 12) that were collected on or 2 days after the last 
dose of investigational product will be analyzed. Summarization will be by treatment group of 
the antecedent studies, current treatment (SHP465) for each enrollment type, and overall.
10.1
Primary Efficacy Endpoint and Analysis
No primary efficacy endpoint is defined for this study.
10.2
Key Secondary Efficacy Endpoint(s) and Analysis
10.2.1
ADHD-RS-5 Child, Home Version
To assess long-term efficacy, ADHD-RS-5 Child, Home version will be administered to children 
aged 4-5 years and 6-12 years. Baseline ADHD-RS-5 total score is defined as the last valid 
assessment prior to taking the first dose of investigational product for Group B and as the 
baseline value from the  antecedent study for Group A. The observed and change from baseline 
in ADHD-RS-5 total score will be summarized at each applicable visit using the number of 
subjects, mean, SD, median, minimum,  maximum values, and 95% confidence interval. A 
corresponding line graph of mean change from baseline and associated 95% CI in ADHD-RS-5 
total score by visit and treatment group of the antecedent studies and current treatment (SHP465) 
for each enrollment type will be presented.
The items in the ADHD-RS-5 will also be grouped into 2 subscales: hyperactivity/ impulsivity (9 
items for hyperactivity/impulsivity) and inattentiveness (9 items for inattentiveness). Each
subscale will be summarized descriptively at each applicable visit. A corresponding line graph
of mean change from baseline and associated 95% CI in the ADHD-RS-5 subscale scores by
visit and treatment group of the antecedent studies and current treatment (SHP465) for each 
enrollment type will be presented. 
Summaries will be repeated by age group (4-5 years and 6-12 years), sex, race (white and non-
white), and ethnicity sub-group.
ADHD-RS-5 scores, including individual, subscale, and total scores, will be listed for FAS.
10.2.2
CGI-I scores
The CGI-S scores will be collected at Baseline Visit (Visit 2) for subjects in Group B and at the 
Screening Visit (study SHP465-112) or the Baseline Visit (study SHP465-309) for subjects in 
Group A and summarized descriptively. The CGI-I will be summarized descriptively at each 
applicable visit using the number of subjects, mean, SD, median, minimum, and maximum 
values.
The CGI-I categories will also be dichotomized into 2 categories: "improved" and "not 
improved". The category of "improved" will include CGI-I scores of 1 ("very much improved") 


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and 2 ("much improved)".  The category "not improved" will include all CGI-I scores >2. 
Missing CGI-I scores will not be imputed. The observed and dichotomized CGI-I values will be 
summarized at each applicable visit, using number of subjects and percentages, as well.
Summaries will be repeated by age group (4-5 years and 6-12 years), sex, race (white and non-
white), and ethnicity subgroups.
A corresponding bar chart showing the percentage of subjects improved by visit and treatment 
group of the antecedent studies and current treatment (SHP465) for each enrollment type will be 
presented.  CGI-I values and CGI-S values will be listed for FAS and CGI-S will be also listed 
for the Safety Set.
10.3
Exploratory Efficacy Endpoint(s) and Analysis
No exploratory efficacy endpoint is defined for this study.


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11.
SAFETY ANALYSES
Safety data will be analyzed for the Safety Set by treatment group of the antecedent studies, 
current treatment (SHP465) for each enrollment type, and overall. Safety endpoints include the 
occurrence of TEAEs, vital signs (systolic and diastolic blood pressure, and pulse ), height, 
weight, body mass index (BMI); clinical laboratory and ECG results, C-SSRS, and sleep 
questionnaires (PSQ and CSHQ). For each safety endpoint, the last value collected before the 
first dose of investigational product in this study will be used as baseline for all analyses of that 
safety endpoint. Except for adverse event data, only post-baseline assessments from Visit 2 
(Week 0) up to Visit 16 (Month 12) that were collected on or 2 days after the last dose of 
investigational product will be analyzed. A Final on-Treatment Assessment (FoTA) will be 
defined as the last valid assessment obtained after Baseline and whilst on investigational product 
(on or before 2 days after the last dose date).
11.1
Adverse Events
Adverse events will be coded using Version 18.0 of Medical Dictionary for Regulatory
Activities (MedDRA).
An AE (classified by preferred term) that occurs during the treatment period will be considered a
TEAE if it has a start date on or after the first dose of investigational product or if it has a start 
date before the date of the first dose of investigational product, but increases in severity on or
after the date of the first dose of investigational product, and no later than 3 days following the 
last dose of investigational product. If more than 1 AE with the same preferred term is reported 
before the date of the first dose of investigational product, then the AE with the greatest severity
will be used as the benchmark for comparison to the AEs occurring during the treatment period 
under the preferred term.
An overall summary of the number of subjects with TEAEs will be presented, including the
number and percentage of subjects with any TEAEs, serious TEAEs, TEAEs related to
investigational product, TEAEs leading to drug withdrawal, TEAEs by maximum severity, and 
serious TEAEs Leading to death.
The number and percentage of subjects reporting TEAEs will be tabulated by system organ
class (SOC) and preferred term; by SOC, preferred term, and severity; and by SOC, preferred
term, and relationship to investigational product. If more than 1 AE occurs with the same
preferred term for the same subject, then the subject will be counted only once for that preferred
term using the most severe and most related occurrence for the summarization by severity and by
relationship to investigational product.
The incidence of common (≥2% of subjects in any treatment group of the antecedent studies, 
rollover or direct enroll group, or overall population) will be summarized by preferred term,
sorted in decreasing frequency in the overall population. The incidence of TEAEs, serious
TEAEs, and TEAEs leading to withdrawal will be summarized by SOC and preferred term,
sorted in decreasing frequency in the overall population.


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For the Safety Set, listings will be presented for all AEs, TEAEs related to investigational 
product, TEAEs leading to drug withdrawal, and serious TEAEs.
11.1.1
Adverse Events of Special Interest
Adverse events of special interest will include psychiatric events of interest (categorized as 
psychosis/mania, suicidal, aggression and other events) listed in Table 3. Adverse event terms of 
special interest will be searched across the TEAE data and summarized with the total exposure (in 
subject-days).
Table 3
Psychiatric Events
Category
Preferred Term/Verbatim term
Signs and/or symptoms of psychosis/mania
Hallucination (any type, including visual, auditory, tactile, 
mixed, etc.)
Delusion (any type including somatic, persecutory, grandeur,
reference)
Schizophrenia (any type)
Psychotic disorder
Transient psychosis
Acute psychosis
Paranoia
Childhood psychosis
Schizophreniform disorder
Schizoaffective disorder
Catatonia
Mania
Hypomania
Suicidal ideation and behavior
Depression suicidal
Gun shot wound
Intentional self-injury
Non-accidental overdose
Overdose
Self injurious behavior
Self injurious ideation
Self-mutilation
Suicidal ideation
Suicidal attempt
Completed suicide
Aggression and violent behavior
Aggression
Anger
Hostility
Homicidal ideation
Sexual offense
Murder
Imprisonment


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Table 3
Psychiatric Events
Category
Preferred Term/Verbatim term
Miscellaneous psychiatric events (include events
with serious outcome only)
Abnormal behavior
Agitation
Amnesia
Confusional state
Depressed mood
Depression
Disorientation
Emotional disorder
Emotional distress
Feeling abnormal
Memoryimpairment
Mood altered
Mood swings
Personality change
Thinking abnormal
Anxiety
Fearfulness
Phobia
Panic attack
Sleep disturbance
Tics
Obsessive or compulsive behavior
Trichotillomania
A separate listing will be provided for psychiatric AEs of special interest.
Adverse events of clinical interest include insomnia (including AEs with preferred terms of 
‘INSOMNIA’, ‘INITIAL INSOMNIA’,‘MIDDLE INSOMNIA’ and ‘TERMINAL 
INSOMNIA’), weight decrease and decreased appetite. The preferred terms for these 3 AEs
will be reviewed prior to database lock to determine which will be used to identify them.
For each of these 3 AEs (insomnia, weight decrease and decreased appetite), the following
information will be presented:

Number and percentage of subjects reporting the TEAE

Number of TEAEs

Summary of onset day of first TEAE: The onset day of first TEAE is calculated as (onset 
date of first TEAE-date of first dose) + 1 for subjects who experienced the TEAE

Summary of duration of TEAE while on study drug: The duration of each event is the 
number of days from the onset of the TEAE, while on study drug during SHP465 
6.25mg, until the earlier of the end date of the TEAE or the date of last dosing + 3 days.


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If the date of the last dose is missing, t h e n  the date of the last day on study will be
used. TEAEs that either overlap in time, or are adjacent in time will be merged into
one TEAE only for the purposes of calculating duration of event. If a subject has
multiple TEAEs that are not overlapping or adjacent in time, then the durations will be
averaged for that subject. Summary statistics are then based on the averaged subject
durations. The calculated duration includes only the duration of TEAEs.

Number and percentage of mild, moderate, and severe TEAEs: Overlapping TEAEs with 
different preferred terms are counted as multiple TEAEs.

Summary of the number of TEAEs per subject: Overlapping TEAEs with different 
preferred terms are counted as multiple TEAEs.

Number and percentage of TEAEs that: 

Resolved while on study drug 

Ongoing

Dose interrupted

Dose withdrawn

TEAEs leading to discontinuation

Number of subjects who discontinued investigational product due to the event

Also, for each of these 3 AEs (insomnia, weight decrease and decreased appetite), the
following information will be presented by actual dose and month:

Number of subjects in the study

Number and percentage of subjects with the TEAE

Number of TEAEs

Number and percentage of subjects who discontinued due to the TEAE

Number and percentage of mild, moderate and severe TEAEs. If a subject has more than 
one TEAE in the same week, then the worst severity is counted.
Month 1 will include TEAEs reported to have started from Visit 2 (Baseline) through Visit 5 
(Month 1); Month 2 will include TEAEs reported to have started after Visit 5 (Month 1) 
through Visit 6 (Month 2), etc.
In addition, for each subject, all occurrences of each of these 3 AEs will be listed separately 
by treatment group of the antecedent studies, subject number, start date and stop date. The
information presented will include: subject, sex, age, race, ethnicity, preferred term/adverse
event, start date, stop date, onset day, study visit, last dose date, duration/imputed duration of
TEAE (days), SAE, severity, effect on dosing and treatment on AE. 
11.2
Clinical Laboratory Variables
Descriptive statistics for clinical laboratory values (in SI units) and changes from Baseline to Visit 
16/ET as well as shift tables from Baseline to Visit 16/ET for quantitative variables will be presented 
by treatment group of the antecedent studies, current treatment (SHP465) for each enrollment type, and 
overall for the following clinical laboratory variables: 


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Biochemistry and Endocrinology
Total cholesterol
Calcium
Aspartate aminotransferase
Urate
Phosphorus
Blood urea nitrogen
Alanine aminotransferase
Total bilirubin
Sodium
Creatinine
Alkaline phosphatase
Glucose
Potassium
Albumin
Gamma-glutamyl transferase
Total protein
Thyroid-stimulating hormone
Lactate dehydrogenase
Thyroxine, Free
Hematology
Hemoglobin
Neutrophils
Hematocrit
Lymphocytes
Red blood cells
Monocytes
Platelet count
Eosinophils
White blood cell count – total and differential 
Basophils
Mean corpuscular hemoglobin
Neutrophils Band Forms
Mean corpuscular hemoglobin concentration 
Mean corpuscular volume
Urinalysis
Glucose
pH
Specific gravity
Urobilinogen
Blood
Color
Ketones
Leukocyte esterase
Protein
Nitrite 
Bilirubin
Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis. At a minimum the microscopic examination will consist of red blood cells, white 
blood cells, casts, and bacteria.


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Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria. The PCI criteria are listed in Table 4 for subjects aged 4-5 years and 
Table 5 for subjects aged 6-12 years. The number and percentage of subjects with post-baseline 
PCI values will be tabulated. The percentages will be calculated relative to the number of 
subjects with available baseline values and at least 1 post-baseline assessment. The numerator is 
the total number of subjects with at least 1 post-baseline PCI value. A supportive listing of 
subjects with post-baseline PCI values will be provided including the subject number, baseline, 
and post-baseline values.
Table 4
Criteria for Potentially Clinically Important Laboratory Tests for Subjects 
Aged 4-5 Years
Parameter
SI Unit
Lower Limit
Higher Limit
Biochemistry
Albumin
g/L
< 30g/L
-
Aspartate transaminase (AST)
-
-
>3 x ULN
Alanine transaminase (ALT)
-
-
> 3 x ULN
Alkaline phosphatase 
>2.5 x ULN
Blood urea nitrogen
mmol/L
-
> 10.7mmol/L or > 2.5 
x ULN
Calcium
mmol/L
< 2 
> 2.9 
Total cholesterol
mmol/L
-
> 7.8
Creatinine
µmol/L
-
> 176.8 µmol/L or > 
1.5 x ULN
Gamma glutamyl transferase
-
-
≥ 2.5 x ULN
Glucose
mmol/L
< 3.1
> 8.9
Lactate dehydrogenase
-
-
> 3 x ULN
Phosphorus, inorganic
mmol/L
< 0.8
> 2.3
Potassium
mmol/L
< 3.0
> 5.5
Thyroid stimulating hormone
-
< LLN
> 2 x ULN
Sodium
mmol/L
< 130
> 150
Urate
µmol/L
-
> 594.8
Bilirubin, total
µmol/L
-
> 34.2 
Total protein
g/L
< 50
> 90
Hematology
Neutrophils Band Form
-
-
0.27x103/μL or 
5%
Basophils
-
-
10%
Hemoglobin
g/L
< 90
> 160
Hematocrit
%
< 30%
> 50%
Platelet count
109/L
75
> 600


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Table 4
Criteria for Potentially Clinically Important Laboratory Tests for Subjects 
Aged 4-5 Years
Parameter
SI Unit
Lower Limit
Higher Limit
Red blood cells
1012/L
2.5
> 7.5
White blood cell count
109/L
3
> 16.0
Neutrophils
109/L
1x109/L or < 30%
> 6.2 109/L or > 70%
Eosinophils 
109/L OR %
-
0.5 x 109/L or > 10%
Lymphocytes 
%
10%
> 70%
Monocytes 
%
-
20%
Urinalysis
Glucose
-
-
Positive 
Value 
(excluding trace)
Protein
-
-
Positive 
Value 
(excluding trace)
Blood
-
-
Positive 
Value 
(excluding trace)
Ketones
-
-
Positive 
Value 
(excluding trace)
Bilirubin
-
-
Positive 
Value 
(excluding trace)
Leukocyte Esterase 
Positive 
Value 
(excluding trace)
Nitrite 
Positive 
Value 
(excluding trace)
LLN: Lower limit of normal value provided by the laboratory
ULN: Upper limit of normal value provided by the laboratory
Age is calculated from the informed consent date from antecedent studies for Group A and from the informed consent date from 
SHP465-308 for Group B.


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Table 5
Criteria for Potentially Clinically Important Laboratory Tests for Subjects 
Aged 6-12 Years
Parameter 
PCI Criteria 
Biochemistry 
Cholesterol-H 
>300mg/dl** (>7.8mmol/L) 
Glucose, serum 
<55mg/dl or >160mg/dl (<3.1mmol/L or >8.9mmol/L) 
Bilirubin, total 
>1.5 x ULN 
Transaminase, SGOT, AST 
>3 x ULN 
Transaminase, SGPT, ALT 
>3 x ULN 
Gamma Glutamyl Transpeptidase (GGT) 
>3 x ULN 
Alkaline phosphatase 
>2.5 x ULN 
Lactate dehydrogenase (LDH) 
>3 x ULN* 
Sodium 
<130mEq/L (grade 3) or >150mEq/L (mmol/L) 
Potassium, serum/plasma 
<3mEq/L (grade 3) or >5.5mEq/L (mmol/L) 
Calcium 
<8mg/dl or >11.5mg/dl (<2mmol/L or >2.9mmol/L) 
Phosphorus, inorganic 
<2.5mg/dl 
or 
>7.0mg/dl** 
(<0.8mmol/L 
or 
>2.3mmol/L) 
Urate
>10mg/dl (>0.6mmol/L or >594.8μmol/L) 
Thyroid Stimulating Hormone (TSH) ~ 
< 0.35 μIU/ml or > 6 μIU/mL (0.35mIU/L or 
>6mIU/L) 
Blood Urea nitrogen (BUN) 
>2.5 x ULN* (or alternatively >30mg/dl**, 
>10.7mmol/L) 
Creatinine, serum 
>1.5 x ULN 
(or 
alternatively 
>2mg/dl**, 
>176.8μmol/L) 
Albumin 
<3g/dl (<30g/L) 
Total protein, plasma or serum 
<5g/dl* or >9g/dl* (<50g/L or >90g/L) 
Hematology 
Hemoglobin (He.) 
<10g/dl (<100g/L) 
Hematocrit 
<32% or >45% (<0.32 or >0.45 Fraction of 1)
Blood Cells (RBC) 
male: <2.5 x106/μL; female: <2.0 x106/μL 
(male: <2.5 x 10^12/L; female: <2.0 x 10^12/L) 
Mean Corpuscular Hemoglobin (MCH)~ 
< 27pg or > 32pg 
Mean Corpuscular Volume (MCV)~ 
< 70fL or > 110fL 
Mean Corpuscular He. Concentration (MCHC)~ 
< 28g/dL or > 41g/dL (<280g/L or >410g/L) 
Platelet count 
<75 x 109/L or >500 x 109/L 


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Table 5
Criteria for Potentially Clinically Important Laboratory Tests for Subjects 
Aged 6-12 Years
Parameter 
PCI Criteria 
Biochemistry 
White Blood Cell Count (WBC) 
<3 x 109/L or >16 x 109/L 
Neutrophils Band Form
> 5% 
Neutrophils 
< 15% 
Eosinophils 
> 10% 
Basophils 
> 15% 
Lymphocytes 
> 80% 
Monocytes 
> 40% 
ANC (%neutrophils x WBC count) 
<1.3x10e9/L 
Urinalysis 
Glucose 
Positive Value (excluding trace) 
Blood 
Positive Value (excluding trace) 
Ketones 
Positive Value (excluding trace) 
Protein 
Positive Value (excluding trace) 
Bilirubin 
Positive Value (excluding trace) 
Leukocyte Esterase 
Positive Value (excluding trace) 
Nitrite 
Positive Value (excluding trace) 
*The NCI has not specified a value, Shire physicians have agreed on lab values provided. 
** Values taken from the Reviewer Guidance, Conducting a Clinical Safety Review of a New Product Application and Preparing 
a Report on the Review, Table 7.1.7.3.2.1 pp 70-72. US DHHS FDA CDER, February 2005. 
~These values were taken from Clinical Laboratory Diagnostics, ed. L. Thomas, MD, Frankfurt, Germany, 1998. 
ULN: Upper limit of normal value provided by the laboratory 
Age is calculated from the informed consent date from antecedent studies for Group A and from the informed consent date from 
SHP465-308 for Group B.
All laboratory data will be listed for the Safety Set.
11.3
Vital Signs (Including Height and Weight)
The averaged values of the 3 measurements collected for blood pressure and pulse at each visit 
will be used for all summaries and determination of PCIs. Summaries for vital signs will be 
presented by treatment group of the antecedent studies, current treatment (SHP465) for each 
enrollment type, and overall.
Descriptive statistics for vital signs (sitting systolic and diastolic blood pressure, pulse and 
weight) and their changes from baseline at each post-baseline visit and FoTA will be presented
in a summary table. These summaries will also include BMI. BMI will be automatically 


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calculated using the height and weight collected at each visit. In the case of multiple assessments 
at post-baseline visits, the first readable value at the visit will be used in the summary tables. 
Additionally, figures with the mean change from baseline ±SD of the vital signs values (sitting 
systolic and diastolic blood pressure, and pulse) will be presented by visit for each treatment 
group of the antecedent studies and current treatment (SHP465) for each enrollment type. 
Height, weight and BMI will also be converted to percentile values based on the subject’s age 
and sex at each visit and summarized categorically (<5th, 5th to <95th, and ≥95th) at each visit 
and at the FoTA. Post-baseline shifts in height, weight and BMI percentile category (<5th, 5th to 
<95th, and ≥95th) from baseline will be summarized at each visit and at the FoTA. In addition, z-
scores for weight and BMI will be based on the subject’s age at each visit and will be 
summarized categorically (<-2, ≥-2 to <-1, ≥-1 to <1, ≥1 to <2, and ≥2) at each visit and at the 
FoTA. Percentiles and z-scores will be derived using the CDC growth charts (Kuczmarski et al. 
2002). A SAS program for the 2000 CDC Growth Charts will be used to derive the percentiles 
and z-scores (www.cdc.gov/nccdphp/dnpao/growthcharts/resources/sas.htm).
Vital sign values will be considered PCI if they meet the criteria listed in Table 6 for Age 4-5 or 
if they meet the criteria in Table 7 for Age 6-12. The number and percentage of subjects with 
PCI post-baseline values will be summarized. The percentages will be calculated relative to the 
number of subjects with baseline and at least 1 post-baseline assessment. The numerator is the 
total number of subjects with at least 1 PCI post-baseline vital sign value. A supportive listing of 
subjects with post-baseline PCI values will be provided including the treatment group of the 
antecedent studies, subject number, site, baseline, and post-baseline PCI values. A listing of all 
AEs for subjects with post-baseline PCI vital sign values will also be provided. 


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Table 6
Criteria for Potentially Clinically Significant Vital Sign Findings in Subjects 
Aged 4-5 Years
Vital Sign Parameter
Flag
Criteriaa
Observed Value
Change from Baseline
Sitting Systolic blood pressure
(mmHg)
High
120
Increase of >10
Low
<75
Decrease of >10
Sitting Diastolic blood pressure 
(mmHg)
High
85
Increase of >10
Low
<40
Decrease of >10
Pulse 
rate
(beats per minute)
High
130
Increase of >15
Low
55
Decrease of >15
Weight (kg)
High
-
Increase of 7%
Low
-
Decrease of 7%
Temperature (deg. C)
High
>39
-
Low
<35
-
BMI (kg/m2)
High
>95th percentile for age 
and sex
-
Low
<5th percentile for age and 
sex
-
a A post-baseline value is considered a PCI finding if its meets either the criteria for observed value or the criteria for the change
from baseline.
Age is calculated from the informed consent date from antecedent studies for Group A and from the informed consent date from 
SHP465-308 for Group B.
Table 7
Criteria for Potentially Clinically Significant Vital Sign Findings for Subjects 
Aged 6-12 Years
Vital Sign Parameter 
PCI Criteria 
Weight Loss (kg) 
≥7% of weight (determined at baseline) 
Systolic BP (mmHg), seated, 6 – 12 years~ 
>120* 
>120* on 2 or more consecutive visits 
>10 increase from baseline 
>10 increase from baseline on 2 or more consecutive 
visits 
>120* and increase >10 from baseline 
>120* and increase >10 from baseline on 2 or more 
consecutive visits 
Diastolic BP (mmHg), seated, 6 – 12 years~ 
>80* 
>80* on 2 or more consecutive visits 
>10 increase from baseline 
>10 increase from baseline on 2 or more consecutive 
visits 


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Table 7
Criteria for Potentially Clinically Significant Vital Sign Findings for Subjects 
Aged 6-12 Years
Vital Sign Parameter 
PCI Criteria 
>80* and increase >10 from baseline 
>80* and increase >10 from baseline on 2 or more 
consecutive visits 
Pulse (beats/minute) 
<=50* 
<=50* and decrease >15 from baseline
>=100* 
>=100* on 2 or more consecutive visits 
>=100* and increase >15 from baseline 
>=100* and increase >15 from baseline on 2 or more 
consecutive visits 
Temperature (tympanic) 
>38.0°C (100.4°F) 
Temperature (oral) 
>37.5°C (99.5°F) 
Respiratory Rate (breaths per minute) 
<10 or >24 
~Given the pharmacological effect of the drugs used in ADHD and based on experience gained in previous ADHD trials, the 
focus is on rise of blood pressure only. 
*The NCI has not specified a value, Shire physicians have agreed on values provided. 
Age is calculated from the informed consent date from antecedent studies for Group A and from the informed consent date from 
SHP465-308 for Group B.
Pulse rate (beats per minute) will be considered abnormal if a value is lower than the 1st 
percentile or higher than the 99th percentile cut-off values listed in Table 8.
Table 8
Normal Range of Pulse Rate (beats/min)
Age
1st Percentile
99th Percentile
Males
4-5 years
69
120
6-8 years
59
114
9-11 years
56
110
12 years
52
108
Females
4-5 years
70
132
6-8 years
61
117
9-11 years
58
113
12 years
54
110
Source: National health statistics report: Resting Pulse Rate Reference Data for Children, Adolescents, and Adults: United States, 
1999–2008
https://www.cdc.gov/nchs/data/nhsr/nhsr041.pdf
The number and percentage of subjects with abnormal pulse rate values for at least 1 post-
baseline assessment will be tabulated by treatment group of the antecedent studies, current 
treatment (SHP465) for each enrollment type, and overall for the lower than the 1st percentile 


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and higher than the 99th percentile cut-off values, respectively, for male and female separately. 
The denominator will be the number of subjects in the Safety Set (per gender) with at least 1 
post-baseline pulse measurement. The numerator is the total number of subjects with at least 1 
abnormal pulse record. A supportive listing of subjects with abnormal pulse rate values will be 
provided.
In addition, following the US Department of Health and Human Services standards, blood 
pressure values higher than the 95th percentile determined by sex, age, and height percentiles 
will be considered abnormal. The cut-off values are presented in Table 9 If a height percentile 
falls between the listed percentiles, as a conservative approach the lower end of the percentiles 
will be used to identify the corresponding 95th percentile of blood pressures. If a height 
percentile is less than 5th percentile, the 5th percentile will be used to identify the corresponding 
95th percentile of blood pressures.


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Table 9
95th Percentile Cut-off Values of Blood Pressure Norms by Sex, Age, and Height Percentiles
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Age (y)
Percentile of Height
Percentile of Height
Boys
5%
10%
25%
50%
75%
90%
95%
5%
10%
25%
50%
75%
90%
95%
4
106
107
109
111
112
114
115
66
67
68
69
70
71
71
5
108
109
110
112
114
115
116
69
70
71
72
73
74
74
6
109
110
112
114
115
117
117
72
72
73
74
75
76
76
7
110
111
113
115
117
118
119
74
74
75
76
77
78
78
8
111
112
114
116
118
119
120
75
76
77
78
79
79
80
9
113
114
116
118
119
121
121
76
77
78
79
80
81
81
10
115
116
117
119
121
122
123
77
78
79
80
81
81
82
11
117
118
119
121
123
124
125
78
78
79
80
81
82
82
12
119
120
122
123
125
127
127
78
79
80
81
82
82
83
Girls
4
105
106
107
108
110
111
112
68
68
69
70
71
71
72
5
107
107
108
110
111
112
113
70
71
71
72
73
73
74
6
108
109
110
111
113
114
115
72
72
73
74
74
75
76
7
110
111
112
113
115
116
116
73
74
74
75
76
76
77
8
112
112
114
115
116
118
118
75
75
75
76
77
78
78
9
114
114
115
117
118
119
120
76
76
76
77
78
79
79
10
116
116
117
119
120
121
122
77
77
77
78
79
80
80
11
118
118
119
121
122
123
124
78
78
78
79
80
81
81
12
119
120
121
123
124
125
126
79
79
79
80
81
82
82
Source: National Heart Lung and Blood Institute; May 2004
http://www nhlbi nih.gov/guidelines/hypertension/child_tbl.htm


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The number and percentage of subjects with any post-baseline blood pressure values higher than 
the 95th percentile (exclusive) will be tabulated by gender and treatment group of the antecedent 
studies, current treatment (SHP465) for each enrollment type, and overall. The denominator will 
be the number of subjects in the Safety Set (per gender) with at least 1 post-Baseline blood 
pressure measurement. The numerator will be the total number of subjects with at least 1 blood 
pressure value higher than the 95th percentile. A supportive listing of all subjects with abnormal 
blood pressure values will be provided.
All vital signs data will be listed for the safety Set.
11.4
Electrocardiogram (ECG)
Electrocardiogram (ECG) data will be summarized by treatment group of the antecedent studies, 
current treatment (SHP465) for each enrollment type, and overall. ECG results and change from 
baseline will be summarized at each visit and at the FoTA. If there are multiple assessments for 
the interpretation at any visit, the worst interpretation will be used in the summary tables. For the 
interval parameters at post- baseline visits, the first readable result will be used if there are 
multiple assessments.
For  the  ECG  interval  parameters, baseline is defined as  the average of all valid ECG 
measurements as the last assessment obtained prior to the first dose of the investigational 
product. For the ECG interpretation, baseline will be the ECG with the worst interpretation 
obtained  at  the  baseline  Visit  (Visit  2),  providing  this  is  prior  to  the  first  dose  of  the 
investigational product.
PCI criteria will be applied to all ECG data at each visit including any repeat/unscheduled 
assessments and presented by visit. PCI criteria are defined in Table 10 for Age 4-5 years or if 
they meet the criteria in Table 11 for Age 6-12 years.


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Table 10
Criteria for Potentially Clinically Important ECG Values for Age 4-5 Years
ECG 
Parameter
Unit
Observed Value
Change from Baseline
Lower 
Limit
Higher Limit
Lower 
Limit
Higher Limit
ECG Result
-
-
Abnormal (core lab) and Clinically 
significant from investigator
-
-
Heart Rate
Beats/minute
<55
>130
Decrease 
>15
Increase >15
PR Interval
msec
-
200
-
-
QT Interval
msec
-
≥440
-
≥30 and <60
60
QTcF Interval
msec
-
≥440 and <480
≥480 and <500
500
-
≥30 and <60
60
QTcB Interval
msec
-
≥440 and <480
≥480 and <500
500
-
≥30 and <60
60
QRS Interval
msec
-
≥90
-
-
Rhythm
-
-
Any rhythm other than sinus
rhythm*
-
-
Age is calculated from the informed consent date from antecedent studies for Group A and from the informed consent date from 
SHP465-308 for Group B.
Table 11
Criteria for Potentially Clinically Important ECG Values for Age 6-12 Years
ECG Parameter 
Outlier Criteria 
ECG result 
Shift from a normal baseline to an abnormal finding or from 
an abnormal baseline to a new abnormal finding 
Heart rate 
≤50 beats/minute* or ≥100 beats/minute* 
PR interval (increase) 
≥200 msec* 
QRS interval 
≥120 msec* 
QTcF/QTcB 
≥450 msec* and <480 msec* 
≥480 msec* and <500 msec* 
≥ 500msec* 
QT/QTc from Baseline 
≥30 msec* and <60 msec* 
≥60 msec* 
*The NCI has not specified a value, Shire physicians have agreed on values provided. 
ECG=electrocardiogram; QTcB=Bazett’s corrected QT interval; QTcF=Fridericia’s corrected QT interval 
Age is calculated from the informed consent date from antecedent studies for Group A and from 
the informed consent date from SHP465-308 for Group B.


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The number and percentage of subjects with post-baseline PCI values will be tabulated.  The 
percentages for the observed value criteria will be calculated relative to the number of subjects 
with at least 1 post-baseline assessment available per parameter and visit. The percentages for 
the change from baseline criteria will be calculated relative to the number of subjects with 
available baseline and at least 1 post-baseline assessment per parameter and visit.  The numerator 
is the total number of subjects with at least 1 PCI post-baseline ECG value.
Additionally, a summary table showing the number and percentage of subjects with the Central 
Reader’s assessment of the ECG result as normal, abnormal or unable to evaluate, and the 
investigator’s assessment of abnormal ECG results as not clinically significant or clinically 
significant at each visit and at the FoTA will be produced. A shift table showing the change in 
evaluation from baseline to the FoTA will also be produced.
Listings of ECG data including the central reader’s assessment and investigator's interpretation 
by individual subject will be produced. Separate listings will be produced for subjects with ECG 
results meeting the PCI criteria. Data from unscheduled visits will be listed, but not summarized.
11.5
Other Safety Variables
Other safety data will be summarized by treatment group of the antecedent studies, current 
treatment (SHP465) for each enrollment type, and overall using the Safety Set.
11.5.1
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a semi-structured interview that captures the occurrence, severity, and
frequency of suicide-related thoughts and behaviors during the assessment period. The interview
includes definitions and suggested questions to solicit the type of information needed to
determine if a suicide-related thought or behavior occurred.
The C-SSRS contains two required items pertaining to suicidal ideation, four required items 
pertaining to suicidal behavior, and one required item pertaining to non-suicidal self-injurious 
behavior. There are eight additional suicidal ideation items and two additional suicidal behavior 
items which are completed in cases of positive responses for other items, as well as two items for 
suicide and suicide behavior present during the interview. Most items are rated on a dichotomous 
scale (yes or no) or 3- or 5-point Likert scale. In addition, the total number of attempts (including 
interrupted and aborted attempts) is recorded. In the event of a positive categorical response the 
interviewer can provide text or narrative that further describes the thought or behavior.
Two versions of C-SSRS, the “Baseline” version and the “Since Last Visit” version, will be used 
in this study. For subjects in Group A, the “Since Last Visit” version will be completed at all 
study visits. The scale will be compared with the “Baseline” version from the antecedent study. 
For subjects in Group B, the “Baseline” version will be administered at the Screening Visit (Visit 
1) and the “Since Last Visit” version will be completed for all subjects at all study visits after the
Screening Visit (Visit 1).
Positive results from the C-SSRS data will be descriptively summarized for overall during the 
study and by visit.


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A listing of the C-SSRS data will be provided for subjects with a positive response.
11.5.2
Post Sleep Questionnaire (PSQ)
The PSQ is a 7-item questionnaire typically used to assess sleep quality with pharmacologic 
treatment. The questionnaire collects data on average time to sleep, sleep latency, frequency of 
interrupted sleep, duration of interrupted sleep, total sleep time and sleep quality over the last 
week. The PSQ will be completed by the parent/LAR with the subject and the responses will be 
reviewed by the clinician during the study visit. 
The PSQ will be conducted at each visit to the site starting with the baseline visit (Visit 2) and 
will be completed by the subject’s parent/LAR.
The PSQ results will be summarized by visit. Continuous variables, for example, time to go to 
sleep and time spent awake, will be summarized using number of subjects, mean and standard 
deviation, median, and minimum and maximum values. Categorical values, for example, quality
of sleep, will be summarized using number of subjects and percentages for each category.
11.5.3
Children’s Sleep Habit Questionnaire (CSHQ)
The Child’s Sleep Habits Questionnaire (CHSQ) consists of 33 items for scoring and several 
extra items intended to provide administrators with other potentially useful information about 
respondents. Each scored question except for Watching TV and Riding in car is rated on a 3-
point scale:
•
occurring “usually” (i.e., 5–7 times within the past week): score = 3
•
occurring “sometimes” (i.e., 2–4 times within the past week): score = 2
•
occurring “rarely” (i.e., never or 1 time within the past week): score = 1
The following six questions should be reversed in scoring for calculation of subscale score and 
total sleep disturbance score so that higher score reflects more disturbed sleep behavior: “Goes to 
bed at same time”, “Falls asleep in own bed”, “Falls asleep in 20 minutes”, “Sleeps the right 
amount”, “Sleeps same amount each day”, “Wakes by himself”. These six questions are rated on 
3-point scale depending on the frequency of occurring: 
•
“usually” ( 5– times within the past week): score = 1
•
“sometimes” ( 2– times within the past week): score = 2
•
“rarely” (never or 1 time within the past week): score = 3
Questions of Watching TV and Riding in car is rated on a 3-point scale (more than 1 occurrences 
can apply for each question, highest score contributes as the question score):
•
occurring “not sleepy”: score = 0
•
occurring “very sleepy”: score = 1
•
occurring “falls asleep”: score = 2
The instrument evaluates the child’s sleep based on behavior within 8 different subscales:


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1. Bedtime resistance (sum of the responses for Goes to bed at same time, Falls asleep in 
own bed, Falls asleep in other’s bed, Needs parent in room to sleep, Struggles at bedtime 
and Afraid of sleeping alone)
2. Sleep-onset delay (Falls asleep in 20 minutes item)
3. Sleep duration (sum of the responses for Sleeps too little, Sleeps the right amount and 
Sleeps same amount each day)
4. Sleep anxiety (sum of the responses for Needs parent in room to sleep, Afraid of 
sleeping in the dark, Afraid of sleeping alone and Trouble sleeping away)
5. Night wakings (sum of the responses for Moves to other’s bed in night, Awakes once 
during night and Awakes more than once)
6. Parasomnias (sum of the responses for Wets the bed at night, Talks during sleep, 
Restless and moves a lot, Sleepwalks, Grinds teeth during sleep, Awakens screaming, 
sweating and Alarmed by scary dream)
7. Sleep-disordered breathing (sum of the responses for Snores loudly, Stops breathing and 
Snorts and gasps)
8. Daytime sleepiness (sum of the responses for Wakes by himself, Wakes up in negative 
mood, Others wake child, Hard time getting out of bed, Takes long time to be alert, 
Seems tired, Watching TV and Riding in car)
Total sleep disturbance score is sum of the 8 subscale scores minus Needs parent in room to 
sleep and Afraid of sleeping alone (as Needs parent in room to sleep and Afraid of sleeping 
alone are included in two subscales (1 and 4) and need to be included once). Missing data will 
not be imputed.
Total sleep disturbance score, each subscale and each individual item will be summarized 
using descriptive statistics (n, mean, SD, minimum, median, and maximum) at each visit (and 
Visit 6/ET) by treatment group of the antecedent studies, current treatment (SHP465) for each 
enrollment type, and overall . All CSHQ data will be listed for the Safety Set.


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12.
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Not applicable.


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13.
OTHER ANALYSES
No other analyses are planned for this study.


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14.
INTERIM ANALYSIS
After no fewer than 50 subjects have completed 6 months of study treatment and approximately 
20 subjects have completed 12 months of study treatment, the database will be archived and all 
available safety and efficacy data will be analyzed for regulatory reporting reasons. Additional 
analyses will be performed as required for regulatory purposes, such as subsequent safety 
updates if required and development of the final clinical study report.
Due to the early termination of the study, the interim analysis above will not be performed. All 
collected data will be included in the final analyses and reported.


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15.
DATA MONITORING/REVIEW COMMITTEE
A data monitoring committee (DMC) will be involved in the management of this study. The 
purpose of the DMC is to monitor safety and tolerability of the investigational product and to 
protect the interests of subjects in the study and of those still to be entered. The data provided to 
the DMC will not be considered ‘clean’ until the database is locked.
The analyses for DMC will be a subset of the analyses specified in this SAP. Further details 
regarding the DMC can be found in the DMC charter, which will be available before the 
administration of investigational product.


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16.
COMPUTER METHODS
Statistical analyses will be performed using  Version 9.3 (or newer) of SASon a 
suitably qualified environment.


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17.
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
Not applicable.


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18.
DATA HANDLING CONVENTIONS
18.1
General Data Reporting Conventions
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, SD, minimum, and maximum. Unless specified otherwise, summary statistics will be 
presented to 1 more significant digit than the raw data. The minimum and maximum values
will be presented to the same number of decimal places as the raw data; the mean and median
will be presented to 1 more decimal place than the raw data; and the SD and standard error will
be presented to 2 more decimal places than the raw data.
Categorical and count variables will be summarized by the number of subjects (n) and the
percent of subjects in each category.  Percentages will be presented to 1 decimal place.
P-values will generally be presented to 4 decimal places; values less than 0.001 will be
presented as <0.001.
18.2
Derived Efficacy Endpoints
The ADHD-RS-5 Child, Home Version total score will be calculated as the sum of the 
individual items from the ADHD-RS-5 Child, Home Version. The ADHD-RS/ADHD-RS-5 
Child, Home Version consists of 18 items designed to reflect current symptomatology of 
ADHD based on Diagnostic and Statistical Manual of Mental Disorders Five Edition (DSM-
5. ) criteria. Each item is scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 
3 (reflecting severe symptoms) with total scores ranging from 0-54. As noted in Section 10.2, 
the items in the ADHD-RS-5 Child, Home Version will also be grouped into 2 subscales: 
hyperactivity/impulsivity (9 items for hyperactivity/impulsivity) and inattentiveness (9 items for 
inattentiveness), with subscale scores ranging from 0-27.
A missing individual item in the ADHD-RS-5 Child, Home Version is imputed as follows 
(DuPaul et al.1998):  if only 1 single item is missing in a given subscale, the mean score for all 
other items in the subscale for the specific visit is imputed as the score rounded up to the nearest 
integer for the missing score. The total score is computed as the sum of the imputed subscale 
scores.  If more than 1 item is missing in a subscale then the subscale score and total score 
would be missing.
18.3
Association of Early Termination Assessments to Scheduled Visits
For purposes of reporting early termination assessments during the study, each early termination 
visit will be assigned the next nominal visit number after the last completed visit. This rule 
applies to both efficacy variables (e g , ADHD-RS-5 - Child, Home Version total score) and
safety variables (e g , vital signs) except for the lab data, which will be analyzed and/or
summarized by visit.


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18.4
Repeated or Unscheduled Assessments of Safety Parameters
If a subject has repeated assessments before the start of investigational product, then the results
from the final assessment made prior to the start of investigational product will be used as 
baseline.
If a subject has repeated assessments at any post-baseline visit, the first recorded assessment will 
be assigned to the visit for generating descriptive statistics. For vital signs (sitting systolic and 
diastolic blood pressure, and pulse), this will be the average of the 3 measurements from the first 
recorded assessment.
If final on-treatment safety assessments are repeated or unscheduled, the last post-baseline 
assessment will be used as the final on-treatment assessment for generating descriptive statistics. 
For vital signs (sitting systolic and diastolic blood pressure, and pulse), this will be the average
of the 3 measurements from the last post-baseline assessment.
However, all post-baseline assessments will be used for PCI value determination and all 
assessments will be presented in the data listings.
All repeat and unscheduled visits will be listed.
18.5
Missing Dispensed or Returned Date or Number of Capsules of Investigational
Product
When the date of the last dose of investigational product is missing for a subject in the Safety
Set, all efforts should be made to obtain the date from the investigator.   If it is still missing 
after all efforts, then the last visit date when investigational product was returned will be used in 
the calculation of investigational product exposure.
18.6
Missing Date Information for Prior or Concomitant Medications
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or
stop date will be imputed. When the start date and the stop date are both incomplete for a 
subject, impute the start date first.
18.6.1
Incomplete Start Date
The following rules will be applied to impute the missing numerical fields.   If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed using 
the stop date.
Missing day and month

If the year of the incomplete start date is the same as the year of the date of the first dose
of investigational product, then the day and month of the date of the first dose of 
investigational product will be assigned to the missing fields

If the year of the incomplete start date is before the year of the date of the first dose
of investigational product, then 31 December will be assigned to the missing fields


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
If the year of the incomplete start date is after the year of the date of the first dose
of investigational product, then 01 January will be assigned to the missing fields.
Missing month only

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
Missing day only

If the month and year of the incomplete start date are the same as the month and year of
the date of the first dose of investigational product, then the day of the date of the first dose
of investigational product will be assigned to the missing day

If either the year is before the year of the date of the first dose of investigational product
or if both years are the same but the month is before the month of the date of the first
dose of investigational product, then the last day of the month will be assigned to the
missing day

If either the year is after the year of the date of the first dose of investigational product or if
both years are the same but the month is after the month of the date of the first dose  of  
investigational product, then the  first day of  the month will be assigned to the
missing day.
18.6.2
Incomplete Stop Date
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of investigational product is missing, then replace it with the last visit date. If the imputed
stop date is before the start date (imputed or non-imputed start date), then the imputed 
stop date will be equal to the start date.
Missing day and month

If the year of the incomplete stop date is the same as the year as of the date of the last dose of 
investigational product, then the day and month of the date of the last dose of investigational 
product will be assigned to the missing fields

If the year of the incomplete stop date is before the year of the date of the last dose of 
investigational product, then 31 December will be assigned to the missing fields

If the year of the incomplete stop date is after the year of the date of the last dose of
investigational product, then 01 January will be assigned to the missing fields.
Missing month only

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
Missing day only

If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of investigational product, then the day of the date of the last dose of 
investigational product will be assigned to the missing day


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
If either the year is before the year of the date of the last dos  of investigational product or if 
both years are the same but the month is before the month of the date of the last dose of 
investigational product, then the last day of the month will be assigned to the missing day

If either the year is after the year of the last dose of investigational product or if both years are 
the same but the month is after the month of the date of the last dose of investigational 
product, then the first day of the month will be assigned to the missing day.
18.7
Missing Date Information for Adverse Events
For AEs, incomplete (i.e., partially missing) start dates will be imputed and will follow the same 
rules as in Section 18.6.1. Incomplete stop dates will not be imputed.
18.8
Missing Severity Assessment for Adverse Events
If severity is missing for an AE starting prior to the date of the first dose of investigational
product, then a severity of “Mild” will be assigned. If the severity is missing for an AE
starting on or after the date of the first dose of investigational product, then a severity of
“Severe” will be assigned. The imputed values for severity assessment will be used for
incidence summaries, while the actual values will be used in data listings.
18.9
Missing Relationship to Investigational Product for Adverse Events
If the relationship to investigational product is missing for an AE starting on or after the date
of the first dose of investigational product, a causality of “Related” will be assigned. The 
imputed values for relationship to investigational product will be used for incidence summaries, 
while the actual values will be presented in data listings.
18.10 Character Values of Clinical Laboratory Variables
The actual values of clinical laboratory variables as reported in the database will be presented in 
data listings. No coded values (e.g., when a character string is reported for a numerical variable) 
are necessary.


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19.
REFERENCES
DuPaul GJ, Power TJ, Anastopoulos AD, Reid R, 1998. ADHD Rating Scale-IV: Checklists, 
Norms, and Clinical Interpretation, New York, NY: Guilford Press. 
Kuczmarski RJ, Ogden CL, Guo SS, et al., 2002. 2000 CDC growth charts for the United States: 
Methods and development. National Center for Health Statistics, Vital Health Stat 
11(246).


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20.
TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS
Table of contents for figures, tables and listings will be provided in a separate document with the 
table, figure and listing templates.