Clinical trial NCT02466386
Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Sponsor: Shire
Start date: 2015-08-21; Completion date: 2020-01-03
Enrollment: 113 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the long-term safety of SPD489 administered as a daily morning dose (5, 10, 15, 20, and 30 mg/day) in preschool children diagnosed with Attention-deficit/Hyperactivity Disorder (ADHD).

Detailed description:
This study is a long-term, open-label study where participants who participated in an antecedent SPD489 study (SPD489-211 \[NCT02402166\] or SPD489-347 \[NCT03260205\]) or through direct enrollment. Participants entering into this study will be classified as either a roll-over participants or a direct-enrolled participants.

Arms: arm 1: Participants will receive 5 milligrams (mg) of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached within 52 weeks.
Interventions: intervention 1: SPD489
Intervention descriptions: intervention 1: Participants will receive 5 mg of SPD489 capsule orally once daily in the morning and titrated in a step-wise fashion up to either 10 mg, 15 mg, 20 mg, or 30 mg until an optimal dose was reached.

Protocol documents:
Prot_002.pdf: 
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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 Pharmacovigilance 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 fax or e-mail using the details below.
Fax:  
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:
:
Fax:  
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 below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULE(S) ...............................................................................................................18
1.
BACKGROUND INFORMATION.......................................................................................22
1.1
Indication and Current Treatment Options ......................................................22
1.2
Product Background and Clinical Information................................................24
1.2.1
Preclinical Information ..............................................................................25
1.2.2
Clinical Information...................................................................................25
2.
STUDY OBJECTIVES AND PURPOSE ..............................................................................26
2.1
Rationale for the Study ....................................................................................26
2.2
Study Objectives ..............................................................................................26
2.2.1
Primary Objectives.....................................................................................26
2.2.2
Secondary Objectives.................................................................................27
3.
STUDY DESIGN ...................................................................................................................27
3.1
Study Design and Flow Chart..........................................................................27
3.2
Duration and Study Completion Definition.....................................................28
3.3
Sites and Regions.............................................................................................28
4.
STUDY POPULATION.........................................................................................................28
4.1
Inclusion Criteria .............................................................................................28
4.2
Exclusion Criteria ............................................................................................29
4.3
Reproductive Potential.....................................................................................30
4.3.1
Female Contraception................................................................................30
4.4
Discontinuation of Subjects.............................................................................30
4.4.1
Management of Blood Pressure and Pulse During the Study....................31
4.4.1.1
Systolic and Diastolic Blood Pressure.......................................................31
4.4.1.2
Pulse...........................................................................................................31
4.4.2
Reasons for Discontinuation......................................................................32
4.4.3
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit......................32
5.
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
5.1
Prior Treatment ................................................................................................32
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5.2
Concomitant Treatment ...................................................................................33
5.2.1
Permitted Treatment...................................................................................33
5.2.2
Prohibited Treatment .................................................................................33
6.
INVESTIGATIONAL PRODUCT ........................................................................................34
6.1
Identity of Investigational Product...................................................................34
6.1.1
Blinding the Treatment Assignment..........................................................34
6.2
Administration of Investigational Product(s)...................................................34
6.2.1
Interactive Response Technology (IRT) for Investigational Product 
Management...............................................................................................34
6.2.2
Allocation of Subjects to Treatment ..........................................................34
6.2.3
Dosing........................................................................................................35
6.2.4
Unblinding the Treatment Assignment......................................................35
6.3
Labeling, Packaging, Storage, and Handling...................................................36
6.3.1
Labeling .....................................................................................................36
6.3.2
Packaging...................................................................................................36
6.3.3
Storage .......................................................................................................36
6.4
Drug Accountability.........................................................................................37
6.5
Subject Compliance .........................................................................................38
7.
STUDY PROCEDURES........................................................................................................38
7.1
Study Schedule.................................................................................................38
7.1.1
Screening and Washout Period..................................................................39
7.1.1.1
Screening Visit (Visit -1)...........................................................................39
7.1.1.2
Washout Telephone Call (Visit Phone Call)..............................................40
7.1.1.3
Visit 0.........................................................................................................41
7.1.2
Treatment Period........................................................................................41
7.1.2.1
Dose-optimization Period (Visits 1 to 6) ...................................................41
7.1.2.2
Dose Maintenance Period (Visits 7 to 18/ET)...........................................42
7.1.2.3
End-of-Study Visit (Visit 18/Early Termination)......................................42
7.1.3
Safety Follow-up Period ............................................................................43
7.1.4
Additional Care of Subjects After the Study .............................................43
7.2
Study Evaluations and Procedures...................................................................43
7.2.1
Demographic and Other Baseline Characteristics .....................................43
7.2.2
Screening Assessments ..............................................................................43
7.2.2.1
Kiddie – Schedule for Affective Disorders and Schizophrenia for 
School-age Children – Present and Lifetime Version-Diagnostic 
Interview.................................................................................................43
7.2.2.2
Peabody Picture Vocabulary Test-Fourth Edition.....................................44
7.2.3
Efficacy......................................................................................................44
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7.2.3.1
Attention-deficit/Hyperactivity Disorder Rating Scale – IV Preschool 
Version ...................................................................................................44
7.2.3.2
Clinical Global Impressions.......................................................................45
7.2.4
Safety .........................................................................................................45
7.2.4.1
Medical and Medication History ...............................................................45
7.2.4.2
Physical Examination (Including Height and Weight)..............................46
7.2.4.3
Adverse Event Collection ..........................................................................46
7.2.4.4
Vital Signs..................................................................................................46
7.2.4.5
Height and Weight .....................................................................................47
7.2.4.6
Clinical Laboratory Evaluations ................................................................47
7.2.4.7
Electrocardiogram......................................................................................49
7.2.4.8
Children’s Sleep Habits Questionnaire and Sleep Diary...........................49
7.2.4.9
Columbia-Suicide Severity Rating Scale- Pediatric/Cognitively 
Impaired Version....................................................................................50
7.2.4.10
Suitability of the Subject to Remain in the Study......................................50
7.2.5
Volume of Blood to be Drawn From Each Subject ...................................51
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................51
8.1
Definition of Adverse Events, Period of Observation, Recording of 
Adverse Events ................................................................................................51
8.1.1
Severity Categorization..............................................................................52
8.1.2
Relationship Categorization.......................................................................52
8.1.3
Outcome Categorization ............................................................................53
8.1.4
Symptoms of the Disease Under Study .....................................................53
8.1.5
Clinical Laboratory and Other Safety Evaluations....................................53
8.1.6
Abuse, Misuse, Overdose, and Medication Error......................................54
8.2
Serious Adverse Event Procedures..................................................................54
8.2.1
Reference Safety Information....................................................................54
8.2.2
Reporting Procedures.................................................................................54
8.2.3
Serious Adverse Event Definition .............................................................55
8.2.4
Serious Adverse Event Collection Time Frame.........................................55
8.2.5
Serious Adverse Event Onset and Resolution Dates .................................56
8.2.6
Fatal Outcome............................................................................................56
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting......................................................................................56
9.
DATA MANAGEMENT AND STATISTICAL METHODS...............................................56
9.1
Data Collection ................................................................................................56
9.2
Clinical Data Management ..............................................................................57
9.3
Data Handling Considerations.........................................................................57
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9.4
Statistical Analysis Process..............................................................................57
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring 
Committee........................................................................................................57
9.6
Sample Size Calculation and Power Considerations .......................................57
9.7
Study Population..............................................................................................58
9.8
Efficacy Analyses ............................................................................................58
9.8.1
Clinician-administered ADHD-RS-IV Preschool Version........................58
9.8.2
Clinical Global Impressions.......................................................................58
9.8.3
Exploratory Efficacy Endpoints.................................................................59
9.9
Safety Analyses................................................................................................59
9.10
Other Analyses.................................................................................................59
10. SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................59
10.1
Sponsor’s Responsibilities...............................................................................59
10.1.1
Good Clinical Practice Compliance...........................................................59
10.1.2
Public Posting of Study Information..........................................................60
10.1.3
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees............60
10.1.4
Study Suspension, Termination, and Completion......................................60
10.2
Investigator’s Responsibilities.........................................................................60
10.2.1
Good Clinical Practice Compliance...........................................................60
10.2.2
Protocol Adherence and Investigator Agreement......................................61
10.2.3
Documentation and Retention of Records.................................................61
10.2.3.1
Case Report Forms.....................................................................................61
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................62
10.2.3.3
Audit/Inspection.........................................................................................62
10.2.3.4
Financial Disclosure...................................................................................62
10.2.4
Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation................63
10.3
Ethical Considerations .....................................................................................63
10.3.1
Informed Consent.......................................................................................63
10.3.2
Institutional Review Board or Ethics Committee......................................63
10.4
Privacy and Confidentiality .............................................................................64
10.5
Study Results / Publication Policy...................................................................64
11. REFERENCES .......................................................................................................................66
12. APPENDICES ........................................................................................................................69
Appendix 1
Protocol History...............................................................................................70
Appendix 2
Diagnostic Criteria/Disease Classification ......................................................71
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Appendix 2.1 DSM-IV-TR Criteria for Attention- Deficit/Hyperactivity Disorder ........72
Appendix 2.2 Blood Pressure Levels for Boys by Age and Height Percentiles...............74
Appendix 2.3 Blood Pressure Levels for Girls by Age and Height PercentileS ..............75
Appendix 2.4 Boys’ Stature-for-Age and Weight-for-Age Percentiles............................76
Appendix 2.5 Girls’ Stature-For-Age and Weight-For-Age Percentiles..........................77
Appendix 3
Scales and Assessments ...................................................................................78
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LIST OF TABLES
Table 1:
Schedule of Assessments...............................................................................18
Table 2:
Common Excluded Treatments and Associated Washout Period–
Relative to Visit 0..........................................................................................33
LIST OF FIGURES
Figure 1:
Chemical Structure of the Active Pharmaceutical Ingredient............................24
Figure 2:
Study Design Flow Chart...................................................................................27
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ABBREVIATIONS
AAP
American Academy of Pediatrics
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS_IV
attention-deficit/hyperactivity disorder rating scale- IV
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase 
AST
aspartate transaminase
CGI-I
clinical global impressions-global improvement
CGI-S
clinical global impressions-severity of illness
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSHQ
children’s sleep habits questionnaire
C-SSRS
Columbia-suicide severity rating scale
DBP
diastolic blood pressure
DMC
data monitoring committee
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
EC
ethics committee
ECG
Electrocardiogram
EMA
European Medicines Agency
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IRB
Institutional Review Board
IRT
interactive response technology
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IWRS
interactive web response system
LAR
legally authorized representative
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
PAPA
preschool age psychiatric assessment
PATS
Preschool ADHD Treatment Study
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
T4
thyroxine
TEAE
treatment-emergent adverse event
TSH
thyroid stimulating hormone
UBC
United BioSource, LLC
UK
United Kingdom
US
United States
WBC
white blood cell
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STUDY SYNOPSIS
Protocol number:  SPD489-348
Drug: Lisdexamfetamine dimesylate
Title of the study:  A Phase 3, Open-label, Multicenter, 12-Month Safety and Tolerability  Study of SPD489 in 
Preschool Children Aged 4-5 Years Diagnosed with Attention-deficit/Hyperactivity Disorder
Number of subjects:
Approximately 100 subjects will be enrolled into this study. Subjects will enroll into this study from antecedent 
study SPD489-211 or SPD489-347, or through direct enrollment. 
The sample size was established to provide long-term safety data in this population.
Investigator(s):  Multicenter
Site(s) and Region(s): 
Approximately up to 60 sites in North America.
Study period (planned):
2014-2019
Clinical phase:
3
Objectives:
Primary:  To evaluate the long-term safety of SPD489 administered as a daily morning dose (5, 10, 15, 20, and 
30 mg/day) in preschool children (4-5 years of age 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), specific evaluation of blood pressure, pulse, weight, height, clinical laboratory evaluations, 
electrocardiogram (ECG) results, and sleep assessments.
Secondary: 
1.
To describe the long-term efficacy of SPD489 using the clinician administered Attention-
deficit/Hyperactivity Disorder Rating Scale-IV Preschool Version (ADHD-RS-IV Preschool Version).
2.
To describe the long-term efficacy of SPD489 using global clinical measures of improvement, as measured 
by the Clinical Global Impressions – Global Improvement (CGI-I).
Rationale:
The purpose of the study is to evaluate the long-term safety of SPD489 in preschool children who are diagnosed 
with ADHD. Based on IMS Health data and discussion at the Food and Drug Administration (FDA) Pediatric 
Advisory Committee in September 2012, it has been noted that there is off-label use of SPD489 in children 
under 5 years old (4%, or approximately 100 000 patients between February 2007 and March 2012).  The lack 
of controlled data regarding the safety and efficacy of SPD489 in the preschool ADHD population, along with 
the prevalence of off-label prescribing of SPD489 supports the need for SPD489 studies in the preschool ADHD 
population.  Importantly, it is not known if the therapeutic effects of stimulant medications in school age 
children with ADHD can be extrapolated to preschool children with ADHD.  There are some indications that the 
effect size may be reduced (Greenhill 2006).  There may also be differences in the safety and pharmacokinetic 
profiles (Wigal 2007; Wigal 2006).
Generating long-term safety data in this population will provide important information on the use of SPD489 in 
the preschool ADHD population.
Investigational product, dose, and mode of administration:
The sponsor will provide SPD489 as 5, 10, 15, 20, and 30 mg strength capsules.
All subjects will be instructed to take 1 capsule daily throughout the study at approximately 7:00AM (±2 hours). 
SPD489 will be administered in one of the following ways: 
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
swallow SPD489 capsules whole, or

open capsules, empty and mix the entire contents either with yogurt, water, or orange juice.
The contents should be mixed until completely dispersed. The subject must ingest the entire amount of the 
mixture immediately within 3 minutes. The subject should not take anything less than one capsule per day and a 
single capsule cannot be split. The empty gelatinous capsule should be discarded. 
Methodology:
This study is a Phase 3 long-term, open-label, safety and tolerability study in preschool children (4-5 years of 
age inclusive at the time of consent) from antecedent study or direct enrollment with Attention-
deficit/Hyperactivity Disorder (ADHD).
The study will have 4 periods: (1) Screening and Washout; (2) Dose-optimization; (3) Dose Maintenance; and 
(4) Safety Follow-up.
The duration of the evaluation phase (Dose-optimization and Maintenance) will be 52 weeks. 
SPD489 will be provided in 5, 10, 15, 20, and 30 mg capsules.
Subjects may be required to visit the site up to 20 times over a 57-week period. 
Inclusion and exclusion criteria
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below (including test 
results).
1.
Subject is male or female aged 4-5 years inclusive at the time of consent from antecedent studies SPD489-
211 or SPD489-347 or at the time of consent if directly enrolled.
2.
Before completing any study-related procedures, subject’s parent(s) 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 Conference on Harmonisation (ICH) GCP 
Guideline E6 (1996) and any updates or revisions, and applicable federal or local regulations..
3.
Subject and parent(s)/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 parent/LAR should be available at 
approximately 7:00AM (+2 hours) to dispense the dose of investigational product for the duration of the 
study.
4.
Roll-over subjects from antecedent SPD489-347study: 
a.
Subject completed the antecedent SPD489-347 study 
5.
Direct enrolled subjects must meet antecedent study inclusion criteria, as listed below:
a.
Subject must meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text 
Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD (any subtype) based on a detailed 
psychiatric evaluation conducted by a sponsor-approved clinician 
b.
Subject has an ADHD-RS-IV Preschool Version total score at the Baseline Visit (Visit 0) of ≥28 for 
boys and ≥24 for girls. 
c.
Subject has a Clinical Global Impressions – Severity of Illness (CGI-S) score 4 at the Baseline Visit 
(Visit 0). 
d.
Subject has a Peabody Picture Vocabulary Test, Fourth Edition standard score of 70 at the Screening 
Visit (Visit -1). 
e.
Subject has undergone an adequate course of non-pharmacological treatment OR the subject has a 
severe enough condition to consider enrollment without undergoing prior non-pharmacological 
treatment, based on investigator judgment.
f.
Subject has, in the opinion of the investigator, participated in a structured group activity (eg, preschool, 
sports, Sunday school) so as to assess symptoms and impairment in a setting outside the home.
g.
Subject has lived with the same parent(s) or guardian for ≥6 months.
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Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1.
Subject was terminated from any antecedent SPD489 study for non-compliance and/or experienced a 
serious adverse event (SAE) or AE resulting in termination.
2.
Subject is required to or anticipates the need to take prohibited medications or medications that have central 
nervous system effects or have an effect on performance, such as, but not limited to, sedating antihistamines 
and decongestant sympathomimetics, or other monoamine oxidase inhibitors.  Stable use of bronchodilator 
inhalers is not exclusionary.
3.
Subject has a concurrent chronic or acute illness (such as, but not limited to, 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 the Screening Visit 
(Visit -1) or the Baseline Visit (Visit 0) or a history of moderate or severe hypertension. 
7.
Subject has a known history of symptomatic cardiovascular disease, unexplained syncope, exertional chest 
pain, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm 
abnormalities, coronary artery disease, or other serious cardiac problems placing them at increased 
vulnerability to the sympathomimetic effects of a stimulant drug.
8.
Subject is taking any medication that is excluded per the protocol.
9.
Subject had any clinically significant electrocardiogram (ECG) or clinical laboratory abnormalities at the 
Screening Visit (Visit -1) or the Baseline Visit (Visit 0), based on investigator judgment.
10. Subject has a history of hyperthyroidism, or current abnormal thyroid function, defined as abnormal thyroid 
stimulating hormone (TSH) and thyroxine (T4) at the Screening Visit (Visit -1) or the Baseline Visit (Visit 
0).  Treatment with a stable dose of thyroid medication for at least 3 months is permitted. 
11. Subject has taken another investigational product or has taken part in a clinical study within 30 days prior to 
the Screening Visit (Visit -1).
12. Subject is well-controlled on his/her current ADHD medication with acceptable tolerability.
13. Subject has glaucoma.
14. Subject has failed to fully respond, based on investigator judgment, to an adequate course of amphetamine 
therapy.
15. Subject has a current, controlled (requiring medication or therapy) or uncontrolled, co-morbid psychiatric 
disorder including but not limited to any of the below co-morbid Axis I disorders and Axis II disorders:
a.
post-traumatic stress disorder (PTSD) or adjustment disorder
b.
bipolar illness, psychosis, or family history of these disorders
c.
pervasive developmental disorder
d.
obsessive-compulsive disorder (OCD) 
e.
psychosis/schizophrenia
f.
a serious tic disorder, or a family history of Tourette’s disorder
g.
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 is currently demonstrating active suicidal ideation. 
h.
a history of physical, sexual, or emotional abuse
i.
any other disorder or agitated state that in the opinion of the investigator, contraindicates SPD489 or 
lisdexamfetamine dimesylate treatment or confound efficacy or safety assessments.
16. Subject has initiated behavioral therapy within 1 month of the baseline visit (Visit 0).  Subject may not 
initiate behavioral therapy during the study.
17. Subject has a height 5th percentile for age and sex at the screening visit (Visit -1).
18. Subject has a weight 5th percentile for age and sex at the screening visit (Visit -1).
19. Subject lives with anyone who currently abuses stimulants or cocaine.
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20. Subject has a history of seizures (other than infantile febrile seizures)
Maximum duration of subject involvement in the study:

Planned duration of screening period: 28 days

Planned duration of treatment period: 52 week period

Planned duration of safety follow-up period: 7 days
Endpoints and statistical analysis:
Subject Populations

The Screened Set will consist of all subjects who have signed informed consent. 

The Enrolled Set will consist of all subjects who have been dispensed SPD489 at the Baseline Visit (Visit 
0). Screen failures will not be considered enrolled subjects and will not be included in the Enrolled Set.

The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of investigational 
product.

The Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at least 1 post-
dose ADHD-RS-IV Preschool Version Total Score assessment during the study.
Safety Endpoints
Safety assessments include the occurrence of treatment emergent adverse events (TEAEs), specific evaluation of 
blood pressure, pulse, height, weight, clinical laboratory evaluations and electrocardiogram (ECG) results, and 
sleep assessments [(including sleep diary data, and Children’s Sleep Habits Questionnaire (CSHQ)].
Additional safety rating scales utilized in the study will include:
Columbia Suicide Rating Scale (C-SSRS)- Pediatric/Cognitively Impaired Version 
Efficacy Endpoint(s)
The efficacy endpoint is defined as the change from baseline on the clinician-administered ADHD-RS-IV 
Preschool Version Total Score, where subjects that rolled over from an antecedent study, baseline is defined as 
the baseline from the antecedent study, and for subjects that directly enrolled into SPD489-348, baseline is 
defined as baseline of the SPD489-348 study.
The additional efficacy endpoint is the Clinical Global Impression-Improvement Scale (CGI-I): Moreover, the 
CGI-I will be used to determine the proportion of subjects with an “improved” measurement. 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 Endpoint(s)
Safety analyses will be summarized using the Safety Analysis Set, and presented by treatment group of the 
antecedent studies, direct-enrolled group and overall for AEs, clinical laboratory results, vital signs, ECGs, 
CSHQ, and sleep diaries.  A listing of the C-SSRS will be provided for subjects with any positive responses.
Statistical Methodology for Efficacy Endpoint(s)
The FAS will be used to report the efficacy data. Descriptive summary statistics will be presented by treatment 
group of the antecedent studies, direct-enrolled group and overall for the observed efficacy variables. Change 
from baseline in total score for the ADHD-RS-IV Preschool Version Total Score at each on-therapy treatment 
visit will be summarized.
Descriptive summary statistics will be presented by treatment group of the antecedent studies, directly enrolled 
group, and overall at each on-treatment visit for CGI-I measurements. Additionally, the number and proportion 
of subjects with an “improved” measurement in CGI-I will be reported at each on-treatment post-dose visit. 
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1
BACKGROUND INFORMATION
Lisdexamfetamine dimesylate capsules (SPD489, previously referred to as NRP104) were 
developed for the once-daily treatment of ADHD.
SPD489 capsules contain 5, 10, 15, 20, or 30 mg of lisdexamfetamine dimesylate, a new 
chemical entity designed for once-daily oral administration. Lisdexamfetamine itself is a 
pharmacologically inactive prodrug. After ingestion it is converted to l-lysine (a naturally 
occurring essential amino acid) and dextroamphetamine (d-amphetamine, responsible for 
pharmacological activity) primarily in the blood.
Amphetamine is a chiral compound that exists as 2 stereoisomers: dextro (d)- and levo (l)-
amphetamine. Lisdexamfetamine is the l-lysine conjugate of the dextro stereoisomer.  After oral 
administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract and 
converted primarily in the blood to l-lysine (a naturally occurring amino acid) and d-
amphetamine, which is responsible for the drug’s pharmacological activity.
Lisdexamfetamine is classified as a psychomotor stimulant.  
Amphetamine appears to exert its pharmacological effects in the CNS by increasing the 
availability of naturally occurring amines that have important functions in nerve terminals. 
Amphetamine increases synaptic levels of dopamine (DA), norepinephrine (NE), and serotonin 
(5-HT) through multiple mechanisms (Hardman et al., 2001). It promotes the release of DA, NE, 
and 5-HT into the extraneuronal space, and also inhibits the reuptake of DA and NE into the pre-
synaptic nerve terminal resulting in prolonged residency of these neurotransmitters in the 
synaptic cleft. In addition to producing a CNS response, amphetamine treatment is also 
associated with cardiovascular effects such as an increase in SBP and DBP, and pulse. 
Amphetamine may also suppress the appetite.
In addition to the approved indication of ADHD, other indications have been explored.
Additional information can be found in the current IB for SPD489.
1.1
Indication and Current Treatment Options 
Attention-deficit/hyperactivity disorder is a heterogeneous neurobehavioral disorder 
characterized by a pattern of developmentally inappropriate inattentiveness, impulsivity, and 
hyperactivity resulting in clinically significant impairment in social, academic, or occupational 
functioning. Although ADHD was originally thought to be a disorder primarily affecting 
elementary school age children, it is now recognized that ADHD may persist across a lifetime, 
and that ADHD symptoms may manifest several years prior to entry into elementary school. 
While there are hundreds of studies investigating the treatment of ADHD in school-age children, 
there are very few studies exploring the treatment of ADHD in preschoolers.  Although 
diagnosing ADHD in a preschool child can be challenging, reliable diagnostic tools and age-
appropriate assessments are available, and it is therefore possible to conduct scientifically 
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rigorous ADHD studies in this population.  It would be beneficial to provide additional evidence-
based support for ADHD treatment decisions in the preschool population.  
Estimates of the prevalence of ADHD in the preschool population vary depending on the referral 
source and the method used to diagnose ADHD; however, it appears that approximately 4-5% of 
preschool children are considered to have ADHD.  Using the Preschool-age Psychiatric 
Assessment, an assessment validated for use in the preschool population, the prevalence of 
ADHD in a sample of 1,073 children aged 2-5 years was reported to be 3.9-5.1% 
(Egger et al., 2006a; Egger and Angold, 2004; Greenhill et al., 2008).  In 2007, the National 
Survey of Children’s Health obtained information from parents of 73,123 children aged 4-17 
years (MMWR, 2010). Parents reported a current diagnosis of ADHD in 5.5% of 4-10 year olds 
(MMWR, 2010).  Some reports utilizing a clinic-based sampling frame (versus a community 
based - sampling frame) report the prevalence in males aged 4-11 is roughly 3 times greater than 
in females  (Szatmari et al., 1989).  There is acknowledgment, however, that males present with 
more disruptive symptoms and are referred for treatment earlier and more often than girls 
(Hinshaw, 2002), so clinic samples are not likely to represent an accurate reflection of the gender 
distribution of ADHD.
Genetic studies indicate that ADHD has high heritability rates (Faraone and Biederman, 1998; 
Tannock, 1998) with an autosomal rather than sex-linked inheritance pattern (Wallis et al., 2008; 
Thapar, 2002) supporting the gender-based prevalence ratios of 1:1 in the community which is 
consistent with the reported 1:1 male:female prevalence of ADHD in adults.  
Attention-deficit/hyperactivity disorder is characterized by symptoms of inattention, 
hyperactivity, and impulsivity that are “maladaptive and inconsistent with developmental level” 
(DSM-IV).   Preschool children, ages 3-5 years, often exhibit symptoms of hyperactivity and 
impulsivity, so it may be challenging to delineate what is “inconsistent with developmental 
level” for this population (Smith and Corkum, 2007).  Nevertheless, it is possible to diagnose 
ADHD in the preschool population in a reliable fashion (Egger et al., 2006a; Egger et al., 2006b;
McGoey et al., 2007).
The presence of ADHD symptoms that are frequent, severe, and developmentally inappropriate, 
can be used to define ADHD in this population (Connor, 2002; Smith and Corkum, 2007).  In 
addition, impairment in 2 or more settings establishes that the constellation of ADHD symptoms 
is maladaptive and not confined to a specific environment.  The severity of ADHD symptoms in 
a preschool child can be reliably measured using scales such as the PAPA and the ADHD-RS-IV 
Preschool Version that have been validated for this population and include age-appropriate 
questions and prompts (Egger et al., 2006a; McGoey et al., 2007).  
It is appropriate to consider whether an ADHD diagnosis in a preschool child will endure or 
resolve as the child matures.  ADHD has been described in terms of a developmental trajectory 
that can be modified by biologic or environmental factors (Sonuga-Barke and Halperin, 2010; 
Sonuga-Barke et al., 2005).  Potential risk factors such as severity of ADHD symptoms, the 
presence of oppositional defiant symptoms, and neuropsychological impairment may affect the 
course of ADHD (Sonuga-Barke and Halperin, 2010).  Although some children may not retain 
the ADHD diagnosis as they grow older, for many children the diagnosis endures beyond their 
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preschool years (Lahey et al., 2004; Tandon et al., 2011).  In a sample of 96 children aged 4-6 
years with ADHD, 79% of the children continued to have an ADHD diagnosis 3 years later as 
compared to 3% of the non-ADHD control children (Lahey et al., 2004).  This finding was 
replicated in a sample of 48 children aged 4-6 years with ADHD who were followed for 2 years 
(Tandon et al., 2011).  These results suggest that when an ADHD diagnosis is first made in a 
preschool child, it is likely to be stable over time. 
The constellation of impairments associated with an ADHD diagnosis in preschool children 
suggests a characteristic profile similar to that for individuals diagnosed after the preschool 
period.  Preschool children with ADHD demonstrate impairments in social functioning and pre-
academic skills (DuPaul et al., 2001; Ghuman et al., 2008).  They are also more likely to be 
aggressive towards others and to sustain an injury (Greenhill et al., 2008; Rappley et al., 1999; 
Connor et al., 2003).  In a longitudinal study which followed children from aged 4-21 years, the 
attention span at age 4 years predicted math and reading skills at age 21 years and completion of 
college at age 25 years (McClelland et al., 2013).
Currently, the lack of a robust body of evidence derived from controlled clinical studies in 
preschool children makes it difficult to create reliable treatment recommendations. The AAP 
ADHD Clinical Practice guideline suggests that preschool children with ADHD initiate 
treatment with behavioral therapy prior to using pharmacotherapy (Subcommittee on ADHD et 
al., 2011); however the PATS results indicates that 13% of preschool children have a satisfactory 
response to behavioral therapy (Greenhill et al., 2006). If the preschool child with ADHD does 
not respond to behavioral therapy, the guideline then suggests the use of methylphenidate. Of 
note, methylphenidate does not have an indication for a population less than 6 years old 
(Subcommittee on ADHD et al., 2011). Immediate-release Adderall (dextroamphetamine 
saccharate, amphetamine aspartate, dextroamphetamine sulfate, and amphetamine sulfate) and 
dextroamphetamine are approved for children with ADHD as young as 3 years old. As a result, if 
a preschool child does not respond to methylphenidate, a trial of an amphetamine product is 
recommended by the AAP. However, the lack of data for amphetamines in preschool children 
with ADHD is acknowledged. Clearly, the implementation of additional studies in preschool
children with ADHD would provide additional evidence in order to inform treatment decisions. 
1.2
Product Background and Clinical Information
The active pharmaceutical ingredient of SPD489 is (2S)-2, 6-diamino-N-[(1S)-1-methyl-
2-phenylethyl] hexanamide dimethanesulfonate.
Figure 1 shows the chemical structure of the active pharmaceutical ingredient: 
Figure 1:
Chemical Structure of the Active Pharmaceutical Ingredient
H
N
NH2
O
CH3
NH2
H3C S OH
O
O
2
·
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Always refer to the latest version of the SPD489 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of SPD489. 
1.2.1
Preclinical Information
Lisdexamfetamine is a pharmacologically inactive prodrug. After ingestion, it is converted in the 
blood to d-amphetamine (responsible for pharmacological activity) and l-lysine (a naturally 
occurring essential amino acid).  A comprehensive set of studies has been conducted to evaluate 
the pharmacological and toxicological properties associated with the parent compound 
lisdexamfetamine.  The safety profiles associated with d-amphetamine and l-lysine are well 
established.
All safety and toxicology studies, except the single dose acute toxicity study in rats, were 
conducted in compliance with Good Laboratory Practice.
Complete preclinical information is presented in the current SPD489 IB.
1.2.2
Clinical Information
The pharmacological profile of lisdexamfetamine and the pharmacologically active metabolite d-
amphetamine have been well characterized in studies enrolling children, healthy adults, and 
adults with a history of stimulant abuse. These studies have demonstrated that oral administration 
of SPD489 resulted in a predictable d-amphetamine pharmacokinetic profile with low intra-
subject and inter-subject variability. The d-amphetamine AUC0-∞ and Cmax generally behaved in a 
linear, dose-proportional manner. The weight-normalized d-amphetamine AUC0-∞ is similar for 
children and adults, with tmax and t½ consistent across age groups.
In the ADHD Clinical Development Program, the efficacy of SPD489 for the treatment of 
ADHD has been demonstrated for children, adolescents, and adults with ADHD. Substantial 
evidence of efficacy was provided in well-controlled studies, where SPD489 was shown to be 
effective compared to placebo. SPD489 was associated with a statistically significant, clinically 
meaningful improvement in ADHD symptoms, functional outcomes, and health-related quality 
of life compared to placebo, in studies that used a variety of study designs, a variety of validated 
assessments, and a variety of raters.
The well-characterized SPD489 safety profile was consistent with that of other stimulants used 
in the treatment of ADHD. When the safety results from the 35 completed Phase 2-4 clinical 
studies in the ADHD Clinical Development Program were examined, the majority of TEAEs 
were mild or moderate in severity, and no differences due to age or sex were noted. The most 
frequently reported AEs were those typically associated with stimulant therapy (including 
decreased appetite, insomnia, headache, dry mouth, irritability, upper abdominal pain, and 
weight decrease), or potentially attributable to intercurrent illnesses (eg, upper respiratory tract 
infection and nasopharyngitis). These TEAEs were generally non-serious and were considered 
by the investigator to have resolved during study participation.
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Stimulant medications like SPD489 cause a modest increase in average blood pressure 
(approximately 2-4 mmHg) and average pulse (approximately 3-6 bpm). Individuals may have 
larger increases.
Always refer to the latest version of the SPD489 IB for the overall risk/benefit assessment and 
the most accurate and current information regarding the drug metabolism, pharmacokinetics, 
efficacy and safety of SPD489.
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Based on IMS Health data and discussion at the FDA Pediatric Advisory Committee in 
September 2012, it has been noted that there is off-label use of SPD489 in children under 5 years 
old (4%, or approximately 100,000 patients between February 2007 and March 2012). The lack 
of controlled data regarding the safety and efficacy of SPD489 in the preschool ADHD 
population, along with the prevalence of off-label prescribing of SPD489 supports the need for 
SPD489 studies in the preschool ADHD population. Importantly, it is not known if the 
therapeutic effects of stimulant medications in school age children with ADHD can be 
extrapolated to preschool children with ADHD. There are some indications that the effect size 
may be reduced (Greenhill et al., 2006). There may also be differences in the safety and 
pharmacokinetic profiles (Wigal et al., 2007;Wigal et al., 2006).
However, recent data from Shire SPD489-211 study preschool aged children with ADHD 
suggests the safety and tolerability profile of SHP489 is similar to that observed in trials with 
children 6 to 12 years old, adolescents and adults. The efficacy results of the SPD489- 211 study, 
were also comparable to older subjects and revealed a mean decrease from baseline of -26.1 
(95% CI: -32.2, -20.0) in the ADHD-RS-IV Preschool Version total score, suggesting a robust 
similar improvement in ADHD symptoms. 
In summary given the abundance of information regarding the safety and efficacy of 
amphetamines; the very well-established PK profile of SPD489; the similar efficacy and safety 
findings between populations with ADHD covering the age span from 6 to 55 years; and the PK, 
safety, and efficacy data from Study SPD489-211 in preschoolers (aged 4-5 years) with ADHD, 
it is expected that findings from previous trials in older age groups can be extrapolated to 
preschool patients with ADHD.
Generating long-term safety data in this population will provide important information on the use 
of SPD489 in the preschool ADHD population.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to evaluate the long-term safety of SPD489 administered 
as a daily morning dose (5, 10, 15, 20, and 30 mg/day) in preschool children (4-5 years of age 
inclusive) diagnosed with ADHD.
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3.2
Duration and Study Completion Definition
The duration of the evaluation phase (Dose Screening & Washout, Dose Optimization, Dose 
Maintenance, and Safety Follow-up) will be 57 weeks. The subject’s maximum duration of 
participation is expected to be approximately 399 days.  
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
This study will be conducted in up to 60 sites in North America.
4
STUDY POPULATION
Each subject/parent or LAR must participate in the informed consent process and provide written 
informed consent and/or assent, as per IRB/EC requirements 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 criteria below 
(including test results):
1. Subject is male or female aged 4-5 years inclusive at the time of consent from antecedent 
studies SPD489-211 or SPD489-347 or at the time of consent if directly enrolled. 
2. Before completing any study-related procedures, subject’s parent(s) or LAR must provide 
signature of informed consent, and there must be documentation of assent (if applicable) by 
the subject indicating that the subject is aware of the investigational nature of the study. The 
subject’s parent(s) or LAR should understand that the required procedures and restrictions 
are being conducted in accordance with the International Council of Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline E6 (1996), any updates or revisions, and applicable 
federal or local regulations.
3. Subject and parent(s)/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 parent/LAR should be available at approximately 7:00AM (+2 hours) to dispense the 
dose of investigational product for the duration of the study.
4. Roll-over subject from antecedent SPD489-347 study:
a.
Subject completed the antecedent study (SPD489-347)
5. Direct enrolled subjects must meet antecedent study inclusion criteria, as listed below
a.
Subject must meet DSM-IV-TR criteria for a primary diagnosis of ADHD (any subtype) 
based on a detailed psychiatric evaluation conducted by a sponsor-approved clinician
b. Subject has an ADHD-RS-IV Preschool Version total score at the Baseline Visit (Visit 0) 
of 28 for boys and 24 for girls.  
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c.
Subject has a Clinical Global Impressions – Severity of Illness (CGI-S) score 4 at the 
Baseline Visit (Visit 0). 
d. Subject has a Peabody Picture Vocabulary Test, Fourth Edition standard score of 70 at 
the Screening Visit (Visit -1). 
e.
Subject has undergone an adequate course of non-pharmacological treatment based on 
investigator judgment OR the subject has a severe enough condition to consider 
enrollment without undergoing prior non-pharmacological treatment, based on 
investigator judgment.  
f.
Subject has, in the opinion of the investigator, participated in a structured group activity 
(eg, preschool, sports, Sunday school) so as to assess symptoms and impairment in a 
setting outside the home.
g. Subject has lived with the same parent(s) or guardian for 6 months.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met: 
1. Subject was terminated from an antecedent SPD489 study for non-compliance and/or 
experienced a serious adverse event (SAE) or AE resulting in termination. 
2. Subject is required to or anticipates the need to take medications that have central nervous 
system effects or affect performance, such as, but not limited to, sedating antihistamines and 
decongestant sympathomimetics, or monoamine oxidase inhibitors.  Stable use of 
bronchodilator inhalers is not exclusionary.
3. Subject has a concurrent chronic or acute illness (such as, but not limited to, 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 the 
screening visit (Visit -1) or the baseline visit (Visit 0) or a history of moderate or severe 
hypertension. 
7. Subject has a known history of symptomatic cardiovascular disease, unexplained syncope, 
exertional chest pain, advanced arteriosclerosis, structural cardiac abnormality, 
cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious 
cardiac problems placing them at increased vulnerability to the sympathomimetic effects of a 
stimulant drug.
8. Subject is taking any medication that is excluded per the protocol.
9. Subject had any clinically significant electrocardiogram (ECG) or clinical laboratory 
abnormalities at the Screening Visit (Visit -1) or baseline visit (Visit 0), based on investigator 
judgment.
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10. Subject has a history of hyperthyroidism, or current abnormal thyroid function, defined as 
abnormal thyroid stimulating hormone (TSH) and thyroxine (T4) at the Screening Visit (Visit 
-1) or Visit 0.  Treatment with a stable dose of thyroid medication for at least 3 months is 
permitted. 
11. Subject has taken another investigational product or has taken part in a clinical study within 
30 days prior to the Screening Visit (Visit -1).
12. Subject is well-controlled on his/her current ADHD medication with acceptable tolerability.
13. Subject has glaucoma.
14. Subject has failed to fully respond, based on investigator judgment, to an adequate course of 
amphetamine therapy.
15. Subject has a current, controlled (requiring medication or therapy) or uncontrolled, co-
morbid psychiatric disorder including but not limited to any of the below co-morbid Axis I 
disorders and Axis II disorders:
a.
post-traumatic stress disorder (PTSD) or adjustment disorder
b. bipolar illness, psychosis, or family history of these disorders
c.
pervasive developmental disorder
d. obsessive-compulsive disorder (OCD) 
e.
psychosis/schizophrenia
f.
subject has a serious tic disorder, or a family history of Tourette’s disorder 
g. 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 is currently demonstrating 
active suicidal ideation. Subjects with intermittent passive suicidal ideation are not 
necessarily excluded based on the assessment of the investigator 
h. a history of physical, sexual, or emotional abuse
i.
any other disorder or agitated state that in the opinion of the investigator, contraindicates 
SPD489 or lisdexamfetamine dimesylate treatment or confound efficacy or safety 
assessments.
16. Subject has initiated behavioral therapy within 1 month of the baseline visit (Visit 0).  
Subject may not initiate behavioral therapy during the study.
17. Subject has a height 5th percentile for age and sex at the screening visit (Visit -1).
18. Subject has a weight 5th percentile for age and sex at the screening visit (Visit -1).
19. Subject lives with anyone who currently abuses stimulants or cocaine.
20. Subject has a history of seizures (other than infantile febrile seizures).
4.3
Reproductive Potential
4.3.1
Female Contraception
Contraception is not applicable as no female subjects in this study are of child bearing potential. 
All female subjects in this study are pre-menarchal, less than age 9 years, and Tanner Stage 1.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
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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 the 
Safety/Follow-up visit 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 source 
documents.  The reason for termination, date of stopping investigational product, and the total 
amount of investigational product taken must be recorded in the CRF and source documents.
4.4.1
Management of Blood Pressure and Pulse During the Study
Potential blood pressure and pulse increases must be further evaluated if they meet any of the 
criteria defined in Section 4.4.1.1 and Section 4.4.1.2. 
4.4.1.1
Systolic and Diastolic Blood Pressure
Blood pressure criteria for further evaluation have been developed based on the normative data 
presented in the National Institutes for Health Fourth Report on the Diagnosis, Evaluation, and 
Treatment of High Blood Pressure in Children and Adolescents (2005). 
Increases in blood pressure (both systolic and diastolic) from the 50th to the 95th percentile 
(representative of a change of 2 standard deviations) range from 17-20 mmHg for both boys and 
girls in this age range.  Based on this range, an increase of >15mmHg from Visit 0 was selected 
for this protocol.
Prior to obtaining vital signs (blood pressure and pulse) the subject should be at rest for at least 5 
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 a dose reduction or potential 
discontinuation based upon the clinical judgment of the investigator and in conjunction with the 
medical monitor. If the dose has been previously decreased, or if the subject is already at the 
lowest dose, then the subject should be discontinued from the study. 
1. Elevations in the average (of 3 readings) sitting systolic blood pressure defined as an increase 
of >15 mmHg from the baseline visit (Visit 0) OR a value >95th percentile for age, sex, and 
height 
2. Elevations in average (of 3 readings) sitting diastolic blood pressure defined as an increase of 
>15 mmHg from the baseline visit (Visit 0) OR a value >95th percentile for age, sex, and 
height 
4.4.1.2
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).
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Any subject that has a resting, sitting pulse rate >126 bpm (based on the average of 3 readings) 
and 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 
>126 bpm (based on the average of 3 readings) or if the subject is symptomatic then the subject’s 
investigator will discuss the findings with the medical monitor. A joint decision between the 
investigator and the medical monitor will be made regarding dose reduction and continued 
participation in the study. If the dose has been previously decreased, or if the subject is already at 
the lowest dose, then the subject will be discontinued from the study. If a visit cannot be 
scheduled the next day, the subject may be discontinued from the study. 
4.4.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF.  If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF.
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).  
4.4.3
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s) or LAR of any 
subject lost to follow-up at any time point prior to 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.
5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy) received since the subject’s 
last visit in the antecedent study and through the final study contact (including protocol-defined 
follow-up period) must be recorded on the appropriate CRF page. 
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
behavioral treatment, non-pharmacological treatment, such as psychotherapy) received within 30 
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days (or pharmacokinetic equivalent of 5 half-lives, whichever is longer) prior to the date of first 
dose of investigational product. Prior treatment information must be recorded on the appropriate 
CRF page.
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 on the appropriate CRF page.
5.2.1
Permitted Treatment
Medications that may be permitted during the study are listed below.  Please consult with the 
Medical Monitor:

Stable dose of thyroid medication, provided the same dose had been used during the 
antecedent study. Stable dose of bronchodilator inhalers (however, beta-agonists and chronic 
use of oral corticosteroids is prohibited)

Any medications that do not affect blood pressure, heart rate, or the CNS, and which are 
considered necessary for the subject’s welfare, may be administered at the discretion of the 
investigator (eg, antibiotics)

Non-sedating antihistamines such as fexofenadine (ALLEGRA, Sanofi), loratadine 
(CLARITIN, Schering-Plough), and cetirizine hydrochloride (ZYRTEC, McNeil-PPC)

Over-the-counter non-stimulant cold remedies
Concomitant psychotherapy must also be recorded in the appropriate section of the source 
documents and in the appropriate CRF page.
5.2.2
Prohibited Treatment
Table 2 details the washout period, relative to Visit 0, for treatments that are excluded during this 
study. Subjects can only be instructed to discontinue a medication for this study after the 
informed consent has been obtained. 
Table 2: Common Excluded Treatments and Associated Washout Period– Relative to Visit 
0
Minimum Number of Days Before Visit 0
Treatment
7
14
30
Psychostimulants, Amphetamines, and Amphetamine-like 
agents
X
Antihypertensives a
X
Antihistamines (centrally and peripherally-active)
X
Herbal preparations (including melatonin)
X
Investigational compounds (other than the investigational 
X
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Table 2: Common Excluded Treatments and Associated Washout Period– Relative to Visit 
0
Minimum Number of Days Before Visit 0
Treatment
7
14
30
compound received during participation in 1 of the respective 
antecedent SPD489 studies).
Sedatives, anxiolytics, antipsychotics a
X
Monoamine oxidase inhibitor (MAOIs) a
X
Antidepressants a
X
Clonidine and guanfacine
X
Selective noradrenaline reuptake inhibitors and noradrenaline 
reuptake inhibitors a
X
a These medications may signal that an exclusionary diagnosis is present. The medical monitor should be consulted prior to 
instructing a subject to discontinue one of these medications for this study.
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is SPD489, which will be provided in 5, 10, 15, 20, and 30 mg capsules. 
Additional information is provided in the current SPD489 IB.
6.1.1
Blinding the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology (IRT) for Investigational Product 
Management
An IRT 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 IRT provider will provide a user manual and training to each site, with detailed instruction 
on the use of the IRT.
6.2.2
Allocation of Subjects to Treatment 
All subjects will receive open-label SPD489 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 the 
antecedent study participation. 
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6.2.3
Dosing
Dosing should begin at approximately 7:00AM (±2 hours) on the morning after Visit 0.  Subjects 
will be instructed to take 1 capsule 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. 
SPD489 will be administered one of the following ways: 

swallow SPD489 capsule whole, or

open capsule, empty and mix the entire contents with either yogurt, water, or orange juice. 
The contents should be mixed until completely dispersed. The subject must ingest the entire 
amount of mixture immediately within 3 minutes. The subject should not take anything less than 
one capsule per day and a single capsule cannot be split. The empty gelatinous capsule should be 
discarded. 
All subjects will begin dosing at 5 mg of SPD489 and should be titrated in a stepwise fashion 
until an optimal dose is reached.  
The objective of dose optimization during the first 6 weeks is to ensure that subjects are titrated 
to an optimal dose of study drug based on TEAEs and clinical criteria.
The investigator will categorize subject response into 1 of the 3 conditions, along with the 
associated actions, below.  Dose optimization should continue during the first 4 weeks until an 
“acceptable response” is achieved.

Intolerable response (ie, subject experiences intolerable side effects): This response 
suggests tapering the subject to a lower dose of investigational product (if available). 
However, 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-IV 
Preschool Version Total Score from Baseline (Visit 0) of the antecedent study and a CGI-I 
score of 1 or 2): This response suggests titrating the subject to the next available dose of 
investigational product (if available, provided there are no tolerability issues).

Acceptable response (ie, subject has achieved at least a 30% reduction in ADHD-RS-IV 
Preschool Version Total Score from Baseline (Visit 0) of the antecedent study 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.
6.2.4
Unblinding the Treatment Assignment
Not applicable.
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6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) 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 statements ‘For clinical trial use only’, and/or ‘CAUTION: New Drug -
Limited by Federal (or US) 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. 
6.3.2
Packaging 
Investigational product is packaged in the following labeled containers:
SPD489 capsules are packaged in 10-count and 35-count high density polyethylene bottles with 
child-resistant closures.  
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that 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 min/max 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 
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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.
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 overall responsibility for administering/dispensing 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 his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol.  Each subject will be given 
only the investigational product carrying his/her treatment assignment.  All dispensed medication 
will be documented on the CRFs and/or other investigational product record. The investigator is 
responsible for assuring the retrieval of all study supplies from subjects.  
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 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 
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amount is to be documented in lieu of counting.  Shipment return forms, when used, must be 
signed prior to shipment from the site.  Validated electronic return systems (i.e., IRT) 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 prior to shipment.  Shipment of all returned investigational product must 
comply with local, state, and national laws.
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
All investigational product provided to pediatric subjects should be supervised by the 
parent(s)/legally-authorized representative/caregiver.
Subjects’ parent(s)/LAR must be instructed to bring their child’s 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/delegated person will record 
details on the drug accountability form. 
Subjects who have taken 80-100% of the investigational product are regarded as being compliant 
with the study protocol.  Compliance must be assessed by the investigator.
The calculation of medication compliance is as follows: 
Protocol
by
Prescribed
Capsules
100
Taken
Capsules
Total
Compliance


When performing the calculation of medication compliance for investigational product, the total 
capsules taken must also include number of capsules not returned by the subject to the site.
7
STUDY PROCEDURES
7.1
Study Schedule
The Schedule of Assessments (Table 1) details 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-IV 
Preschool Version, CGI-S, CGI-I, CSHQ and Columbia Suicide Rating Scale (C-SSRS)
Pediatric/Cognitively Impaired Version must be completed by the same rater whenever possible.
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Throughout the Dose-Optimization Period of the study, visits should be scheduled as outlined 
(days), and throughout the Dose-Maintenance Period of the study, visits should be scheduled 
as outlined (5 days) with reference to Visit 0. The Follow-up Telephone Call should be 
scheduled 7 days post-last dose with a +3 day visit window.
Subjects will be required to visit the site up to 20 times over a 57-week period.
Additional unscheduled visits and/or assessments may occur as needed for safety (eg, 
unscheduled visits for blood pressure and/or pulse measurements will be conducted as described 
in Section 4.4.1) 
7.1.1
Screening and Washout Period 
The principal investigator or his/her designee must obtain written informed consent from the 
subject’s parent(s)/LAR prior to any study-related procedures conducted during the Screening 
Visit (Visit -1). 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, prior to the performance of any study-related procedures.
A washout period may be required to discontinue any prohibited medication (see Table 2).  A 
subject cannot be instructed to wash out any medication for this study until after informed 
consent is obtained.
Screening assessments may take place across multiple days to allow enough time to complete all 
procedures and confirm initial study eligibility. Screening procedures and dates should be well 
documented in the source documents and CRF. The screening date is the date the parent(s)/LAR 
and/or subject has signed informed consent for this study. A screen failure is a subject who has 
given informed consent and failed to meet any of the inclusion and/or met at least 1 of the 
exclusion criteria and has not been administered investigational product.
For screen failure subjects, the investigator or assigned site staff designee will access the IWRS 
to record the subject as a screen failure. 
Subjects cannot be rescreened once they have been designated as a screen failure. Reassessment 
of subjects who failed specific inclusion/exclusion criteria is not allowed.
7.1.1.1
Screening Visit (Visit -1) 
Subjects will be screened at Visit -1 to establish eligibility for study participation.  For roll-over 
subjects, the EOS visit in the antecedent SPD489-347 study will serve as the Screening visit for 
SPD489-348.
Some screening assessments (vital signs, height, weight, clinical laboratory tests, and ECGs) 
must be repeated prior to Baseline if more than 30 days have elapsed since collection.
Table 1 details all procedures to be completed at the Screening Visit (Visit -1). Additional 
clarification on the procedures performed during the Screening Visit (Visit -1) is provided 
below:
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
All AEs occurring after signature of informed consent must be recorded in the source 
documents and CRF. Any AE ongoing at the time of the End of Study Visit from the 
antecedent study must be recorded on the CRF for this study. 

For roll-over subjects, document any new findings on the Medical History CRF with enough 
detail to permit detection of change over time.

Twelve-lead ECG will be performed after approximately 5 minutes of rest.  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.

After 5 minutes of rest, blood pressure and pulse will be collected 3 times (with 
approximately 2 minutes in between each collection) during the visit.  The average of each 
set of 3 measurements will be used to determine continued participation in the study (see 
Section 4.4.1).

The “Lifetime Recent” version of the C-SSRS will be administered at the Screening Visit 
(Visit -1) for direct-enrolled subjects.  The “Since Last Visit” version will be administered at 
the Screening Visit (Visit -1) for roll-over subjects.  Record historical/concomitant 
medications as follows:

All lifetime psychoactive medications and lifetime non-pharmacological interventions 
(behavioral therapy) for ADHD

Other medications used during the 30 days prior to the Screening Visit (Visit -1). 
7.1.1.2
Washout Telephone Call (Visit Phone Call) 
The Washout Period should be initiated after clinical laboratory test results and 12-lead ECG 
results have been received and reviewed by the investigator.  For roll-over subjects, the follow-
up call for the antecedent SPD489-347 study will serve as the wash-out call for the SPD489-348 
study.  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 a minimum of
5 times the half-life of the medication.  Washout periods for prohibited medications are defined 
in Table 2.
As part of the Washout Telephone Call, site personnel should perform the following procedures:

Schedule Visit 0

Review the inclusion/exclusion criteria

Ask about any concomitant medications that the subject is taking.  If any concomitant 
medications that require washout are noted, instructions for appropriate washout should be 
provided

Determine if any AEs have occurred since the Screening Visit (Visit -1).
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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
Visit 0
The Baseline visit should be initiated after clinical laboratory test results and 12-lead ECG 
results have been received and reviewed by the investigator.  For subjects with more than 30 
days since the safety measurements at the Screening Visit (Visit -1) were collected, an 
abbreviated physical examination, clinical laboratory tests and 12-lead ECG must be repeated, 
and the results reviewed by the investigator prior to the subject being enrolled.
Inclusion/exclusion criteria must be reviewed during this visit to ensure subjects continue to 
meet all eligibility criteria.
Table 1 outlines all procedures to be conducted during Visit 0 with further clarification provided 
below:

After 5 minutes of rest, blood pressure and pulse will be collected 3 times (with 
approximately 2 minutes in between each collection) during the visit.  The average of each 
set of 3 measurements will be used to determine continued participation in the study (see 
Section 4.4.1). 

For eligible subjects, the investigator or assigned study center staff designee will access the 
IRT to enroll the subject and obtain an investigational medicinal product bottle number to 
dispense to the subject.  Subjects will be dispensed a 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 following Visit 0.

The C-SSRS “Since Last Visit” Version should be completed.
7.1.2
Treatment Period 
7.1.2.1
Dose-optimization Period (Visits 1 to 6) 
During the first 6 weeks of treatment, visits will be scheduled every 7 days (±3 days) to assess 
safety, efficacy, and tolerability and to allow investigators to titrate subjects to their optimal dose 
of SPD489 based on TEAEs and the dosing guidelines in Section 6.2.3. 
If the optimal dose is well tolerated and, in the opinion of the investigator, the subject would 
potentially receive additional symptom reduction, the subject may be titrated to the next allowed 
dose.
Throughout the Dose-optimization Period, subjects may attend the clinic for unscheduled visits 
to address any medical needs that arise between scheduled visits.
See Table 1 for procedures that are completed at Visits 1 to 6.  Further clarification for these 
visits is outlined below:
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
At each visit during the Dose-optimization Period, subjects must return any empty or unused 
bottles to permit drug accountability and compliance to be assessed.

Subjects will be dispensed a 10-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 following each visit.

After 5 minutes of rest, blood pressure and pulse will be collected 3 times (with 
approximately 2 minutes in between each collection) during the visit.  The average of each 
set of 3 measurements will be used to determine continued participation in the study (see 
Section 4.4.1).

Scales should be completed by the same rater whenever possible.

The sleep diary is to be completed by the same parent/LAR, whenever possible.

The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired Version 
should be completed during the Optimization Period.
7.1.2.2
Dose Maintenance Period (Visits 7 to 18/ET) 
Following titration to an optimal dose of SPD489, subjects will continue daily morning treatment 
for an additional 48 weeks. Subjects will attend the clinic every 4 weeks for procedures to be 
performed. 
Throughout the Maintenance Period, subjects may attend the clinic for unscheduled visits to 
address any medical needs that arise between scheduled visits.
Table 1 outlines the procedures to be completed at each visit during the Maintenance Period.  
Additional clarification on the procedures to be performed during the Maintenance Period is 
provided below:

Scales are to be completed by the same rater whenever possible

At each visit during the Maintenance Period, subjects must return any empty or unused 
bottles to permit drug accountability and compliance to be assessed.

Subjects will be dispensed a 35-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 following each visit

After 5 minutes of rest, blood pressure and pulse will be collected 3 times (with 
approximately 2 minutes in between each collection) during the visit.  The average of each 
set of 3 measurements will be used to determine continued participation in the study (see 
Section 4.4.1).
7.1.2.3
End-of-Study Visit (Visit 18/Early Termination) 
All subjects who complete the study or discontinue early will complete the End-of-Study Visit.
Table 1 lists the procedures to be completed at Visit 18/ET and should serve as the primary point 
of reference regarding visit-specific study procedures.
Further clarification on the procedures performed during the End-of-Study Visit is provided 
below:
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Unused investigational product and empty containers will be collected to calculate medication
compliance.
Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in between 
each collection) during the visit.  The average of each set of 3 measurements will be used to 
determine if additional follow-up is needed (see Section 4.4.1).
7.1.3
Safety Follow-up Period 
The follow-up period for this protocol is 7 days +3 days from the last dose of investigational 
product.
At the end of this period there will be a telephone call initiated by the site to query for any SAE 
follow-up SAEs, AEs, and concomitant treatments.  All AEs and SAEs that are not resolved at 
the time of this contact will be followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects After the Study
There is no planned care for subjects after 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 below.  
Assessments are to be performed according to the schedule shown in Table 1.
Care must be taken by the site personnel or the investigator to fully explain the scale prior to 
completion.
If the subject terminates treatment early, all assessments listed in Table 1 for Visit 13/ET or Visit 
18/ET and the Follow-up Telephone 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.
7.2.2
Screening Assessments
Direct-enrolled subjects only: 
7.2.2.1
Kiddie – Schedule for Affective Disorders and Schizophrenia for 
School-age Children – Present and Lifetime Version-Diagnostic Interview
The sponsor-approved clinician at the site who is trained and experienced in the evaluation of 4-
to 5-year-old children with ADHD, will determine a diagnosis of ADHD based on a psychiatric 
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interview and mental status examination utilizing the K-SADS-PL using the DSM-IV-TR criteria 
for ADHD.
The K-SADS-PL is a semistructured diagnostic interview designed to assess current and past 
episodes of psychopathology in children and adolescents according to Diagnostic and Statistical 
Manual of Mental Disorders, Third Edition-Revised and DSM-IV-TR criteria. Probes and 
objective criteria are provided to rate individual symptoms. The primary diagnoses assessed with 
the K-SADS-PL include, but are not limited to: major depression, dysthymia, mania, bipolar 
disorders, schizoaffective disorders, panic disorder, agoraphobia, separation anxiety disorder, 
avoidant disorder of childhood and adolescence, simple phobia, social phobia, overanxious 
disorder, generalized anxiety, obsessive compulsive disorder, ADHD, conduct disorder, and 
oppositional defiant disorder.
The K-SADS-PL is administered by interviewing the parent(s)/LAR(s), the subject, and finally 
achieving summary ratings, which include all sources of information (parent/LAR, child, school, 
chart, and other). 
The K-SADS-PL will be administered by an individual experienced with the scale and qualified 
to establish a diagnosis. The site should maintain documentation of the K-SADS-PL training in 
the site’s files. All individuals performing this assessment must be pre-approved by the sponsor 
or delegated vendor. Based on the above criteria, suitable K-SADS-PL administrators may 
include physicians, nurse practitioners, or licensed psychologists.
7.2.2.2
Peabody Picture Vocabulary Test-Fourth Edition
The Peabody Picture Vocabulary Test measures an individual’s receptive (hearing) vocabulary 
for Standard American English and provides a quick estimate of verbal ability or scholastic 
aptitude (Dunn and Dunn 1981). For purposes of this study, the Peabody Picture Vocabulary 
Test, Fourth Edition, will be used as a proxy for general cognitive ability. 
The Peabody Picture Vocabulary Test should be administered by site personnel with training and 
experience in general psychological testing. All individuals performing this assessment must be 
pre-approved by the sponsor or delegated vendor.
7.2.3
Efficacy
7.2.3.1
Attention-deficit/Hyperactivity Disorder Rating Scale – IV Preschool 
Version
The ADHD-RS-IV Preschool Version (McGoey et al., 2007), the secondary efficacy measure, is 
completed by the Sponsor approved clinician at the site and will be administered at Visit 1 and 
each subsequent visit up to and including the End of Study Visit  to capture the ADHD 
symptoms within each study period.  The ADHD-RS-IV Preschool Version was adapted from 
the ADHD Rating Scale-IV (DuPaul et al., 1998) and provides examples appropriate for the 
developmental level of preschool children.  The ADHD-RS-IV Preschool Version is an 18-item 
questionnaire that requires the respondent to rate the frequency of occurrence of ADHD 
symptoms as defined by DSM-IV-TR criteria.  Each item is scored on a 4-point scale ranging 
from 0 (never or rarely) to 3 (very often) with total scores ranging from 0-54.  The 18 items may 
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be grouped into 2 subscales: hyperactivity/impulsivity (even numbered items 2-18) and 
inattentiveness (odd numbered items 1-17).
The ADHD-RS-IV Preschool Version will be completed by a clinician trained and experienced 
in the evaluation of preschool children with ADHD.  Since the ADHD-RS-IV Preschool Version 
is used to guide dosing decisions, if it is not completed by the principal investigator or 
subinvestigator who is medically/clinically responsible for the subject, it must be reviewed and 
signed by them. All individuals performing this assessment must be pre-approved by the Sponsor 
or delegated vendor.
The title, version, and date of the ADHD-RS-IV Preschool Version used in this study are 
included in Table 1.
7.2.3.2
Clinical Global Impressions
The CGI Scale (Guy, 1976) permits a global evaluation of the subject’s severity and 
improvement over time.  CGI has been used extensively in clinical studies of ADHD (Michelson 
et al., 2001;Weiss et al., 2005; Wilens et al., 2001).
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 Visit 0 
of the antecedent study or at Visit 0 of this study for directly enrolled subjects.  The investigator 
should establish 3 target areas of improvement with the subjects and the subject’s parent(s)/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.
At each visit from Visit 1 up to and including Visit 18/ET the investigator will assess the 
subject’s improvement relative to the 3 target areas of improvement recorded at Visit 0 of the 
antecedent study or Visit 0 of this study for directly enrolled subjects, on the CGI-I, a 7-point 
scale ranging from 1 (very much improved) to 7 (very much worse).
The CGI-S and the CGI-I should be completed by a clinician trained and experienced in the 
evaluation of preschool children with ADHD.  Since the CGI-I is used to guide dosing decisions, 
if it is not completed by the principal investigator or sub investigator who is medically/clinically 
responsible for the subject, it must be reviewed and signed by them. All individuals performing 
this assessment must be pre-approved by the Sponsor or delegated vendor.
The title, version, and date of the CGI-S and CGI-I used in this study are included in Table 1.
7.2.4
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.
7.2.4.1
Medical and Medication History
Any new medical history, ie, medical conditions, which arose after the recording of the medical 
history in the antecedent study should be recorded at Visit 0 for roll-over subjects.
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7.2.4.2
Physical Examination (Including Height and Weight)
A full physical examination will be performed at the Screening Visit (Visit -1).  Additionally, , 
an abbreviated physical examination is required prior to Visit 0 if more than 30 days have 
elapsed since the physical examination was completed as part of the Screening Visit (Visit -1) 
was performed.
A physical examination will be performed by a qualified, licensed individual (eg, physician, 
physician assistant or a 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)

Musculoskeletal

Neurological.
If an abbreviated physical examination is required prior to Visit 0, a review of the body systems 
will include the following:

General Appearance

Respiratory

Cardiovascular.
Abnormalities identified at the Screening Visit (Visit -1) will be documented as AEs.  Changes 
after the Screening Visit (Visit -1) will be captured as AEs on the AE CRF page, as deemed by 
the investigator.
7.2.4.3
Adverse Event Collection
At each study visit, subjects 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. Any AE ongoing from 
the antecedent study must be entered. Any AE ongoing from the antecedent study must be 
recorded on the CRF for this study. (Please refer to Section 8, Adverse and Serious Adverse 
Events Assessment.)
7.2.4.4
Vital Signs
Measurements of oral or tympanic temperature and sitting respiratory rate will be performed at 
the Screening Visit (Visit -1).  Measurements of sitting systolic and diastolic blood pressure and 
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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 5 minutes.
Blood pressure will be determined by manual 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 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 a manual cuff and should be 
performed by the same study center personnel (if possible) throughout the study.  Three 
measurements should be obtained using the manual cuff while sitting and the subject has been at 
rest for a minimum of 5 minutes, with approximately 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 and CRF.
Any clinically significant deviations from Baseline (Visit 0) vital signs which are deemed 
clinically significant in the opinion of the investigator are to be recorded as an AE.
7.2.4.5
Height and Weight
Height will be captured at each 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.
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.
7.2.4.6
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 assessments will be performed at the Screening Visit (Visit -1), Visit 9, Visit 
16, and Visit 18/ET.  Additionally, clinical laboratory tests are required to be repeated prior to 
Visit 0 with results reviewed before enrolling the subject in the study if more than 30 days have 
elapsed since the clinical laboratory assessments completed as part of the Screening Visit 
(Visit -1) were performed.
Subjects will have the option for laboratory assessments to be collected by a home health care 
nurse, managed by United Biosource, LLC, (UBC) at their residence. 
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The following clinical laboratory assessments will be performed: 
Biochemistry and Endocrinology
A blood sample (~5 mL) for biochemistry will be taken to assess the following parameters:
Total Cholesterol
Calcium
AST
Uric Acid
Phosphorus
Blood Urea Nitrogen
ALT
Total Bilirubin
Sodium
Creatinine
ALP
Glucose
Potassium
Albumin
GGT
Total Protein
TSH
Lactate Dehydrogenase
Free T4
Hematology
A blood sample (~4 mL) for hematology will be taken to assess the following parameters:
Hemoglobin
Neutrophils
Hematocrit
Lymphocytes
RBC
Monocytes
Platelet count
Eosinophils
WBC count – total and differential 
Basophils
MCH
Bands
MCHC
MCV
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 RBC, WBC, casts, and bacteria.
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7.2.4.7
Electrocardiogram
A 12-lead ECG will be performed at the Screening Visit (Visit -1), Visit 0, Visit 1-6, and Visit 8, 
Visit 11, Visit 14, Visit 17, and Visit 18/ET. Additionally, a 12-lead ECG is required to be 
repeated prior to Visit 0 with results reviewed before enrolling the subject in the study if more 
than 30 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.
The mean interval values of the 3 ECGs is used to establish the subject’s baseline intervals. All 
ECGs will be performed after 5 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 by the investigator.  The ECG tracing will then be 
evaluated by a cardiologist at the central ECG reading vendor (Cardiocore) for analysis and 
returned to the site with a determination of normal or abnormal.  Upon review of the report from 
Cardiocore, the investigator will reevaluate 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 must be transmitted to the central ECG reader and all ECGs 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 CRF 
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.
7.2.4.8
Children’s Sleep Habits Questionnaire and Sleep Diary 
The CSHQ is 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 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 completed at every visit to the site and will be completed by the 
subject’s parent/LAR. 
The subject’s parent/LAR will complete a sleep diary to log daytime napping, bedtime and wake 
time. 
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7.2.4.9
Columbia-Suicide Severity Rating Scale- Pediatric/Cognitively Impaired 
Version
The C-SSRS (Posner, 2007) 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 2 required items pertaining to suicidal ideation, 4 required items pertaining 
to suicidal behavior, and 1 required item pertaining to non-suicidal self-injurious behavior.  
There are 8 additional suicidal ideation items and 2 additional suicidal behavior items which are 
completed in cases of positive responses for other items, as well as 2 items for completed suicide 
and suicide behavior present during the interview. Thus, there is a maximum of 19 items to be 
completed.
The C-SSRS must be performed by an individual who is trained and certified and is preapproved 
by the sponsor or delegated vendor and the site investigator. 
The Pediatric/Cognitively Impaired Version of the scale will be used in the study. There are two 
versions of the C-SSRS. 
If the subject participated in an antecedent study:

The “Since Last Visit” version will be completed for all subjects at each visit in this study.
If the subject is directly enrolled in this study and did not participate in an antecedent study:

The “Lifetime recent” version will be administered at the Screening Visit (Visit -1).

The “Since Last Visit” version will be completed for all study visits after the Screening Visit 
(Visit -1).
The title, version, and date of the C-SSRS “Lifetime recent” version and the C-SSRS “Since Last 
Visit” version used in this study are included in Table 1.
7.2.4.10
Suitability of the Subject to Remain in the Study
At each visit (except for Visit 18/ET) starting with Visit 1, 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 weight and BMI) and will evaluate for the 
presence of decreased appetite potentially leading to weight loss.  In cases where the subject has 
clinically significant decrease in appetite, the investigator should intervene as necessary based on 
clinical judgment (eg, diet/behavioral interventions) and consider discontinuation of treatment if 
necessary. In cases where the subject has had >7% weight loss, the investigator must discuss the 
case with the medical monitor and assess whether it’s in the best interest of the subject to remain 
in the study.  
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 
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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.  The investigator should also ensure that there is 
appropriate documentation of this assessment in the subject’s source notes.  As part of this 
assessment, if appropriate, the investigator should discuss risk factors for suicide with the 
subject.  Where a subject has suffered an accidental injury, the investigator should ensure that 
this was a true accidental injury, rather than an episode of self-harming or a suicide attempt.
The subject’s source notes should clearly document that the assessment of continued suitability 
including assessment of the subject’s appetite, weight loss, 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.
7.2.5
Volume of Blood to be Drawn From Each Subject
Assessment
Sample Volume 
(mL)
Number of Samples 
Total Volume (mL) 
Safety
Biochemistry 
5
5
25
Hematology
4
5
20
Total mL
45
During this study, it is expected that approximately 45mL of blood will be drawn from each 
subject. Subjects will have the option for blood draws to be collected by a qualified home health 
care professional at their home. Routine laboratory home draws have a + 1 day window from the 
study visit date, with the exception of the last visit/early termination draw which has a -1 day 
window.
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 45 mL. When more than 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.  
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).  
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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 on the appropriate 
AE pages in the CRF and in source documents.  In addition to untoward AEs, unexpected 
benefits outside the investigational product indication should also be captured on the AE CRF.
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 pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
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 CRF).
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.
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 document.
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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 CRF.  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
Clinical laboratory assessments, vital sign, and ECG assessments are performed at the Screening 
Visit (Visit 1) and Visit 8/ET. The Investigator is required to review these assessments prior to 
determining subject eligibility.  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 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 which were not present at the pre-treatment 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.
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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
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as 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 categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical 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 pre-specified total daily dose of 30 mg 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 below.
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 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/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the IB 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 
Pharmacovigilance Department (drugsafety@shire.com) and the CRO/Shire medical monitor 
within 24 hours of the first awareness of the event.  Note: The 24-hour reporting requirement for 
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SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (see Section 
8.1.6) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
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 
e-mail the form to the Shire Pharmacovigilance Department. A copy of the Shire Clinical Trial 
Serious Adverse Event 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 Pharmacovigilance Department and the CRO/Shire medical monitor within 24 hours 
of the first awareness of the event. 
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 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
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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 
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, the 
action taken with the investigational product should be recorded as “dose not changed” or “not 
applicable” (if the subject never received investigational product).
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site
Reporting
The sponsor and the 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 SPD489 program.  
The investigator is responsible for notifying the local IRB/EC/REB, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
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 CRF.  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 CRF entry within approximately 3 business days of the subject’s 
visit.
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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 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 prior to database lock.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis or adaptive design for this study.
A 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 
patients in the study and of those still to be entered. Data will be provided to the DMC by an 
independent statistical and reporting group not assigned to the study. The data provided to the 
DMC will not be considered ‘clean’ until the database is locked.
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product.  
9.6
Sample Size Calculation and Power Considerations
Approximately 100 subjects will be enrolled into this study to ensure that at least 50 subjects are 
exposed to SPD489 for one year and complete the study. Subjects will enroll into this study from 
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antecedent study SPD489-211 or SPD489-347 or directly enroll into this study without 
participating in either antecedent study. 
The sample size for this study is not based on statistical considerations. 
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Enrolled Set will consist of all subjects who have been dispensed SPD489 at the Baseline 
Visit (Visit 0). Screen failures will not be considered enrolled subjects and will not be included 
in the Enrolled Set.
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of 
investigational product. 
The FAS will consist of all subjects in the Safety Set who have at least 1 post-dose ADHD-RS-
IV Preschool Version Total Score assessment during the study.
9.8
Efficacy Analyses
The FAS will be used to summarize the efficacy data. 
9.8.1
Clinician-administered ADHD-RS-IV Preschool Version 
The efficacy endpoint for the ADHD-RS-IV Preschool Version is defined as the change from 
baseline on the clinician-administered ADHD-RS-IV Preschool Version Total Score. Where 
subjects that rolled over from an antecedent study, baseline is defined as the baseline from the 
antecedent study, and for subjects that directly enrolled into SPD489-348, baseline is defined as 
baseline of the SPD489-348 study. 
The observed and change from baseline ADHD-RS-IV Preschool Version Total Score will be 
summarized at each  visit as well as the last on-treatment visit using descriptive summary 
statistics of number of subjects, mean, standard deviation, median, minimum, and maximum 
values by treatment group of the antecedent studies, directly enrolled group and overall.
9.8.2
Clinical Global Impressions 
The efficacy endpoint for the CGI-I will be analyzed by a method similar to that used for the 
ADHD-RS-IV total scores. In addition, CGI-I, will also be analyzed using the proportion of 
subjects with an “improved” CGI-I measurement at the last on-treatment visit. The CGI-I 
categories of “very much improved” and “much improved” will be classified as “improved” and 
all other assessed categories will be grouped together as “not improved”.  
Descriptive summary statistics will be presented by treatment group of the antecedent studies, 
directly enrolled group and overall for the CGI-I scores at each visit as well as the last on-
treatment assessment. The change from baseline and observed dichotomized CGI-I values will 
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be summarized at each visit as well as the last on-treatment visit using number of subjects and 
percentages.
9.8.3
Exploratory Efficacy Endpoints
Not applicable.
9.9
Safety Analyses
The Safety Analysis Set will be used to report the safety data. 
Safety analyses will be presented by treatment group of the antecedent studies, directly enrolled 
and overall for the occurrence of TEAEs, clinical laboratory results, vital signs, ECG results, and 
sleep assessments including sleep diary data and CSHQ. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  The 
number of events, incidence, and percentage of TEAEs will be calculated overall, by system 
organ class and, by preferred term.  Treatment-emergent adverse events 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 and overall. 
Potentially clinically important findings will also be summarized and listed.
The CSHQ will be summarized using appropriate descriptive statistics at each visit. 
The C-SSRS data will be listed for all subjects with any positive response. 
9.10
Other Analyses
No other analyses are planned in this study.
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH and any updates 
or revisions, 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), any updates or revisions, as well 
as all applicable national and local laws and regulations.
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Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
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 non-pediatric 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 
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), any updates or revisions, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
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qualification.  Curriculum 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 parent(s)/LAR consent, inform them 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), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any subinvestigators 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.
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 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.
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The clinical research associate CRA/study monitor will verify the contents against the source 
data per the monitoring plan.  If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
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, subject sleep diary cards and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, 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 CRA/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 etc).  
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 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 
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; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
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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 and their parent(s)/LAR prior to any study-related procedures including screening 
assessments.  All consent and assent documentation must be in accordance with applicable 
regulations and GCP.  Each subject, parent(s), or the subject’s legally-authorized representative, 
as applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject, parent(s), or LAR 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, as 
applicable (ie, a complete set of subject information sheets and fully executed signature pages) 
must be given to the subject, parent(s) or the subject’s legally-authorized representative, as 
applicable.  This document may require translation into the local language.  Signed consent 
forms must remain in each subject’s study file and must be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent(s)/legally-authorized representative/caregiver 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, 
as applicable which was reviewed by the IRB/EC and which received their favorable 
opinion/approval.  A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action.  Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
It is the responsibility of the investigator to submit this protocol, the informed consent document 
(approved by the sponsor or their designee), relevant supporting information and all types of 
subject recruitment information to the IRB/EC for review, and all must be approved prior to site 
initiation.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
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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 apprised of the progress of the study and 
of any changes made to the protocol, but in any case at least once a year.; The investigator must 
also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All sites and laboratories or entities providing support for this study, must, where applicable, 
comply with HIPAA of 1996 and any other local privacy requirements.  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 SPD489; 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).
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 2-4 and certain other studies as determined by Shire.  The purpose of the 
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publication steering committee is to act as a non-commercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.  The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications.  To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results.  Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication.  If requested in writing by 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, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section.  The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the ICMJE current standards.  Participation as an 
investigator does not confer any rights to authorship of publications.
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11
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disorder. J Child Adolesc Psychopharmacol, 17, 153-64.
Wigal, T., Greenhill, L., Chuang, S., McGough, J., Vitiello, B., Skrobala, A., Swanson, J., Wigal, 
S., Abikoff, H., Kollins, S., McCracken, J., Riddle, M., Posner, K., Ghuman, J., Davies, 
M., Thorp, B. & Stehli, A. 2006. Safety and tolerability of methylphenidate in preschool 
children with ADHD. J Am Acad Child Adolesc Psychiatry, 45, 1294-303.
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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Protocol Amendment 2
SPD489-348
20 Oct 2017
12
APPENDICES
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Protocol Amendment 2
SPD489-348
20 Oct 2017
APPENDIX 2
DIAGNOSTIC CRITERIA/DISEASE CLASSIFICATION
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Protocol Amendment 2
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20 Oct 2017
APPENDIX 2.1
DSM-IV-TR CRITERIA FOR ATTENTION-
DEFICIT/HYPERACTIVITY DISORDER
A. Either (1) or (2):
(1)
six (or more) of the following symptoms of inattention have persisted for at 
least 
6 months to a degree that is 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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Protocol Amendment 2
SPD489-348
20 Oct 2017
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. 
Some hyperactive-impulsive or inattentive symptoms that caused impairment were 
present before age 7 years.
C. 
Some impairment from the symptoms is present in 2 or more settings (eg, at school 
[or work] and at home).
D. 
There must be 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, fourth Edition. Copyright 1994 
American Psychiatric Association
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Protocol Amendment 2
SPD489-348
20 Oct 2017
APPENDIX 2.4 BOYS’ STATURE-FOR-AGE AND WEIGHT-FOR-AGE 
PERCENTILES
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Protocol Amendment 2
SPD489-348
20 Oct 2017
APPENDIX 2.5 GIRLS’ STATURE-FOR-AGE AND WEIGHT-FOR-AGE 
PERCENTILES
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Protocol Amendment 2
SPD489-348
20 Oct 2017
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 Rating Scale – IV Preschool Version
N/A
2007
Clinical Global Impressions – Global 
Improvement and Clinical Global 
Impressions – Severity of Illness 
N/A
1976
Columbia-Suicide Severity Rating Scale 
Baseline
Since Last Visit
Baseline 1/14/09 
Since Last Visit 1/14/09
Children’s Sleep Habits Questionnaire
N/A
2009
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.
For non-commercial use only

SAP_003.pdf: 
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SPD489-348 Statistical Analysis Plan
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17 Jul 2019
TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................2
LIST OF TABLES...........................................................................................................................4
LIST OF FIGURES .........................................................................................................................4
LIST OF ABBREVIATIONS..........................................................................................................5
1.
INTRODUCTION ....................................................................................................................6
2.
STUDY DESIGN .....................................................................................................................7
General Study Design.................................................................................................7
2.1
Randomization ...........................................................................................................9
2.2
Blinding......................................................................................................................9
2.3
Schedule of Assessments ...........................................................................................9
2.4
Determination of Sample Size..................................................................................19
2.5
Multiplicity Adjustments for Type I Error Control..................................................19
2.6
3.
OBJECTIVES.........................................................................................................................20
Primary Objectives...................................................................................................20
3.1
Secondary Objectives...............................................................................................20
3.2
4.
SUBJECT POPULATION SETS...........................................................................................21
Screened Set .............................................................................................................21
4.1
Enrolled Set..............................................................................................................21
4.2
Safety Analysis Set...................................................................................................21
4.3
Full Analysis Set ......................................................................................................21
4.4
5.
SUBJECT DISPOSITION......................................................................................................22
6.
PROTOCOL DEVIATIONS ..................................................................................................23
7.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................24
Demographic and Other Baseline Characteristics....................................................24
7.1
Medical History........................................................................................................24
7.2
8.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE .......................................26
Exposure to Investigational product.........................................................................26
8.1
Measurement of Treatment Compliance ..................................................................27
8.2
Investigational Product Accountability....................................................................27
8.3
9.
PRIOR AND CONCOMITANT MEDICATION..................................................................28
10. EFFICACY ANALYSES .......................................................................................................29
Efficacy Endpoints and Analysis .............................................................................29
10.1
10.1.1 ADHD-RS-IV Preschool Version..........................................................................29
10.1.2 Clinical Global Impression ....................................................................................30
11. SAFETY ANALYSES ...........................................................................................................31
Adverse Events.........................................................................................................31
11.1
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Clinical Laboratory Variables ..................................................................................32
11.2
Vital Signs................................................................................................................34
11.3
Electrocardiogram (ECG).........................................................................................35
11.4
Other Safety Variables .............................................................................................38
11.5
11.5.1 Children’s Sleep Habits Questionnaire (CSHQ) and Sleep Diary.........................38
11.5.2 Columbia-Suicide Severity Rating Scale (C-SSRS)..............................................38
11.5.3 Follow-up Phone Call ............................................................................................39
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES............40
13. OTHER ANALYSES .............................................................................................................41
14. INTERIM ANALYSIS...........................................................................................................42
15. DATA MONITORING/REVIEW COMMITTEE.................................................................43
16. COMPUTER METHODS ......................................................................................................44
17. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL.................................................45
18. DATA HANDLING CONVENTIONS..................................................................................46
General Data Reporting Conventions ......................................................................46
18.1
Treatment Group ......................................................................................................46
18.2
Visit Mapping...........................................................................................................46
18.3
Derived Efficacy Endpoints .....................................................................................48
18.4
Repeated or Unscheduled Assessments of Safety Parameters .................................48
18.5
Missing Date of Investigational Product..................................................................49
18.6
Missing Date Information for Prior or Concomitant Medications...........................49
18.7
18.7.1 Incomplete Start Date ............................................................................................49
18.7.2 Incomplete Stop Date.............................................................................................50
Missing Date Information for Adverse Events ........................................................50
18.8
18.8.1 Incomplete Start Date ............................................................................................51
18.8.2 Incomplete Stop Date.............................................................................................51
Missing Severity Assessment for Adverse Events ...................................................51
18.9
Missing Relationship to Investigation Product for Adverse Events ........................52
18.10
Character Values of Clinical Laboratory Variables .................................................52
18.11
19. REFERENCES .......................................................................................................................53
20. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS ..............................54
Tables .......................................................................................................................54
20.1
Figures......................................................................................................................57
20.2
Listings.....................................................................................................................57
20.3
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SPD489-348 Statistical Analysis Plan
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17 Jul 2019
LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................10
Table 2
Schedule of Assessments for “A” Subjects...................................................14
Table 3
Schedule of Assessments for "B" Subjects....................................................16
Table 4
Criteria for Potentially Clinically Important Laboratory Tests .....................33
Table 5
Criteria for Potentially Clinically Significant Vital Signs.............................35
Table 6
Criteria for Potentially Clinically Important ECG Values ............................37
Table 7
Visit Mapping for "A" Subjects.....................................................................47
Table 8
Visit Mapping for Subjects for “B” Subjects and those under Protocol 
Amendent 2, 20 Oct 2017..............................................................................48
Table 9
Examples for Coding of Special Character Values for Clinical 
Laboratory Variables.....................................................................................52
LIST OF FIGURES
Figure 1
Study Design Flow Chart ................................................................................7
Figure 2
Study Design Flow Chart for “A” Subjects.....................................................8
Figure 3
Study Design Flow Chart for “B” Subjects.....................................................9
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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
LIST OF ABBREVIATIONS
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS-IV
ADHD Rating Scale-IV
AE
adverse event
BMI
body mass index
CDC
Centers for Disease Control and Prevention
CGI-I
Clinical Global Impression – Global Improvement
CGI-S
Clinical Global Impression – Severity of Illness
CI 
Confidence interval
CSHQ
Children’s Sleep Habits Questionnaire 
C-SSRS
Columbia-Suicide Severity Rating Scale 
DINFC
date of informed consent
DMC
data monitoring committee
DOB
Date of birth
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders Fourth Edition –
Text Revision
eCRF
electronic case report form
ECG
electrocardiogram
ET
early termination 
FAS
Full Analysis Set
IWRS
interactive web response system 
MedDRA
Medical Dictionary for Regulatory Activities
PCI
potentially clinically important
PT
preferred term
QTcB
QT Interval Corrected for Heart Rate using Bazett’s Formula
QTcF
QT Interval Corrected for Heart Rate using Fridericia’s Formula
SAP
statistical analysis plan
SD
standard deviation
SI
International System of Units
SOC
system organ class
TEAE 
treatment-emergent adverse event
WHO
World Health Organization
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SPD489-348 Statistical Analysis Plan
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17 Jul 2019
1.
INTRODUCTION
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of safety, tolerability and efficacy data as described in the final study protocol SPD489-
348 Amendment 2.0 dated 20 Oct 2017. Specifications for tables, figures, and listings are 
contained in a separate document.  
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SPD489-348 Statistical Analysis Plan
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17 Jul 2019
2.
STUDY DESIGN 
General Study Design
2.1
Approximately 100 subjects will be enrolled in this long-term, open-label study to evaluate 
safety and tolerability of SPD489, administered as a daily morning dose in the treatment of 
children 4-5 years of age with attention-deficit/hyperactivity disorder (ADHD). SPD489 is 
proposed to be provided in 5, 10, 15, 20, and 30 mg capsules. 
This study will enroll subjects who participated in an antecedent SPD489 study (SPD489-211 or 
SPD489-347) or through direct enrollment. Subjects entering into this study will be classified as 
either a roll-over subject or a direct-enrolled subject, as defined below: 

Roll-over subject: Subject completed the antecedent study (SPD489-211 or SPD489-347)

Directly enrolled subject: Subject is directly enrolled in this study and did not participate 
in antecedent study SPD489-211 or SPD489-347
The study design consists of up to 4 periods: Screening and Washout, Dose Optimization, Dose 
Maintenance, and Safety Follow-up. These subjects will be required to visit the site up to 20
times over a 57-week period. The study design is demonstrated below in Figure 1:
Figure 1
Study Design Flow Chart
V0
V1
V2
V3
V6
V4
V5
V9
V10
Dose Optimization Period
V11
V12
V13
V14
V15
V17
V16
V18/ ET
W0
W1
W2
W3
W4
W5
W6
W16 W20
W24
W28
W32
W48
W44
W40
W36
W52
W53
W-4 to 
 W-1
Screening
and
Washout
Period
V -1
Safety 
Follow-up 
Period
Baseline
Dose Maintenance Period
V7
V8
W8 W12
ET=early termination; V=visit; W=week.
Subjects will be screened at Visit -1 to establish eligibility for study participation. For roll-over 
subjects, the EOS visit in the antecedent SPD489-347 study will serve as the Screening visit for 
SPD489-348. Screening assessments (vital signs, height, weight, clinical laboratory tests, and 
electrocardiograms (ECGs)) must be repeated for this study if more than 30 days have elapsed 
since the conclusion of the antecedent study. The Washout Period should be initiated after the 
clinical laboratory test results and 12-lead ECG results have been received and reviewed by the 
investigator. The roll-over subjects, the follow-up call for the antecedent SPD489-347 study will 
serve as the wash-out call for the SPD489-348 study. During washout, a subject’s current 
prohibited medications (if applicable) will be discontinued for a period of a minimum of 5 times 
the half-life of the medication.
During the Dose Optimization Period (Visits 1 to 6), the investigator may titrate subjects to their 
optimal dose of SPD489 based upon treatment-emergent adverse events (TEAEs) and dosing 
guidelines. If optimal dose is well tolerated and, in the opinion of the investigator, the subject 
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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
required to visit the site up to 20 times over a 57-week period.  The study design is demonstrated 
below in Figure 3. 
Figure 3
Study Design Flow Chart for “B” Subjects
V0
V1
V2
V3
V6
V4
V5
V9
V10
Dose Optimization Period
V11
V12
V13
V14
V15
V17
V16
V18/ ET
W0
W1
W2
W3
W4
W5
W6
W16 W20
W24
W28
W32
W48
W44
W40
W36
W52
W53
W-4 to 
 W-1
Screening
and
Washout
Period
V -1
Safety 
Follow-up 
Period
Baseline
Dose Maintenance Period
V7
V8
W8 W12
ET=early termination; V=visit; W=week.
Randomization
2.2
There is no randomization for this study. All subjects will receive open-label SPD489 during this 
study. 
Blinding
2.3
Not applicable.
Schedule of Assessments 
2.4
Table 1, Table 2 and Table 3 below present a schematic of the study procedures. 
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SPD489-348 Statistical Analysis Plan
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17 Jul 2019
Table 1
Schedule of Assessments
Period
Screening and Washout
Dose Optimization
Dose Maintenance 
Period
Safety 
Follow-up
Visit a
-1
(Screening)b
Phone 
Callc
Visit 
0
1
2
3
4
5
6 7
8
9
10
11
12
13
14
15
16
17
18/ET
Telephone Call
Assessment 
Week
-4 to -1
-1 to
0
0
1
2
3
4
5
6 8
12
16
20
24
28
32
36
40
44 48
52
53
Assessment 
Day
-28 to -1
0
7 14
21
28
35
42 56
84
112
140
168
196
224
252
280
308 336
364
371
Informed 
consent/assent

Inclusion/ 
exclusion 
criteriad



Psychiatric 
Evaluation 
(utilizing the 
K-
SADS-PL)e

Peabody 
Picture 
Vocabulary 
Test, Fourth 
Editi
e

Demographics

Medical and 
medication 
history

Physical 
examination f


Vital signs f,g



















Height f,h



















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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
Table 1
Schedule of Assessments
Period
Screening and Washout
Dose Optimization
Dose Maintenance 
Period
Safety 
Follow-up
Visit a
-1
(Screening)b
Phone 
Callc
Visit 
0
1
2
3
4
5
6 7
8
9
10
11
12
13
14
15
16
17
18/ET
Telephone Call
Assessment 
Week
-4 to -1
-1 to
0
0
1
2
3
4
5
6 8
12
16
20
24
28
32
36
40
44 48
52
53
Assessment 
Day
-28 to -1
0
7 14
21
28
35
42 56
84
112
140
168
196
224
252
280
308 336
364
371
Body weight f,h



















Clinical 
laboratory testf,i





12-lead ECG f,j













ADHD-RS-IV k


















CGI-I k

















CGI-Se,k

CSHQ k



















C-SSRS l



















Sleep diarym


















Suitability of 
subject to remain 
in studyn
















Investigator dose 
assessment
















Access IWRS



















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SPD489-348 Statistical Analysis Plan
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17 Jul 2019
Table 1
Schedule of Assessments
Period
Screening and Washout
Dose Optimization
Dose Maintenance 
Period
Safety 
Follow-up
Visit a
-1
(Screening)b
Phone 
Callc
Visit 
0
1
2
3
4
5
6 7
8
9
10
11
12
13
14
15
16
17
18/ET
Telephone Call
Assessment 
Week
-4 to -1
-1 to
0
0
1
2
3
4
5
6 8
12
16
20
24
28
32
36
40
44 48
52
53
Assessment 
Day
-28 to -1
0
7 14
21
28
35
42 56
84
112
140
168
196
224
252
280
308 336
364
371
Investigational 
product 
distributed

















Investigational 
product returned

















Investigational 
product 
compliance

















Concomitant 
medications





















Adverse events





















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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
Table 1
Schedule of Assessments
Period
Screening and Washout
Dose Optimization
Dose Maintenance 
Period
Safety 
Follow-up
Visit a
-1
(Screening)b
Phone 
Callc
Visit 
0
1
2
3
4
5
6 7
8
9
10
11
12
13
14
15
16
17
18/ET
Telephone Call
Assessment 
Week
-4 to -1
-1 to
0
0
1
2
3
4
5
6 8
12
16
20
24
28
32
36
40
44 48
52
53
Assessment 
Day
-28 to -1
0
7 14
21
28
35
42 56
84
112
140
168
196
224
252
280
308 336
364
371
a Visit Window for Visits 1-6 is ±3 days, and Visit Window for Visits 7-17 is ±5 days [in reference to the Visit 0 date]; Visit Window for Visit 18 is ±5 days; Visit Window for 
Safety Follow-up Telephone call is + 3 days.
b For roll-over subjects, the Screening (visit -1) is the same day as the End of Study Visit for the antecedent SPD489-347 study
c Following successful screening, a study center representative will contact the subject/parent/LAR to provide instruction on discontinuing any prohibited medication for the 
Washout Period (if applicable). For roll-over subjects, the Wash-out phone call is the same day as the Follow-up phone call for the antecedent SPD489-347 study
d Inclusion/exclusion criteria must be reviewed at the Washout Telephone Call and at Visit 0.
e For direct-enrolled subjects only.
f An abbreviated physical examination, vital signs, height, weight, clinical laboratory assessments, and ECG are required to be repeated if > 30 days have elapsed since the 
Screening visit. The results must be obtained and reviewed by the investigator prior to determining eligibility and the subject being enrolled at (Visit 0).
g Includes oral or tympanic temperature, sitting blood pressure, pulse, and respiratory rate. Measurement of temperature and respiratory rate will be performed at the Screening 
Visit (Visit -1) only.
Measurement of blood pressure and pulse will be collected 3 times after subjects have remained sitting for a minimum of 5 minutes(with approximately 2 minutes in between each 
collection) using a manual cuff. The average of each set of 3 measurements will be used to determine continued participation in the study. Blood pressure, pulse and respiratory 
rate will be determined after subjects have remained seated for approximately 5 minutes. Refer to Protocol Section 4.4.1
h Height and weight to be measured without shoes.
i Clinical laboratory tests will include hematology, chemistry, endocrinology, and urinalysis. Patients will have the option for blood draws to be collected by a home health care 
professional at their home. Home draws have a ±1 day window from study visit date, with the exception of Visit 18/ET home draw which has a -1 day window.
j A single ECG will be collected at Screening (Visit -1), Visits 0, 3, 6, 9, 12, 15and 18/ET
k Scales to be completed by same rater whenever possible
l For roll-over subjects, C-SSRS pediatric/cognitively impaired “Since Last Visit” version is completed for all visits. The scale will be compared to the C-SSRS 
pediatric/cognitively impaired “Lifetime recent” from the antecedent study. If subject is directly enrolled, C-SSRS pediatric/cognitively impaired “Lifetime Recent” version is 
completed at the Screening Visit (Visit -1). C-SSRS pediatric/cognitively impaired “Since Last Visit” version completed for all subsequent visits
m Sleep diary to be completed by parent/LAR. Sleep diaries will be dispensed at Visits 0-17 and collected at Visits 1-18.
n Includes assessment of decreased appetite
ADHD-RS-IV=ADHD Rating Scale-IV; CGI-I=Clinical Global Impressions-Global Improvement; CGI-S=Clinical Global Impressions-Severity of Illness; CSHQ=Children’s 
Sleep Habits Questionnaire; C-SSRS=Columbia-Suicide Severity Rating Scale- Pediatric/Cognitively Impaired; ECG=electrocardiogram; ET=early termination; IWRS=Interactive 
Web Response System
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CONFIDENTIAL
Page 14
SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
Table 2
Schedule of Assessments for “A” Subjects
Period
Dose Maintenance Period
Safety
Follow-up
Visit a
Visit 0b  
1
2
3
4
5
6
7
8
9
10
11
12
13/ET
Telephone
Call
Assessment Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
Assessment Day
0
28
56
84
112
140
168
196
224
252
280
308
336
364
371
Informed 
consent/assent

Inclusion/exclusion 
criteriac

Demographicsd

Medical and 
medication history

Physical 
examination

Vital signs e














Height f














Body weight














Clinical laboratory 
testg 



12-lead ECGh






ADHD-RS-IV i













CGI-I i













CSHQ i














C-SSRS j














Sleep diary k














Suitability of 
subject to remain in 
study












Investigator dose 
assessment












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CONFIDENTIAL
Page 15
SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
Table 2
Schedule of Assessments for “A” Subjects
Period
Dose Maintenance Period
Safety
Follow-up
Visit a
Visit 0b  
1
2
3
4
5
6
7
8
9
10
11
12
13/ET
Telephone
Call
Assessment Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
Assessment Day
0
28
56
84
112
140
168
196
224
252
280
308
336
364
371
Access IWRS














Investigational 
product distributed













Investigational 
product returned













Investigational 
product compliance













Concomitant 
medications















Adverse events 















a Visit Window for Visits 1-6 is 2 days, and Visit Window for Visits 7-17 is 5 days [in reference to the Visit 0 date]; Visit Window for Visit 18 is +5 days;  Visit Window  for 
Safety Follow-up Telephone call is + 2 days. 
b Visit 0 is the same day as the End of Study Visit for the antecedent study
c Inclusion/exclusion criteria must be reviewed at the Washout Telephone Call and at Visit 0.
d Demographic data will be pulled programmatically from antecedent study.
eIncludes oral or tympanic temperature, sitting blood pressure, pulse, and respiratory rate. Measurement of temperature and respiratory rate will be performed as part of the End of 
Study Visit of the antecedent study.  Measurement of blood pressure and pulse will be collected 3 times (with approximately 2 minutes in between each collection) using the 
provided automated cuff. The average of each set of 3 measurements will be used to determine continued participation in the study. Blood pressure, pulse and respiratory rate will 
be determined after subjects have remained seated for approximately 5 minutes.
f Height to be measured without shoes. 
g Clinical laboratory tests will include hematology, chemistry, endocrinology, and urinalysis.
h A single ECG will be collected at, Visits 0, 3, 6, 9, 12, 15 and 18/ET 
i Scales to be completed by same rater whenever possible.
j C-SSRS pediatric/cognitively impaired “Since Last Visit” version is completed for all visits. The scale will be compared to the C-SSRS pediatric/cognitively impaired “Baseline” 
from the antecedent study.
k Sleep diary to be completed by parent/LAR. Sleep diaries will be dispensed at Visits 0-17 and collected at Visits 1-18. 
ADHD-RS-IV=ADHD Rating Scale-IV; CGI-I=Clinical Global Impressions-Global Improvement; CGI-S=Clinical Global Impressions-Severity of Illness; CSHQ=Children’s 
Sleep Habits Questionnaire; C-SSRS=Columbia-Suicide Severity Rating Scale- Pediatric/Cognitively Impaired; ECG=electrocardiogram; ET=early termination; IWRS=Interactive 
Web Response System
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For non-commercial use only


For non-commercial use only


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Page 19
SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
Determination of Sample Size
2.5
Approximately 100 subjects will be enrolled into this study to ensure that at least 50 subjects are 
exposed to SPD489 for one year. Subjects will enroll into this study from an antecedent study
(SPD489-211 or SPD489-347) or directly enroll onto this study without participating in either 
antecedent study.  
The sample size for this study is not based on statistical considerations.
Multiplicity Adjustments for Type I Error Control
2.6
Not applicable as there will be no hypothesis testing for this study. 
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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
3.
OBJECTIVES
Primary Objectives
3.1
The primary objective of this study is to evaluate the long-term safety of SPD489 administered 
as a daily morning dose (proposed as 5, 10, 15, 20, and 30 mg/day) in preschool children (4-5 
years of age inclusive) diagnosed with ADHD.
The evaluation of safety and tolerability will be based on the occurrence of TEAEs, specific 
evaluation of blood pressure, pulse, weight, height, clinical laboratory evaluations, ECG results, 
and sleep assessments.
Secondary Objectives
3.2
The secondary objectives of this study are: 

To describe the long-term efficacy of SPD489 using the clinician-administered Attention-
deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) Preschool Version.

To describe the long-term efficacy of SPD489 using global clinical measures of 
improvement, as measured by the Clinical Global Impression – Global Improvement
(CGI-I).
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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
4.
SUBJECT POPULATION SETS
Screened Set
4.1
The Screened Set will consist of all subjects who have signed an informed consent for study 
SPD489-348.
Enrolled Set 
4.2
The Enrolled Set will consist of all subjects who have been dispensed SPD489 at the Baseline 
Visit (Visit 0) in study SPD489-348. The screen failures will not be considered enrolled subjects 
and will not be included in the Enrolled Set.
Safety Analysis Set 
4.3
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of 
investigational product in study SPD489-348.
Full Analysis Set 
4.4
The Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at 
least 1 post-dose ADHD-RS-IV Preschool Version total score assessment in study SPD489-348.
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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
5.
SUBJECT DISPOSITION
Subject disposition data will be summarized by treatment group (SPD489 or Placebo) of the 
antecedent studies, those who were directly enrolled and overall. 
A listing of all screen failures (i.e., subjects who were screened but not treated) will be presented 
along with reasons for screen failure and details of any AEs.  
The number of subjects included in each subject set (i.e., Screened, Enrolled, Safety and FAS) 
will be summarized. 
The number and percentage of subjects who completed and prematurely discontinued during the 
study will be presented for the Screened Set.  Reasons for premature discontinuation from the 
study as recorded on the termination page of the electronic case report form (eCRF) will be 
summarized (number and percentage) for the Safety Analysis Set.  All subjects who prematurely 
discontinued during the study will be listed with discontinuation reason for the Screened Set.
The number of subjects enrolled and completed will be tabulated by site.  In addition, the 
duration of enrollment, in days, will be summarized for each site and overall.  Duration of 
enrollment will be calculated as (last date of contact for any subject at that site - the first date of 
informed consent for any subject at that site + 1).
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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
6.
PROTOCOL DEVIATIONS
Protocol deviations will be recorded by the site separately from the clinical database. The 
contract research organization will classify the protocol deviations per the agreed protocol 
deviation plan. The Shire study team will review the protocol deviations and their classification 
throughout the study and before database lock. 
Confirmed protocol deviations will be documented in the Protocol Deviation tracker for the 
study. A summary of the number and percentage of subjects in the Safety Analysis Set with 
protocol deviations will be produced by treatment group of the antecedent studies, directly 
enrolled and overall. 
All protocol deviation data will be listed for the Safety Analysis Set.
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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
7.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Demographic and Other Baseline Characteristics
7.1
Demographic and baseline characteristics data collected in the antecedent studies will be 
summarized by treatment group of the antecedent studies and overall for the Safety Analysis Set 
and FAS. For those directly enrolled, demographic and baseline characteristics are as collected in 
the SPD489 CRF will be summarized.
The following demographic characteristics will be summarized in the following order in the 
tables: age (at date of informed consent for antecedent study), current age (at date of informed 
consent for SPD489-348 study), sex, ethnicity, race, weight, height, body mass index (BMI) and 
BMI category. Baseline characteristic to be summarized include Peabody Picture Vocabulary 
Test standard score, CGI-S and ADHD subtypes. Continuous variables will be summarized by 
descriptive statistics including number of subjects, mean, standard deviation (SD), median, 
minimum, and maximum. Categorical variables will be summarized by the number of subjects in 
each category and the percentage of subjects out of the total in the respective analysis set. 
Antecedent study age will be calculated as the difference between date of birth (DOB) and date 
of informed consent (DINFC) for the antecedent study and current age will be calculated using 
date of informed consent for SPD489-348, truncated to months then minus 1 if the day of birth is 
later than the day of informed consent. This number is then divided by 12 and truncated to obtain 
the age in years. The formula in SAS programming language is as follows:
Age = floor((intck('month', DOB, DINFC) - (day(DINFC) < day(DOB))) / 12)
Height and weight will be collected and used to calculate BMI using the following formula:
Weight [kg]
BMI =
(Height [m])2
BMI should be rounded to 1 decimal place for reporting. BMI categories will be derived using 
the Centers for Disease Control and Prevention (CDC) BMI percentiles for children and 
adolescents: Underweight – BMI less than the 5th percentile; Healthy Weight – BMI 5th 
percentile up to less than the 85th percentile; Overweight – BMI 85th percentile to less than the 
95th percentile; Obese – BMI greater than or equal to the 95th percentile.
All demographic and baseline characteristics data (baseline information from the antecedent 
studies and data collected during this study for Peabody Picture Vocabulary Test standard score, 
CGI-S and ADHD subtypes) will be listed for the Safety Analysis Set.  
Medical History
7.2
Medical history is collected at Screening Visit (Visit -1). Any new medical history which arose 
after the recording of the medical history in the antecedent study should be recorded for roll-over 
subjects. Medical history will be listed for the Safety Analysis Set.
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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
Prior and Ongoing psychiatric evaluation will be established with the Screening Visit (Visit -1) 
interview for directly enrolled subjects using the Kiddie-Schedule for Affective Disorders and 
Schizophrenia for School-age Children-Present and Lifetime Version-Diagnostic Interview (K-
SADS-PL). Both assessment results will be listed for the Safety Analysis Set. 
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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
8.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
Exposure to Investigational product 
8.1
Under the original Protocol SPD489-348 dated 21 Oct 2014, a subject from the open-label 
antecedent study (SPD489-211) will enter this study on their optimal dose, if entering this study 
within 3 days. However, if a subject is entering this study from the double-blind antecedent study 
(SPD489-347), or the subject does not immediately enter following the dose maintenance period 
of the unblinded study (SPD489-211), then the subject will begin dosing at 5mg of SPD489 and 
should be titrated in a stepwise fashion until an optimal dose is reached.
Under Protocol Amendment dated 20 Oct 2017, all subjects will begin dosing at 5mg of SPD489 
and should be titrated in a stepwise fashion until optimal dose is reached.
Exposure to investigational product for the Safety Analysis Set will be summarized by treatment 
group of the antecedent studies, directly enrolled and overall. The following statistics will be 
calculated by visit and period for the investigational product:

Days of dosing: number of days on which dose information was available and non-zero
(derived using date of last dose from bottle – date of first dose from bottle +1) 

Total dose (mg): Total number of capsules taken × dose level 

Average daily dose (mg/day): the total dose / total days of dosing 

Cumulative dose (mg): sum of total dose since start of treatment
The following overall statistics will also be calculated for the investigational product: 

Total days of dosing: sum of the days of dosing 

Duration of exposure in weeks: the total days of dosing / 7

Duration of exposure: categorical summary in 4 week intervals

Total dose (mg): Total number of capsules taken × dose level 

Average daily dose (mg/day): the total dose / total days of dosing

Optimized dose: dose during the dose maintenance period
An appropriate statistical summary will be applied in order to present each of the above 
statistical quantities.
In addition, person-time (overall total exposure in years) will be derived. It is calculated as total 
number of days in which the investigational product was taken for each subject and then sum 
over all subjects for the whole duration of the study and then divided by 365.25. Dosing 
information will be listed that will present exposure information, such as total dose, average 
daily dose, optimized dose level, etc.
If a subject is lost to follow-up without returning the leftover investigational product, and 
without providing subsequent safety information, then the subject’s dose information will be 
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SPD489-348 Statistical Analysis Plan
Lisdexamfetamine dimesylate
17 Jul 2019
treated as missing. In particular, for the subjects lost to follow up after the Baseline Visit (Visit 
0), we will not assume any ingestion of the investigational product unless there is a post-baseline 
safety assessment. 
Measurement of Treatment Compliance
8.2
Investigational product dosing compliance is defined as the total number of capsules actually 
taken by a subject during the study divided by the number of capsules expected to be taken 
during the study multiplied by 100.  The total number of capsules 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 0. The number of capsules 
expected to be taken is calculated as the number of days in the treatment period (Dose-
optimization period and Dose maintenance period) multiplied by the number of capsules to be 
taken per day during the treatment period. If the number of capsules taken or returned is 
missing, then the compliance will be missing.
Descriptive statistics (counts and percentages) for investigational product compliance will be 
presented by treatment group of the antecedent studies and directly enrolled for each period 
between 2 consecutive visits as well as for the entire study for the Safety Analysis Set. The 
investigational product treatment compliance will be categorized as <80%, 80-120%, or >120%. 
The categorical data will be presented for the Safety Analysis Set.
Treatment compliance data will also be listed for all subjects in the Safety Analysis Set.
Investigational Product Accountability
8.3
The total number of capsules dispensed, returned and the difference (dispensed minus returned) 
will be summarized by treatment group of the antecedent study, directly enrolled and overall for 
the Safety Analysis Set. This information will also be listed for all subjects in the Safety 
Analysis Set.
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SPD489-348 Statistical Analysis Plan
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17 Jul 2019
9.
PRIOR AND CONCOMITANT MEDICATION 
Version 2015MAR01 DDE (Enhanced) of the World Health Organization (WHO) drug 
dictionary will be used to classify prior and concomitant medications by therapeutic class.
Prior medication is defined as any medication with the start date prior to the date of the first dose 
of investigational product in the SPD489-348 study.  Concomitant medication is defined as any 
medication with a start date prior to the date of the first dose of investigational product in the 
SPD489-348 study and continuing after the first dose of investigational product in the SPD489-
348 study or with a start date between the dates of the first and last doses of investigational 
product in the SPD489-348 study, inclusive.  Any medication with a start date after the date of 
the last dose of investigational product in the SPD489-348 study will not be considered a 
concomitant medication. Any such medications will be listed only and flagged as a post-
treatment medication.
Both prior and concomitant medication usage (including ADHD medication) will be summarized 
by the number and proportion of subjects in each treatment group of the antecedent studies and 
directly enrolled subjects, receiving each medication within each preferred term for the Safety 
Analysis 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. Both prior and 
concomitant ADHD medication usage (based on indication), excluding investigational product, 
will also be summarized by the number and proportion of subjects in each treatment group of the
antecedent studies receiving each medication within each preferred term for the Safety Analysis 
Set. 
All medication will be listed for the Safety Analysis Set. Separate listings will also be provided 
for ADHD medication and ADHD Behavioral Therapy.
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SPD489-348 Statistical Analysis Plan
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17 Jul 2019
10.
EFFICACY ANALYSES
All efficacy analyses will be based on the FAS.  Efficacy data will be summarized by treatment 
group of the antecedent studies, directly enrolled subjects and overall.  Baseline for all efficacy 
analyses is defined as the baseline value from the antecedent study, and for subjects that directly 
enrolled into SPD489-348, baseline is defined as the last observation prior to the first dose of 
investigational product in SPD489-348 study. There is no primary efficacy endpoint defined for 
this study.  An efficacy measurement that is assessed more than 3 days after the date of the last 
dose of the investigational product will not be included for analysis.
All confidence intervals will be 2-sided 95% confidence intervals.   
Efficacy Endpoints and Analysis 
10.1
10.1.1
ADHD-RS-IV Preschool Version
The ADHD-RS-IV Preschool Version is an 18-item questionnaire that requires the respondent to 
rate the frequency of occurrence of ADHD symptoms as defined by Diagnostic and Statistical 
Manual of Mental Disorders Fourth Edition – Text Revision (DSM-IV-TR) criteria. Each item is 
scored on a 4-point scale ranging from 0 (never or rarely) to 3 (very often) with total score 
ranging from 0-54. The 18 items may be grouped into 2 subscales: hyperactivity/impulsivity 
(even numbered items 2-18) and inattentiveness (odd-numbered items 1-17).
A missing individual item in the ADHD-RS-IV Preschool Version will be imputed as follows:

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 will be 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 will be set to missing. 

Both subscales must be non-missing in order to calculate the total score.
The efficacy endpoint for the ADHD-RS-IV Preschool Version is defined as the change from 
baseline on the clinician-administered ADHD-RS-IV Preschool Version total score.
The observed and change from baseline ADHD-RS-IV Preschool Version Total score will be 
summarized at each applicable visit using descriptive statistics (n, mean, SD, minimum, median, 
and maximum). The 95% confidence interval of the mean of the change from baseline value will 
also be presented for informational purposes.
The observed and change from baseline ADHD-RS-IV Preschool Version 
Hyperactivity/Impulsivity and Inattentiveness subscales will also be summarized.
Additionally, a corresponding line graph of the mean of the change from baseline value and 
associated 95% CI in ADHD-RS-IV Preschool Version Total Score by antecedent treatment 
group, directly enrolled and overall, and visit will be presented. A similar plot for 
Hyperactivity/Impulsivity and Inattentiveness subscales will also be presented.
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SPD489-348 Statistical Analysis Plan
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17 Jul 2019
All ADHD-RS-IV assessments will be listed.
10.1.2
Clinical Global Impression
The efficacy endpoint for the CGI-I will be analyzed by a method similar to that used for the 
ADHD-RS-IV total scores. In addition, CGI-I will also be analyzed using the proportion of 
subjects who had an “improved” CGI-I measurement.  The CGI-I categories of “very much 
improved” and “much improved” will be classified as “improved” and all other assessed 
categories will be grouped together as “not improved”.
The observed dichotomized CGI-I values will be summarized at each applicable visit using 
number of subjects and percentages. A corresponding bar chart showing the percentage of 
subjects improved by visit, antecedent treatment group, directly enrolled and overall will be 
presented, with 95% Clopper-Pearson (Exact) confidence interval.
Descriptive summary statistics will be presented by treatment group of the antecedent studies, 
directly enrolled and overall, for the CGI-I scores at each applicable visit. 
The CGI data will be listed for the FAS.
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11.
SAFETY ANALYSES
The safety analysis will be performed using the Safety Analysis Set. Safety data will be 
summarized by treatment group of the antecedent studies, directly enrolled subjects and overall 
except for adverse events (AEs), which will be summarized by the last dose received prior to the 
AE start date. Safety variables include AEs, clinical laboratory variables, vital signs, physical 
examinations, Children’s Sleep Habits Questionnaire (CSHQ), sleep diary, and ECG variables. 
Baseline for all safety variables is defined as the baseline value from the antecedent study or last 
observation prior to the first dose in SPD489-348 study for directly enrolled subjects.  
Adverse Events 
11.1
Adverse events (AEs) will be coded using Version 18.0 or newer of the Medical Dictionary for 
Regulatory Activities (MedDRA).
Only AEs recorded on the SPD489-348 eCRF will be included in summary tables and listings.  
AEs that are only recorded on the antecedent study eCRF will not be included.   
An AE will be considered a treatment-emergent adverse event (TEAE) if it has a start date on or 
after the first dose of investigational product in this study, or if it has an AE start date before the 
date of the first dose of investigational product but increases in its severity on or after the date of 
the first dose of investigational product in this study.  An AE that occurs more than 3 days after 
the date of the last dose of investigational product in the SPD489-348 study will not be counted 
as a TEAE.
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 withdrawal, severe TEAEs, and TEAEs leading to 
death. 
The number and percentage of subjects reporting TEAEs in each onset dose level will be 
tabulated by system organ class (SOC) and preferred term.  Further summaries will be produced 
for TEAEs by maximum severity and TEAEs related 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. 
Serious TEAEs, TEAEs related to investigational product, TEAEs leading to discontinuation of 
investigational product and serious TEAEs leading to death will be summarized by SOC, 
preferred term and onset dose level.
All information about AEs collected on the eCRF will be listed alongside the dose, preferred 
term, and SOC. For Serious TEAEs, deaths, AEs related to the investigational product, and 
TEAEs leading to study discontinuation, a separate listing will also be provided.
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Clinical Laboratory Variables
11.2
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for clinical laboratory 
values (in International System of Units (SI)) and changes from baseline at each assessment time 
point as well as shift tables from baseline to each visit for quantitative variables will be presented 
for the following clinical laboratory variables.
Biochemistry and Endocrinology
Total cholesterol
Calcium
Aspartate transaminase (AST)
Uric acid
Phosphorus
Blood urea nitrogen
Alanine transaminase (ALT)
Total bilirubin
Sodium
Creatinine
Alkaline phosphatase
Glucose
Potassium
Albumin
Gamma glutamyl transferase (GGT)
Total protein
Thyroid stimulating hormone (TSH)
Lactate dehydrogenase
Free thyroxine (T4)
Hematology
Hemoglobin
Neutrophils
Hematocrit
Lymphocytes
Red blood cells (RBC)
Monocytes
Platelet count
Eosinophils
White blood cell (WBC) count – total and differential 
Basophils
Mean corpuscular hemoglobin (MCH)
Bands
Mean corpuscular hemoglobin concentration (MCHC)
Mean corpuscular volume (MCV)
Urinalysis
Glucose
pH
Specific gravity
Urobilinogen
Blood
Color
Ketones
Leukocyte esterase
Protein
Nitrate
Bilirubin
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If urinalysis detects protein and/or blood, a microscopic examination will be conducted.  The 
microscopic examination will consist of RBC, WBC, casts, and bacteria. These variables will be 
listed but not summarized.
Qualitative urinalysis variables will be summarized by the number of subjects in each category 
and the percentage of subjects out of the total in the safety analysis set with a valid result at the 
given visit.  
All clinical laboratory values will be listed for the Safety Analysis Set.
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 4. The number and percentage of subjects with post-
baseline PCI values will be tabulated by treatment group of the antecedent studies, directly 
enrolled and overall.  The percentages will be calculated relative to the number of subjects with 
at least 1 available post-baseline assessment per parameter.  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, site, baseline, and post-
baseline values.
Table 4
Criteria for Potentially Clinically Important Laboratory Tests
Parameter
SI Unit
Lower Limit
Higher Limit
Biochemistry
Albumin
g/dL
< 3g/dL
-
Aspartate transaminase (AST)
-
-
≥ 3 x ULN
Alanine transaminase (ALT)
-
-
≥ 3 x ULN
Blood urea nitrogen
mg/dl
-
> 30mg/dl or > 2.5 x 
ULN
Calcium
mg/dL
< 8mg/dL
> 11.5mg/dL
Total cholesterol
mg/dL
-
> 300mg/dl
Creatinine
mg/dl
-
> 2mg/dl or > 1.5 x 
ULN
Gamma glutamyl transferase (GGT)
-
-
≥ 2.5 x ULN
Glucose
mg/dL
< 55mg/dL
> 160mg/dL
Lactate dehydrogenase
-
-
> 3 x ULN
Phosphorus
mg/dL
< 2.5mg/dL
> 7mg/dL
Potassium
mmol/l
< 3mmol/l
> 5.5mmol/l
Thyroid stimulating hormone (TSH)
-
< LLN
> 2 x ULN
Sodium
mEq/L
< 130mEq/L
> 150mEq/L
Uric acid
mg/dL
-
> 10mg/dL
Total bilirubin
mg/dL
-
> 2 mg/dL
Total protein
g/dL
< 5g/dL
> 9g/dL
Hematology
Bands
-
-
0.27x103/μL or 5%
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Table 4
Criteria for Potentially Clinically Important Laboratory Tests
Parameter
SI Unit
Lower Limit
Higher Limit
Basophils
-
-
10%
Hemoglobin
g/dL
< 9g/dl
> 16g/dl
Hematocrit
%
< 30%
> 50%
Platelet count
103/μL
75x103/μL
> 600x103/μL
Red blood cells (RBC)
106/μL
2.5x106/μL
-
White blood cell (WBC) count
103/μL
3x103/μL
> 16x103/μL
Neutrophils
-
1x103/μL or < 30%
-
Eosinophils 
%
-
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)
LLN:  Lower limit of normal value provided by the laboratory; ULN:  Upper limit of normal value provided by the laboratory
Vital Signs
11.3
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for vital signs (systolic 
and diastolic blood pressure, pulse rate, body weight, temperature, and respiration rate) and their 
changes from baseline at each post-baseline visit will be presented by treatment group of the 
antecedent studies, directly enrolled subjects and overall.
Blood pressure and pulse measurements will be obtained 3 times with approximately 2 minutes 
in between each collection. The average of the three measurements collected at each nominal 
time point will be used for analysis. Blood pressure, pulse and respiratory rate will be determined 
after subject have remained seated for a minimum of 5 minutes.
Weight and BMI will also be converted to percentile values based on the subject’s age at each 
visit and at the last on treatment assessment and summarized categorically.  Descriptive statistics
(n, mean, SD, minimum, median, and maximum) for weight and BMI percentile values and their 
changes from baseline at each post-baseline visit will also be presented by treatment group of the 
antecedent studies and overall.  Post-baseline shifts in weight percentile category (<5th, 5th to 
<95th, and 95th) and BMI percentile category (<5th, 5th to <85th, 85th to <95th, and 95th) from 
baseline will be summarized at each visit as well as at the last on treatment assessment.  In 
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addition, z-scores for weight and BMI will be based on the subject’s age at each visit and will be 
summarized categorically by visit and at the last on treatment assessment.  Percentiles and 
z-scores will be derived using the CDC growth charts (Kuczmarski et al., 2002).
Additionally, figures with the mean change from baseline ± SD of the vital signs values (systolic 
and diastolic blood pressure, and pulse), weight, and BMI will be presented by antecedent 
treatment group, directly enrolled, overall and visit. All vital sign values will be listed for the 
Safety Analysis Set.
Vital sign values will be considered PCI if they meet either the observed value criteria or the 
change from baseline criteria listed in Table 5.  The number and percentage of subjects with PCI 
post-baseline values will be tabulated by treatment group of the antecedent studies, directly 
enrolled and overall, and for each visit. The percentages will be calculated relative to the 
number of subjects with at least 1 post-baseline assessment per parameter and visit by antecedent 
study treatment group, directly enrolled and overall.  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 subject number, site, baseline, and post-
baseline PCI values.  
Table 5
Criteria for Potentially Clinically Significant Vital Signs
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 as a PCI value if it meets either the criteria for observed value or the criteria for change 
from baseline.
Electrocardiogram (ECG)
11.4
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for ECG variables (heart 
rate, PR interval, RR interval, QRS interval, QT interval, and QTc interval) and their changes 
from baseline at each assessment time point will be presented by treatment group of the 
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antecedent studies, directly enrolled subjects and overall.  QTc interval will be calculated using 
both Bazett (QTcB=QT/(RR)1/2) and Fridericia (QTcF=QT/(RR)1/3) corrections; and if RR is not 
available, it will be replaced with 60/hr in the correction formula. ECG interpretation will be 
summarized by visit. A shift table from baseline to each visit for qualitative ECG results will 
also be presented. 
All ECG values will be listed for the Safety Analysis Set.
Electrocardiogram variable values will be considered PCI if they meet either the observed  value 
criteria or the change from baseline criteria listed in Table 6. The number and percentage of 
subjects with post-baseline PCI values will be tabulated by treatment group of the antecedent 
studies, directly enrolled and overall for each visit.  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 by antecedent study treatment group, directly 
enrolled and overall.  The numerator is the total number of subjects with at least 1 PCI post-
baseline ECG value.  A listing of all subjects with post-baseline PCI value will be provided 
including the subject number, site, baseline, and post-baseline PCI values.
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Table 6
Criteria for Potentially Clinically Important ECG Values
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
ECG evaluation –abnormal rhythm
•
Complete Heart Block
•
Tachycardia
•
Bradycardia
•
Wandering Atrial Pacemaker
•
Ectopic Atrial Rhythm
•
Atrial Fibrillation
•
Atrial Flutter
•
Multifocal Atrial Tachycardia
•
Supraventricular Tachycardia
•
Atrial Bigeminy
•
Ventricular Bigeminy
•
Atrial Couplets
•
Ventricular Couplets
•
Ventricular Tachycardia
•
Torsade des Pointes
•
Ventricular Fibrillation
•
Junctional Rhythm
•
Idioventricular Rhythm
•
Escape Beat
•
Atrial Pacemaker
-
-
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Other Safety Variables
11.5
11.5.1
Children’s Sleep Habits Questionnaire (CSHQ) and Sleep Diary
The CSHQ 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 sleep based on behavior within 8 different subscales: 
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), 
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). 
The total score is the sum of the 33 individual items.  
The total 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 18/ET). All 
Children’s Sleep Habits Questionnaire data will be listed for the Safety Analysis Set.
Sleep diary data will be summarized at each visit (and Visit 18/ET) for total daytime napping 
time, nighttime sleep time and time to fall asleep using descriptive statistics (n, mean, SD, 
minimum, median, and maximum). Sleep diary data is collected daily. The average daily value 
per visit and their change from baseline will be summarized.  Sleep diary data will also be listed
for the Safety Analysis Set.
11.5.2
Columbia-Suicide Severity Rating Scale (C-SSRS)
The Pediatric/Cognitively Impaired Version of the scale will be used in the study. There are two 
versions of the C-SSRS.
If the subject participated in the antecedent study:

The “Since Last Visit” version will be completed for all subjects at each visit in the 
study.
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If the subject is directly enrolled in this study and did not participate in an antecedent study:

The “Lifetime recent” version will be administered at the Screening Visit (Visit -1).

The “Since Last Visit” version will be completed for all study visits after the Screening 
Visit (Visit -1).
Number of subjects and frequency with suicide-related events, based on the C-SSRS data, will be 
tabulated for the Safety Analysis Set for the following categories: 
1. Wish to be dead
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent 
6. Preparatory acts or behavior
7. Aborted suicide, attempt
8. Interrupted attempt   
9. Actual attempt (non-fatal) 
10. Completed suicide  
11. Self-Injurious behavior without suicidal intent
A listing of the C-SSRS data will be provided for subjects with a positive response for the Safety 
Analysis Set.
11.5.3
Follow-up Phone Call
A listing will be created to show the date of the follow-up phone call. 
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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
A Data Monitoring Committee (DMC) was set up to review the data pertaining to safety, 
tolerability, and benefit/harm of the study therapy for the duration of the Pediatric Written 
Request program. No interim statistical inference for any efficacy variable will be performed.  
For further details of the DMC, see Section 15.
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15.
DATA MONITORING/REVIEW COMMITTEE
An external independent DMC is involved in the management of this study. The purpose of the 
DMC, for this study, 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. Data will be provided 
to the DMC by a non-sponsor independent statistical and reporting group that is not assigned to 
the study. 
Data used for DMC reporting purposes will have, at a minimum, the coding done for adverse 
events.  Otherwise, while data may not be cleaned specifically for the DMC, routine cleaning 
will be done throughout the course of the study by subsets of subjects, as they complete / early 
terminate from the study.
Further details regarding the DMC can be found in the DMC charter.
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16.
COMPUTER METHODS 
Statistical analyses will be performed using Version 9.4 (or newer) of SASon a suitably 
qualified environment.
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17.
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
There are no changes to the analyses specified in the protocol. 
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18.
DATA HANDLING CONVENTIONS
General Data Reporting Conventions
18.1
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, SD, minimum, maximum. 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 one 
more decimal place than the raw data. The SD will be presented to two 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 reported to 1 decimal place, 
except when the percentage equals exactly 100 where it will be displayed as an integer (100). For 
zero, only count and no percentage will be displayed. Post-baseline is defined as any visit which 
occurs after the first dose of investigational product in this study.
Treatment Group
18.2
For all tables summarized by the treatment group in the antecedent study, the actual treatment 
received will be used (SPD489 or Placebo) rather than the planned treatment.
Visit Mapping
18.3
The visits need to be mapped in the analysis datasets so that the visit numbers are aligned by the 
relative week as shown in Table 7 and Table 8.
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Table 7
Visit Mapping for "A" Subjects
Protocol Visit Name
Protocol Visit Number
Mapped Visit Name
Mapped Visit Number
Not applicable (from antecedent 
study)
Not applicable
Baseline
0
Visit 0 (Baseline)a
0
Week 0
3
Visit 1 (Week 4)
4
Week 4
7
Visit 2 (Week 8)
7
Week 8
10
Visit 3 (Week 12)
8
Week 12
11
Visit 4 (Week 16)
9
Week 16
12
Visit 5 (Week 20)
10
Week 20
13
Visit 6 (Week 24)
11
Week 24
14
Visit 7 (Week 28)
12
Week 28
15
Visit 8 (Week 32)
13
Week 32
16
Visit 9 (Week 36)
14
Week 36
17
Visit 10 (Week 40)
15
Week 40
18
Visit 11 (Week 44)
16
Week 44
19
Visit 12 (Week 48)
17
Week 48
20
Visit 13/ET (Week 52)
18
Week 52/ET
21
Safety Follow-up (Week 53)
-
Week 53
22
a Visit 0 is the same day as the End of Study Visit for the antecedent study
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Table 8
Visit Mapping for Subjects for “B” Subjects and those under Protocol 
Amendent 2, 20 Oct 2017
Protocol Visit Name
Protocol Visit Number
Mapped Visit Name
Mapped Visit 
Number
Not applicable (from antecedent 
study)
Not applicable
Baseline
0
Visit -1 (Screening)a
-1
Week -4 to -1
1
Phone Call
-
Week -1 to 0
2
Visit 0 (Baseline)
0
Week 0
3
Visit 1 (Week 1)
1
Week 1
4
Visit 2 (Week 2)
2
Week 2
5
Visit 3 (Week 3)
3
Week 3
6
Visit 4 (Week 4)
4
Week 4
7
Visit 5 (Week 5)
5
Week 5
8
Visit 6 (Week 6)
6
Week 6
9
Visit 7 (Week 8)
7
Week 8
10
Visit 8 (Week 12)
8
Week 12
11
Visit 9 (Week 16)
9
Week 16
12
Visit 10 (Week 20)
10
Week 20
13
Visit 11 (Week 24)
11
Week 24
14
Visit 12 (Week 28)
12
Week 28
15
Visit 13 (Week 32)
13
Week 32
16
Visit 14 (Week 36)
14
Week 36
17
Visit 15 (Week 40)
15
Week 40
18
Visit 16 (Week 44)
16
Week 44
19
Visit 17 (Week 48)
17
Week 48
20
Visit 18/ET (Week 52)
18
Week 52/ET
21
Safety Follow-up (Week 53)
-
Week 53
22
a For roll-over subjects, the Screening (visit -1) is the same day as the End of Study Visit for the antecedent 
SPD489-347 Study.
Derived Efficacy Endpoints 
18.4
Not applicable.
Repeated or Unscheduled Assessments of Safety Parameters 
18.5
If end of study assessments are repeated or unscheduled, the last post-baseline assessment whilst 
on investigational product will be used.  However, all post-baseline assessments will be used for 
PCI value determination and all assessments will be presented in the data listings. 
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Missing Date of Investigational Product 
18.6
When the date of the last dose of investigational product is missing for a subject in the Safety 
Analysis 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 treatment duration. If date of last visit when product was returned is 
missing, then use the date of discontinuation in the calculation of treatment duration, otherwise 
use date of cut-off.
Missing Date Information for Prior or Concomitant Medications 
18.7
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.  The first and last dose of investigational product refers to the 
SPD489-348 study.  
18.7.1
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

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
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CONFIDENTIAL
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17 Jul 2019

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.
18.7.2
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

If either the year is before the year of the date of the last dose 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.
Missing Date Information for Adverse Events 
18.8
For AEs, the default is to only impute incomplete (i.e., partially missing) start dates.  Incomplete 
stop dates may also be imputed when calculation of the duration of an AE is required per the 
protocol.  If imputation of an incomplete stop date is required, and both the start date and the 
stop date are incomplete for a subject, impute the start date first.  The first dose of investigational 
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17 Jul 2019
product refers to the SPD489-348 study.  For all subjects, the last dose of investigational product 
refers to the SPD489-348 study.
18.8.1
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

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.
18.8.2
Incomplete Stop Date 
No imputation will be performed on incomplete stop dates.
Missing Severity Assessment for Adverse Events
18.9
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 
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17 Jul 2019
assigned.  The imputed values for severity assessment will be used for incidence summaries, 
while the actual values will be used in data listings.
Missing Relationship to Investigation Product for Adverse Events
18.10
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.
Character Values of Clinical Laboratory Variables 
18.11
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis due 
to, for example, that a character string is reported for a numerical variable. The appropriately 
determined coded value will be used in the statistical analysis.  However, the actual values as 
reported in the database will be presented in data listings.
Table 9
Examples for Coding of Special Character Values for Clinical Laboratory 
Variables
Clinical Laboratory Test
Possible Results (in SI units)
Coded Value for Analysis
Chemistry:  ALT
<5
0
Chemistry:  AST
<5
0
Chemistry:  Total Bilirubin
<2
0
Urinalysis:  Glucose
55
Positive
0
Negative
Urinalysis:  pH
8.0
8.0
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CONFIDENTIAL
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17 Jul 2019
19.
REFERENCES
Kuczmarski, R. J., Ogden, C. L., Guo, S. S., Grummer-Strawn, L. M., Flegal, K. M., Mei, Z., 
Wei, R., Curtin, L. R., Roche, A. F.and Johnson, C. L. 2002. 2000 CDC Growth Charts 
for the United States: methods and development. Vital Health Stat 11, 1-190.
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17 Jul 2019
20.
TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS
Tables
20.1
Table 
Title (Population) 
Shire Std
14.1.1
Disposition by Antecedent Study Treatment Group (Screened Set)
Y
14.1.2
Protocol Deviations by Site and Antecedent Study Treatment Group 
(Safety Analysis Set) 
Y
14.1.3
Enrollment Duration by Site and Antecedent Study Treatment 
Group (Screened Set)
Y
14.1.4.1
Demographic Characteristics by Antecedent Study Treatment 
Group (Safety Analysis Set)
Y
14.1.4.2
Baseline Characteristics by Antecedent Study Treatment Group 
(Safety Analysis Set)
Y
14.1.4.3
Demographic Characteristics by Antecedent Study Treatment 
Group (Safety Analysis Set)
Y
14.1.4.4
Baseline Characteristics by Antecedent Study Treatment Group 
(Full Analysis Set)
Y
14.1.4.5
Prior Medications by Antecedent Study Treatment Group (Safety 
Analysis Set)
Y
14.1.4.6
Prior ADHD Medications by Antecedent Study Treatment Group 
(Safety Analysis Set)
Y
14.1.4.7
Concomitant Medications by Antecedent Study Treatment Group 
(Safety Analysis Set)
Y
14.1.4.8
Concomitant ADHD Medications by Antecedent Study Treatment 
Group (Safety Analysis Set)
Y
14.1.5
Investigational Product Accountability by Antecedent Study 
Treatment Group (Safety Analysis Set)
Y
14.2.2.1
Summary and Analysis of Change from Baseline in the ADHD-RS-
IV Preschool Version Total Score by Antecedent Study Treatment 
Group (Full Analysis Set)
Y
14.2.2.2
Summary and Analysis of Change from Baseline in the ADHD-RS-
IV Preschool Version Subscales by Antecedent Study Treatment 
Group (Full Analysis Set)
Y
14.2.2.3
Summary of Dichotomized CGI-I by Visit and Antecedent 
Treatment Group (Full Analysis Set)
Y
14.2.2.4
Summary and Analysis of CGI by Visit and Antecedent Treatment 
Group (Full Analysis Set)
Y
14.3.1.1
Overall Treatment-Emergent Adverse Events (TEAEs) by Dose 
Taken Prior to Event (Safety Analysis Set)
Y
14.3.1.2
Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Dose Taken Prior to Event (Safety Analysis 
Set)
Y
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17 Jul 2019
Table 
Title (Population) 
Shire Std
14.3.1.3
Treatment-Emergent Adverse Events by Preferred Term, and Dose 
Taken Prior to Event (Safety Analysis Set)
Y
14.3.2.1
Treatment-Emergent Adverse Events by Maximum Severity, 
System Organ Class, Preferred Term, and Dose Taken Prior to 
Event (Safety Analysis Set)
Y
14.3.2.2
Treatment-Emergent Adverse Events Considered Related to 
Investigational Product by System Organ Class, Preferred Term, 
and Dose Taken Prior to Event (Safety Analysis Set) 
Y
14.3.3.1
Treatment-Emergent Adverse Events Leading to Death by System 
Organ Class, Preferred Term, and Dose Taken Prior to Event 
(Safety Analysis Set)
Y
14.3.3.2
Treatment-Emergent Adverse Events Leading to Drug Withdrawal 
by System Organ Class, Preferred Term, and Dose Taken Prior to 
Event (Safety Analysis Set)
Y
14.3.3.3
Serious Treatment-Emergent Adverse Events by System Organ 
Class, Preferred Term, and Dose Taken Prior to Event (Safety 
Analysis Set)
Y
14.3.4.1
Quantitative Clinical Laboratory Results by Visit and Antecedent 
Study Treatment Group: Hematology (Safety Analysis Set)
Y
14.3.4.2
Quantitative Clinical Laboratory Results by Visit and Antecedent 
Study Treatment Group: Biochemistry and Endocrinology (Safety 
Analysis Set)
Y
14.3.4.3
Quantitative Clinical Laboratory Results by Visit and Antecedent 
Study Treatment Group: Urinalysis (Safety Analysis Set)
Y
14.3.4.4
Qualitative Clinical Laboratory Results by Visit and Antecedent 
Study Treatment Group: Urinalysis (Safety Analysis Set)
Y
14.3.4.5
Shift from Baseline in Clinical Laboratory Results: Hematology 
(Safety Analysis Set)
Y
14.3.4.6
Shift from Baseline in Clinical Laboratory Results: Biochemistry 
and Endocrinology (Safety Analysis Set)
Y
14.3.4.7
Shift from Baseline in Clinical Laboratory Results: Urinalysis 
(Safety Analysis Set)
Y
14.3.4.8
Potentially Clinically Important (PCI) Laboratory Results by 
Antecedent Study Treatment Group: Hematology (Safety Analysis 
Set)
Y
14.3.4.9
Potentially Clinically Important (PCI) Laboratory Results by 
Antecedent Study Treatment Group: Biochemistry and 
Endocrinology (Safety Analysis Set)
Y
14.3.4.10
Potentially Clinically Important (PCI) Laboratory Results by 
Antecedent Study Treatment Group: Urinalysis (Safety Analysis 
Set)
Y
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17 Jul 2019
Table 
Title (Population) 
Shire Std
14.3.4.11
Normal Ranges and Potentially Clinically Important (PCI) Criteria: 
Hematology
Y
14.3.4.12
Normal Ranges and Potentially Clinically Important (PCI) Criteria: 
Biochemistry and Endocrinology
Y
14.3.4.13
Normal Ranges and Potentially Clinically Important (PCI) Criteria: 
Urinalysis
Y
14.3.5.1
Actual Values and Change from Baseline in Vital Signs by Visit 
and Antecedent Study Treatment Group (Safety Analysis Set)
Y
14.3.5.2
Actual Values and Change from Baseline in Percentiles of Weight 
and Body Mass Index (BMI) by Visit and Antecedent Study 
Treatment Group (Safety Analysis Set)
N
14.3.5.3
Weight by Visit and Antecedent Study Treatment Group (Safety 
Analysis Set)
N
14.3.5.4
Shift from Baseline in Weight (Safety Analysis Set)
N
14.3.5.5
Weight Z-Scores by Antecedent Study Treatment Group (Safety 
Analysis Set)
N
14.3.5.6
Body Mass Index (BMI) by Antecedent Study Treatment Group 
(Safety Analysis Set)
N
14.3.5.7
Shift from Baseline in Body Mass Index (BMI) (Safety Analysis 
Set)
N
14.3.5.8
Body Mass Index (BMI) Z-Scores by Antecedent Study Treatment 
Group (Safety Analysis Set)
N
14.3.5.9
Potentially Clinically Important (PCI) Vital Signs by Visit and 
Antecedent Study Treatment Group (Safety Analysis Set)
Y
14.3.6.1
Actual Values and Change from Baseline in ECG by Visit and 
Antecedent Study Treatment Group (Safety Analysis Set)
Y
14.3.6.2
ECG Interpretation by Visit and Antecedent Study Treatment 
Group (Safety Analysis Set)
Y
14.3.6.3
Shift from Baseline in Qualitative ECG Results (Safety Analysis 
Set)
Y
14.3.6.4
Potentially Clinically Important (PCI) ECG Results by Visit and 
Antecedent Study Treatment Group (Safety Analysis Set)
Y
14.3.7.1
Overall Investigational Product Exposure by Antecedent Study 
Treatment Group (Safety Analysis Set)
Y
14.3.7.2
Investigational Product Exposure by Visit and Antecedent Study 
Treatment Group (Safety Analysis Set)
Y
14.3.7.3
Investigational Product Exposure by Period and Antecedent Study 
Treatment Group (Safety Analysis Set)
Y
14.3.7.4
Investigational Product Compliance by Visit and Antecedent Study 
Treatment Group (Safety Analysis Set)
Y
14.3.7.5
Summary of Children’s Sleep Habits Questionnaire (CSHQ) by 
Visit and Antecedent Study Treatment Group (Safety Analysis Set)
N
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17 Jul 2019
Table 
Title (Population) 
Shire Std
14.3.7.6
Summary of Sleep Diary Data by Antecedent Study Treatment 
Group (Safety Analysis Set)
N
14.3.7.7
Post-baseline Columbia-Suicide Severity Rating Scale by 
Antecedent Treatment Group (Safety Analysis Set)
Y
14.3.7.8
Post-baseline Columbia-Suicide Severity Rating Scale by 
Antecedent Treatment Group: Most Severe Case (Safety Analysis 
Set)
Y
Figures
20.2
Table 
Title (Population) 
Shire Std
14.2.1
Plot of Mean Change from Baseline in ADHD-RS-IV Preschool 
Version Total Score by Visit and Antecedent Study Treatment 
Group (Full Analysis Set)
N
14.2.2
Plot of Mean Change from Baseline in ADHD-RS-IV Preschool 
Version Subscale Total Score by Visit and Antecedent Study 
Treatment Group (Full Analysis Set)
N
14.2.3
Summary of Improved CGI-I by Visit and Antecedent Treatment 
Group (Full Analysis Set)
N
14.3
Plot of Mean Change from Baseline in Vital Signs by Visit and
Antecedent Treatment Group (Safety Analysis Set)
N
Listings
20.3
Listing
Title
Shire 
Std
16.2.1.1
Subject Disposition (Screened Set)
Y
16.2.1.2
Subjects Who Terminated from the Study (Screened Set)
Y
16.2.1.3
Study Analysis Set Classification (Screened Set) 
Y
16.2.2.1
Deviations from Inclusion/Exclusion Criteria (Screened Set)
Y
16.2.2.2
Listing of Protocol Deviations (Safety Analysis Set)
Y
16.2.4.1
Subject Demographics (Safety Analysis Set)
Y
16.2.4.2
Subject Baseline Characteristics (Safety Analysis Set)
Y
16.2.4.3
Medical History (Safety Analysis Set)
Y
16.2.4.4
K-SADS PL at Screening
N
16.2.4.5
Prior and Concomitant Medications (Safety Analysis Set)
Y
16.2.4.6
Prior and Concomitant ADHD Medications (Safety Analysis Set)
Y
16.2.4.7
Prior and Concomitant ADHD Behavioral Therapies (Safety Analysis Set)
Y
16.2.5.1 
Investigational Product Accountability (Safety Analysis Set)
Y
16.2.5.2
Investigational Product Exposure and Compliance (Safety Analysis Set)
N
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17 Jul 2019
Listing
Title
Shire 
Std
16.2.6.1
ADHD-RS-IV Preschool Version Records by Individual Subject – Part 1 
(Full Analysis Set)
Y
16.2.6.2
ADHD-RS-IV Preschool Version Records by Individual Subject – Part 2 
(Full Analysis Set)
Y
16.2.6.3
Clinical Global Impression (Full Analysis Set)
Y
16.2.7.1
Adverse Events (Safety Analysis Set)
Y
16.2.7.2
Subjects Reporting Serious Treatment-Emergent Adverse Events (Safety 
Analysis Set)
Y
16.2.7.3
Treatment-Emergent Adverse Events Considered Related to 
Investigational Product (Safety Analysis Set)
Y
16.2.7.4
Treatment-Emergent Adverse Events Leading to Withdrawal of 
Investigational Product (Safety Analysis Set)
Y
16.2.7.5
Adverse Events with Fatal Outcome (Safety Analysis Set)
Y
16.2.8.1
Clinical Laboratory Test Results (Safety Analysis Set)
Y
16.2.8.2
Subjects with Potentially Clinically Important Laboratory Test Results 
(Safety Analysis Set)
Y
16.2.8.3
Vital Signs (Safety Analysis Set)
Y
16.2.8.4
Subjects with Potentially Clinically Important Vital Signs (Safety 
Analysis Set)
Y
16.2.8.5
12-Lead ECG Results and Interpretation (Safety Analysis Set)
Y
16.2.8.6
Subjects with Potentially Clinically Important ECG Results (Safety 
Analysis Set)
Y
16.2.8.7
Children’s Sleep Habits Questionnaire (CSHQ) (Safety Analysis Set)
N
16.2.8.8
Sleep Diary (Safety Analysis Set)
N
16.2.8.9
Columbia-Suicide Severity Rating Scale: Suicidal Ideation (Safety 
Analysis Set)
Y
16.2.8.10
Columbia-Suicide Severity Rating Scale: Intensity of Ideation (Safety 
Analysis Set)
Y
16.2.8.11
Columbia-Suicide Severity Rating Scale: Suicidal Behavior (Safety 
Analysis Set)
Y
16.2.8.12
Columbia-Suicide Severity Rating Scale: Suicidal Behavior - Actual 
Attempts (Safety Analysis Set)
Y
16.2.8.13
Follow-Up Call (Safety Analysis Set)
N
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Protocol Amendment 1
SPD489-348
28 Jun 2017
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 Pharmacovigilance 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 fax or e-mail using the details below.
Fax:  
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:
Phone:
Fax:  
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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Protocol Amendment 1
SPD489-348
28 Jun 2017
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 below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)
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Page 7
Protocol Amendment 1
SPD489-348
28 Jun 2017
TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
SUMMARY OF CHANGES FROM PREVIOUS VERSION........................................................3
EMERGENCY CONTACT INFORMATION................................................................................5
PRODUCT QUALITY COMPLAINTS..........................................................................................6
LIST OF TABLES.........................................................................................................................12
LIST OF FIGURES .......................................................................................................................12
ABBREVIATIONS .......................................................................................................................13
STUDY SYNOPSIS ......................................................................................................................15
STUDY SCHEDULE(S) ...............................................................................................................19
1
BACKGROUND INFORMATION.......................................................................................22
1.1
Indication and Current Treatment Options...............................................................22
1.2
Product Background and Clinical Information ........................................................24
1.2.1
Preclinical Information ..............................................................................25
1.2.2
Clinical Information...................................................................................25
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................26
2.1
Rationale for the Study.............................................................................................26
2.2
Study Objectives ......................................................................................................26
2.2.1
Primary Objectives.....................................................................................26
2.2.2
Secondary Objectives.................................................................................27
3
STUDY DESIGN ...................................................................................................................27
3.1
Study Design and Flow Chart ..................................................................................27
3.2
Duration and Study Completion Definition .............................................................28
3.3
Sites and Regions .....................................................................................................28
4
STUDY POPULATION.........................................................................................................28
4.1
Inclusion Criteria......................................................................................................28
4.2
Exclusion Criteria.....................................................................................................29
4.3
Reproductive Potential .............................................................................................30
4.3.1
Female Contraception................................................................................30
4.4
Discontinuation of Subjects .....................................................................................31
4.4.1
Management of Blood Pressure and Pulse During the Study....................31
4.4.1.1
Systolic and Diastolic Blood Pressure.......................................................31
4.4.1.2
Pulse...........................................................................................................32
4.4.2
Reasons for Discontinuation......................................................................32
4.4.3
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit......................32
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................32
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5.1
Prior Treatment ........................................................................................................33
5.2
Concomitant Treatment............................................................................................33
5.2.1
Permitted Treatment...................................................................................33
5.2.2
Prohibited Treatment .................................................................................33
6
INVESTIGATIONAL PRODUCT ........................................................................................34
6.1
Identity of Investigational Product...........................................................................34
6.1.1
Blinding the Treatment Assignment..........................................................34
6.2
Administration of Investigational Product(s)...........................................................34
6.2.1
Interactive Response Technology (IRT) for Investigational Product 
Management...............................................................................................34
6.2.2
Allocation of Subjects to Treatment ..........................................................34
6.2.3
Dosing........................................................................................................35
6.2.4
Unblinding the Treatment Assignment......................................................36
6.3
Labeling, Packaging, Storage, and Handling ...........................................................36
6.3.1
Labeling .....................................................................................................36
6.3.2
Packaging...................................................................................................36
6.3.3
Storage .......................................................................................................36
6.4
Drug Accountability.................................................................................................37
6.5
Subject Compliance..................................................................................................38
7
STUDY PROCEDURES........................................................................................................38
7.1
Study Schedule.........................................................................................................38
7.1.1
Screening and Washout Period..................................................................39
7.1.1.1
Screening Visit (Visit -1)...........................................................................39
7.1.1.2
Washout Telephone Call (Visit Phone Call)..............................................40
7.1.1.3
Visit 0.........................................................................................................41
7.1.2
Treatment Period........................................................................................41
7.1.2.1
Dose-optimization Period (Visits 1 to 6) ...................................................41
7.1.2.2
Dose Maintenance Period (Visits 7 to 18/ET)...........................................42
7.1.2.3
End-of-Study Visit (Visit 18/Early Termination)......................................42
7.1.3
Safety Follow-up Period ............................................................................43
7.1.4
Additional Care of Subjects After the Study .............................................43
7.2
Study Evaluations and Procedures ...........................................................................43
7.2.1
Demographic and Other Baseline Characteristics .....................................43
7.2.2
Screening Assessments ..............................................................................43
7.2.2.1
Kiddie – Schedule for Affective Disorders and Schizophrenia for 
School-age Children – Present and Lifetime Version-Diagnostic 
Interview.................................................................................................44
7.2.2.2
Peabody Picture Vocabulary Test-Fourth Edition.....................................44
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7.2.3
Efficacy......................................................................................................44
7.2.3.1
Attention-deficit/Hyperactivity Disorder Rating Scale – IV Preschool 
Version ...................................................................................................44
7.2.3.2
Clinical Global Impressions.......................................................................45
7.2.4
Safety .........................................................................................................45
7.2.4.1
Medical and Medication History ...............................................................46
7.2.4.2
Physical Examination (Including Height and Weight)..............................46
7.2.4.3
Adverse Event Collection ..........................................................................46
7.2.4.4
Vital Signs..................................................................................................47
7.2.4.5
Height and Weight .....................................................................................47
7.2.4.6
Clinical Laboratory Evaluations ................................................................47
7.2.4.7
Electrocardiogram......................................................................................49
7.2.4.8
Children’s Sleep Habits Questionnaire and Sleep Diary...........................49
7.2.4.9
Columbia-Suicide Severity Rating Scale- Pediatric/Cognitively 
Impaired Version....................................................................................50
7.2.4.10
Suitability of the Subject to Remain in the Study......................................50
7.2.5
Volume of Blood to be Drawn From Each Subject...................................51
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................51
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................51
8.1.1
Severity Categorization..............................................................................52
8.1.2
Relationship Categorization.......................................................................52
8.1.3
Outcome Categorization ............................................................................53
8.1.4
Symptoms of the Disease Under Study .....................................................53
8.1.5
Clinical Laboratory and Other Safety Evaluations....................................53
8.1.6
Abuse, Misuse, Overdose, and Medication Error......................................54
8.2
Serious Adverse Event Procedures ..........................................................................54
8.2.1
Reference Safety Information....................................................................54
8.2.2
Reporting Procedures.................................................................................54
8.2.3
Serious Adverse Event Definition .............................................................55
8.2.4
Serious Adverse Event Collection Time Frame.........................................55
8.2.5
Serious Adverse Event Onset and Resolution Dates .................................56
8.2.6
Fatal Outcome............................................................................................56
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting......................................................................................56
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................56
9.1
Data Collection.........................................................................................................56
9.2
Clinical Data Management.......................................................................................57
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9.3
Data Handling Considerations..................................................................................57
9.4
Statistical Analysis Process......................................................................................57
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......57
9.6
Sample Size Calculation and Power Considerations................................................57
9.7
Study Population ......................................................................................................58
9.8
Efficacy Analyses.....................................................................................................58
9.8.1
Clinician-administered ADHD-RS-IV Preschool Version........................58
9.8.2
Clinical Global Impressions.......................................................................58
9.8.3
Exploratory Efficacy Endpoints.................................................................59
9.9
Safety Analyses........................................................................................................59
9.10
Other Analyses .........................................................................................................59
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................59
10.1
Sponsor’s Responsibilities .......................................................................................59
10.1.1
Good Clinical Practice Compliance...........................................................59
10.1.2
Public Posting of Study Information..........................................................60
10.1.3
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees............60
10.1.4
Study Suspension, Termination, and Completion......................................60
10.2
Investigator’s Responsibilities .................................................................................60
10.2.1
Good Clinical Practice Compliance...........................................................60
10.2.2
Protocol Adherence and Investigator Agreement......................................61
10.2.3
Documentation and Retention of Records.................................................61
10.2.3.1
Case Report Forms.....................................................................................61
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................62
10.2.3.3
Audit/Inspection.........................................................................................62
10.2.3.4
Financial Disclosure...................................................................................62
10.2.4
Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation................63
10.3
Ethical Considerations..............................................................................................63
10.3.1
Informed Consent.......................................................................................63
10.3.2
Institutional Review Board or Ethics Committee......................................63
10.4
Privacy and Confidentiality......................................................................................64
10.5
Study Results / Publication Policy ...........................................................................64
11 REFERENCES .......................................................................................................................66
12 APPENDICES ........................................................................................................................69
Appendix 1
Protocol History.........................................................................................70
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Appendix 2
Diagnostic Criteria/Disease Classification ................................................71
Appendix 2.1 DSM-IV-TR Criteria for Attention-  Deficit/Hyperactivity Disorder .......72
Appendix 2.2 Blood Pressure Levels for Boys by Age and Height Percentiles...............74
Appendix 2.3 Blood Pressure Levels for Girls by Age and Height PercentileS ..............75
Appendix 2.4 Boys’ Stature-for-Age and Weight-for-Age Percentiles............................76
Appendix 2.5 Girls’ Stature-For-Age and Weight-For-Age Percentiles..........................77
Appendix 3
Scales and Assessments .............................................................................78
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LIST OF TABLES
Table 1:
Schedule of Assessments...............................................................................19
Table 2:
Common Excluded Treatments and Associated Washout Period–
Relative to Visit 0..........................................................................................33
Table 3:
Volume of Blood to be Drawn From Each Subject.......................................51
LIST OF FIGURES
Figure 1:
Chemical Structure of the Active Pharmaceutical Ingredient .......................24
Figure 2:
Study Design Flow Chart ..............................................................................27
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ABBREVIATIONS
AAP
American Academy of Pediatrics
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS-IV
attention-deficit/hyperactivity disorder rating scale- IV
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase 
AST
aspartate transaminase
CGI-I
clinical global impressions-global improvement
CGI-S
clinical global impressions-severity of illness
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSHQ
children’s sleep habits questionnaire
C-SSRS
Columbia-suicide severity rating scale
DBP
diastolic blood pressure
DMC
data monitoring committee
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
EC
ethics committee
ECG
Electrocardiogram
EMA
European Medicines Agency
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IRB
Institutional Review Board
IRT
interactive response technology
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IWRS
interactive web response system
LAR
legally authorized representative
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
PAPA
preschool age psychiatric assessment
PATS
Preschool ADHD Treatment Study
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
T4
thyroxine
TEAE
treatment-emergent adverse event
TSH
thyroid stimulating hormone
UBC
United BioSource, LLC
UK
United Kingdom
US
United States
WBC
white blood cell
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STUDY SYNOPSIS
Protocol number:  SPD489-348
Drug: Lisdexamfetamine dimesylate
Title of the study:  A Phase 3, Open-label, Multicenter, 12-Month Safety and Tolerability  Study of SPD489 in 
Preschool Children Aged 4-5 Years Diagnosed with Attention-deficit/Hyperactivity Disorder
Number of subjects:
Approximately 100 subjects will be enrolled into this study. Subjects will enroll into this study from antecedent 
study SPD489-211 or SPD489-347, or through direct enrollment. 
The sample size was established to provide long-term safety data in this population.
Investigator(s):  Multicenter
Site(s) and Region(s): 
Approximately up to 60 sites in North America.
Study period (planned):
2014-2019
Clinical phase:
3
Objectives:
Primary:  To evaluate the long-term safety of SPD489 administered as a daily morning dose (5, 10, 15, 20, and 
30 mg/day) in preschool children (4-5 years of age 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), specific evaluation of blood pressure, pulse, weight, height, clinical laboratory evaluations, 
electrocardiogram (ECG) results, and sleep assessments.
Secondary: 
1.
To describe the long-term efficacy of SPD489 using the clinician administered Attention-
deficit/Hyperactivity Disorder Rating Scale-IV Preschool Version (ADHD-RS-IV Preschool Version).
2.
To describe the long-term efficacy of SPD489 using global clinical measures of improvement, as measured 
by the Clinical Global Impressions – Global Improvement (CGI-I).
Rationale:
The purpose of the study is to evaluate the long-term safety of SPD489 in preschool children who are diagnosed 
with ADHD. Based on IMS Health data and discussion at the Food and Drug Administration (FDA) Pediatric 
Advisory Committee in September 2012, it has been noted that there is off-label use of SPD489 in children 
under 5 years old (4%, or approximately 100 000 patients between February 2007 and March 2012).  The lack 
of controlled data regarding the safety and efficacy of SPD489 in the preschool ADHD population, along with 
the prevalence of off-label prescribing of SPD489 supports the need for SPD489 studies in the preschool ADHD 
population.  Importantly, it is not known if the therapeutic effects of stimulant medications in school age 
children with ADHD can be extrapolated to preschool children with ADHD.  There are some indications that the 
effect size may be reduced (Greenhill 2006).  There may also be differences in the safety and pharmacokinetic 
profiles (Wigal 2007; Wigal 2006).
Generating long-term safety data in this population will provide important information on the use of SPD489 in 
the preschool ADHD population.
Investigational product, dose, and mode of administration:
The sponsor will provide SPD489 as 5, 10, 15, 20, and 30 mg strength capsules.
All subjects will be instructed to take 1 capsule daily throughout the study at approximately 7:00AM (±2 hours). 
SPD489 will be administered in one of the following ways: 

swallow SPD489 capsules whole, or

open capsules, empty and mix the entire contents either with yogurt, water, or orange juice.
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The contents should be mixed until completely dispersed. The subject must ingest the entire amount of the 
mixture immediately within 3 minutes. The subject should not take anything less than one capsule per day and a 
single capsule cannot be split. The empty gelatinous capsule should be discarded. 
Methodology:
This study is a Phase 3 long-term, open-label, safety and tolerability study in preschool children (4-5 years 
of age inclusive at the time of consent) from antecedent study or direct enrollment with 
Attention-deficit/Hyperactivity Disorder (ADHD).
The study will have 4 periods: (1) Screening and Washout; (2) Dose-optimization; (3) Dose Maintenance; and 
(4) Safety Follow-up.
The duration of the evaluation phase (Dose-optimization and Maintenance) will be 52 weeks. 
SPD489 will be provided in 5, 10, 15, 20, and 30 mg capsules.
Subjects may be required to visit the site up to 20 times over a 57-week period.
Inclusion and exclusion criteria
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below (including test 
results).
1.
Subject is male or female aged 4-5 years inclusive at the time of consent from antecedent studies 
SPD489-211 or SPD489-347 or at the time of consent if directly enrolled.
2.
Before completing any study-related procedures, subject’s parent(s) 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 Conference on Harmonisation (ICH) GCP 
Guideline E6 (1996) and any updates or revisions, and applicable federal or local regulations.
3.
Subject and parent(s)/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 parent/LAR should be available at 
approximately 7:00AM (+2 hours) to dispense the dose of investigational product for the duration of the 
study.
4.
Roll-over subjects from antecedent SPD489-347study: 
a.
Subject completed the antecedent SPD489-347 study 
5.
Direct enrolled subjects must meet antecedent study inclusion criteria, as listed below:
a.
Subject must meet Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text 
Revision (DSM-IV-TR) criteria for a primary diagnosis of ADHD (any subtype) based on a detailed 
psychiatric evaluation conducted by a sponsor-approved clinician
b.
Subject has an ADHD-RS-IV Preschool Version total score at the Baseline Visit (Visit 0) of ≥28 for 
boys and ≥24 for girls. 
c.
Subject has a Clinical Global Impressions – Severity of Illness (CGI-S) score 4 at the Baseline Visit 
(Visit 0). 
d.
Subject has a Peabody Picture Vocabulary Test, Fourth Edition standard score of 70 at the Screening 
Visit (Visit -1). 
e.
Subject has undergone an adequate course of non-pharmacological treatment OR the subject has a 
severe enough condition to consider enrollment without undergoing prior non-pharmacological 
treatment, based on investigator judgment.
f.
Subject has, in the opinion of the investigator, participated in a structured group activity (eg, preschool, 
sports, Sunday school) so as to assess symptoms and impairment in a setting outside the home.
g.
Subject has lived with the same parent(s) or guardian for ≥6 months.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Subject was terminated from any antecedent SPD489 study for non-compliance and/or experienced a 
serious adverse event (SAE) or AE resulting in termination.
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2.
Subject is required to or anticipates the need to take prohibited medications or medications that have central 
nervous system effects or have an effect on performance, such as, but not limited to, sedating antihistamines 
and decongestant sympathomimetics, or other monoamine oxidase inhibitors.  Stable use of bronchodilator 
inhalers is not exclusionary.
3.
Subject has a concurrent chronic or acute illness (such as, but not limited to, 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 the Screening Visit 
(Visit -1) or the Baseline Visit (Visit 0) or a history of moderate or severe hypertension. 
7.
Subject has a known history of symptomatic cardiovascular disease, unexplained syncope, exertional chest 
pain, advanced arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm 
abnormalities, coronary artery disease, or other serious cardiac problems placing them at increased 
vulnerability to the sympathomimetic effects of a stimulant drug.
8.
Subject is taking any medication that is excluded per the protocol.
9.
Subject had any clinically significant electrocardiogram (ECG) or clinical laboratory abnormalities at the 
Screening Visit (Visit -1) or the Baseline Visit (Visit 0), based on investigator judgement.
10. Subject has a history of hyperthyroidism, or current abnormal thyroid function, defined as abnormal thyroid 
stimulating hormone (TSH) and thyroxine (T4) at the Screening Visit (Visit -1) or the Baseline Visit 
(Visit 0).  Treatment with a stable dose of thyroid medication for at least 3 months is permitted. 
11. Subject has taken another investigational product or has taken part in a clinical study within 30 days prior to 
the Screening Visit (Visit -1).
12. Subject is well-controlled on his/her current ADHD medication with acceptable tolerability.
13. Subject has glaucoma.
14. Subject has failed to fully respond, based on investigator judgment, to an adequate course of amphetamine 
therapy.
15. Subject has a current, controlled (requiring medication or therapy) or uncontrolled, co-morbid psychiatric 
disorder including but not limited to any of the below co-morbid Axis I disorders and Axis II disorders:
a.
post-traumatic stress disorder (PTSD) or adjustment disorder
b.
bipolar illness, psychosis, or family history of these disorders
c.
pervasive developmental disorder
d.
obsessive-compulsive disorder (OCD) 
e.
psychosis/schizophrenia
f.
a serious tic disorder, or a family history of Tourette’s disorder
g.
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 is currently demonstrating active suicidal ideation. 
h.
a history of physical, sexual, or emotional abuse
i.
any other disorder or agitated state that in the opinion of the investigator, contraindicates SPD489 or 
lisdexamfetamine dimesylate treatment or confound efficacy or safety assessments.
16. Subject has initiated behavioral therapy within 1 month of the baseline visit (Visit 0).  Subject may not 
initiate behavioral therapy during the study.
17. Subject has a height 5th percentile for age and sex at the screening visit (Visit -1).
18. Subject has a weight 5th percentile for age and sex at the screening visit (Visit -1).
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19. Subject lives with anyone who currently abuses stimulants or cocaine.
20. Subject has a history of seizures (other than infantile febrile seizures).
Maximum duration of subject involvement in the study:

Planned duration of screening period: 28 days

Planned duration of treatment period: 52 week period

Planned duration of safety follow-up period: 7 days
Endpoints and statistical analysis:
Subject Populations

The Screened Set will consist of all subjects who have signed informed consent. 

The Enrolled Set will consist of all subjects who have been dispensed SPD489 at the Baseline Visit 
(Visit 0). Screen failures will not be considered enrolled subjects and will not be included in the 
Enrolled Set.

The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of investigational 
product.

The Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at least 
1 post-dose ADHD-RS-IV Preschool Version Total Score assessment during the study.
Safety Endpoints
Safety assessments include the occurrence of treatment emergent adverse events (TEAEs), specific evaluation of 
blood pressure, pulse, height, weight, clinical laboratory evaluations and electrocardiogram (ECG) results, and 
sleep assessments [(including sleep diary data, and Children’s Sleep Habits Questionnaire (CSHQ)].
Additional safety rating scales utilized in the study will include:
Columbia Suicide Rating Scale (C-SSRS)- Pediatric/Cognitively Impaired Version 
Efficacy Endpoint(s)
The efficacy endpoint is defined as the change from baseline on the clinician-administered ADHD-RS-IV 
Preschool Version Total Score, where subjects that rolled over from an antecedent study, baseline is defined as 
the baseline from the antecedent study, and for subjects that directly enrolled into SPD489-348, baseline is 
defined as baseline of the SPD489-348 study.
The additional efficacy endpoint is the Clinical Global Impression-Improvement Scale (CGI-I): Moreover, the 
CGI-I will be used to determine the proportion of subjects with an “improved” measurement. 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 Endpoint(s)
Safety analyses will be summarized using the Safety Analysis Set, and presented by treatment group of the 
antecedent studies, direct-enrolled group and overall for AEs, clinical laboratory results, vital signs, ECGs, 
CSHQ, and sleep diaries.  A listing of the C-SSRS will be provided for subjects with any positive responses.
Statistical Methodology for Efficacy Endpoint(s)
The FAS will be used to report the efficacy data. Descriptive summary statistics will be presented by treatment 
group of the antecedent studies, direct-enrolled group and overall for the observed efficacy variables. Change 
from baseline in total score for the ADHD-RS-IV Preschool Version Total Score at each on-therapy treatment 
visit will be summarized.
Descriptive summary statistics will be presented by treatment group of the antecedent studies, directly enrolled 
group, and overall at each on-treatment visit for CGI-I measurements. Additionally, the number and proportion 
of subjects with an “improved” measurement in CGI-I will be reported at each on-treatment post-dose visit. 
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1
BACKGROUND INFORMATION
Lisdexamfetamine dimesylate capsules (SPD489, previously referred to as NRP104) were 
developed for the once-daily treatment of ADHD.
SPD489 capsules contain 5, 10, 15, 20, or 30 mg of lisdexamfetamine dimesylate, a new 
chemical entity designed for once-daily oral administration. Lisdexamfetamine itself is a 
pharmacologically inactive prodrug. After ingestion it is converted to l-lysine (a naturally 
occurring essential amino acid) and dextroamphetamine (d-amphetamine, responsible for 
pharmacological activity) primarily in the blood.
Amphetamine is a chiral compound that exists as 2 stereoisomers: dextro (d)- and 
levo (l)-amphetamine. Lisdexamfetamine is the l-lysine conjugate of the dextro stereoisomer.  
After oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract 
and converted primarily in the blood to l-lysine (a naturally occurring amino acid) and 
d-amphetamine, which is responsible for the drug’s pharmacological activity.
Lisdexamfetamine is classified as a psychomotor stimulant.  
Amphetamine appears to exert its pharmacological effects in the CNS by increasing the 
availability of naturally occurring amines that have important functions in nerve terminals. 
Amphetamine increases synaptic levels of dopamine (DA), norepinephrine (NE), and serotonin 
(5-HT) through multiple mechanisms (Hardman et al., 2001). It promotes the release of DA, NE, 
and 5-HT into the extraneuronal space, and also inhibits the reuptake of DA and NE into the 
pre-synaptic nerve terminal resulting in prolonged residency of these neurotransmitters in the 
synaptic cleft. In addition to producing a CNS response, amphetamine treatment is also 
associated with cardiovascular effects such as an increase in SBP and DBP, and pulse. 
Amphetamine may also suppress the appetite.
In addition to the approved indication of ADHD, other indications have been explored.
Additional information can be found in the current IB for SPD489.
1.1
Indication and Current Treatment Options 
Attention-deficit/hyperactivity disorder is a heterogeneous neurobehavioral disorder 
characterized by a pattern of developmentally inappropriate inattentiveness, impulsivity, and 
hyperactivity resulting in clinically significant impairment in social, academic, or occupational 
functioning. Although ADHD was originally thought to be a disorder primarily affecting 
elementary school age children, it is now recognized that ADHD may persist across a lifetime, 
and that ADHD symptoms may manifest several years prior to entry into elementary school. 
While there are hundreds of studies investigating the treatment of ADHD in school-age children, 
there are very few studies exploring the treatment of ADHD in preschoolers.  Although 
diagnosing ADHD in a preschool child can be challenging, reliable diagnostic tools and 
age-appropriate assessments are available, and it is therefore possible to conduct scientifically 
rigorous ADHD studies in this population.  It would be beneficial to provide additional 
evidence-based support for ADHD treatment decisions in the preschool population.  
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Estimates of the prevalence of ADHD in the preschool population vary depending on the 
referral source and the method used to diagnose ADHD; however, it appears that approximately 
4-5% of preschool children are considered to have ADHD.  Using the Preschool-age 
Psychiatric Assessment, an assessment validated for use in the preschool population, the 
prevalence of ADHD in a sample of 1,073 children aged 2-5 years was reported to be 3.9-5.1% 
(Egger et al., 2006a; Egger et al., 2006b; Egger and Angold, 2004; Greenhill et al., 2008).  In 
2007, the National Survey of Children’s Health obtained information from parents of 
73,123 children aged 4-17 years (Centers for Disease Control and Prevention, 2010).  Parents 
reported a current diagnosis of ADHD in 5.5% of 4-10 year olds (Centers for Disease Control 
and Prevention, 2010).  Some reports utilizing a clinic-based sampling frame (versus a 
community based - sampling frame) report the prevalence in males aged 4-11 is roughly 3 times 
greater than in females (Szatmari et al., 1989).  There is acknowledgment, however, that males 
present with more disruptive symptoms and are referred for treatment earlier and more often than 
girls (Hinshaw, 2002), so clinic samples are not likely to represent an accurate reflection of the 
gender distribution of ADHD.
Genetic studies indicate that ADHD has high heritability rates (Faraone and Biederman, 1998; 
Tannock, 1998) with an autosomal rather than sex-linked inheritance pattern (Wallis et al., 2008; 
Thapar, 2002) supporting the gender-based prevalence ratios of 1:1 in the community which is 
consistent with the reported 1:1 male:female prevalence of ADHD in adults.  
Attention-deficit/hyperactivity disorder is characterized by symptoms of inattention, 
hyperactivity, and impulsivity that are “maladaptive and inconsistent with developmental level” 
(DSM-IV).   Preschool children, ages 3-5 years, often exhibit symptoms of hyperactivity and 
impulsivity, so it may be challenging to delineate what is “inconsistent with developmental 
level” for this population (Smith and Corkum, 2007).  Nevertheless, it is possible to diagnose 
ADHD in the preschool population in a reliable fashion (Egger et al., 2006a; Egger et al., 2006b;
McGoey et al., 2007).
The presence of ADHD symptoms that are frequent, severe, and developmentally inappropriate, 
can be used to define ADHD in this population (Connor, 2002; Smith and Corkum, 2007).  In 
addition, impairment in 2 or more settings establishes that the constellation of ADHD symptoms 
is maladaptive and not confined to a specific environment.  The severity of ADHD symptoms in 
a preschool child can be reliably measured using scales such as the PAPA and the ADHD-RS-IV 
Preschool Version that have been validated for this population and include age-appropriate 
questions and prompts (Egger et al., 2006a; McGoey et al., 2007).  
It is appropriate to consider whether an ADHD diagnosis in a preschool child will endure or 
resolve as the child matures.  ADHD has been described in terms of a developmental trajectory 
that can be modified by biologic or environmental factors (Sonuga-Barke and Halperin, 2010;
Sonuga-Barke et al., 2005).  Potential risk factors such as severity of ADHD symptoms, the 
presence of oppositional defiant symptoms, and neuropsychological impairment may affect the 
course of ADHD (Sonuga-Barke and Halperin, 2010).  Although some children may not retain 
the ADHD diagnosis as they grow older, for many children the diagnosis endures beyond their 
preschool years (Lahey et al., 2004; Tandon et al., 2011).  In a sample of 96 children aged 
4-6 years with ADHD, 79% of the children continued to have an ADHD diagnosis 3 years later 
as compared to 3% of the non-ADHD control children (Lahey et al., 2004).  
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This finding was replicated in a sample of 48 children aged 4-6 years with ADHD who were 
followed for 2 years (Tandon et al., 2011).  These results suggest that when an ADHD diagnosis 
is first made in a preschool child, it is likely to be stable over time. 
The constellation of impairments associated with an ADHD diagnosis in preschool children 
suggests a characteristic profile similar to that for individuals diagnosed after the preschool 
period.  Preschool children with ADHD demonstrate impairments in social functioning and 
pre-academic skills (DuPaul et al., 2001; Ghuman et al., 2008).  They are also more likely to be 
aggressive towards others and to sustain an injury (Greenhill et al., 2008; Rappley et al., 1999;
Connor et al., 2003).  In a longitudinal study which followed children from aged 4-21 years, the 
attention span at age 4 years predicted math and reading skills at age 21 years and completion of 
college at age 25 years (McClelland et al., 2013).
Currently, the lack of a robust body of evidence derived from controlled clinical studies in 
preschool children makes it difficult to create reliable treatment recommendations. The 
AAP ADHD Clinical Practice guideline suggests that preschool children with ADHD 
initiate treatment with behavioral therapy prior to using pharmacotherapy (Subcommittee on 
ADHD et al., 2011); however the PATS results indicates that 13% of preschool children have a 
satisfactory response to behavioral therapy (Greenhill et al., 2006). If the preschool child with 
ADHD does not respond to behavioral therapy, the guideline then suggests the use of 
methylphenidate. Of note, methylphenidate does not have an indication for a population less than 
6 years old (Subcommittee on ADHD et al., 2011). Immediate-release Adderall 
(dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and 
amphetamine sulfate) and dextroamphetamine are approved for children with ADHD as young as 
3 years old. As a result, if a preschool child does not respond to methylphenidate, a trial of an 
amphetamine product is recommended by the AAP. However, the lack of data for amphetamines
in preschool children with ADHD is acknowledged. Clearly, the implementation of additional 
studies in preschool children with ADHD would provide additional evidence in order to inform 
treatment decisions. 
1.2
Product Background and Clinical Information
The active pharmaceutical ingredient of SPD489 is (2S)-2, 6-diamino-N-[(1S)-1-methyl-
2-phenylethyl] hexanamide dimethanesulfonate.
Figure 1 shows the chemical structure of the active pharmaceutical ingredient: 
Figure 1:
Chemical Structure of the Active Pharmaceutical Ingredient
H
N
NH2
O
CH3
NH2
H3C S OH
O
O
2
·
Always refer to the latest version of the SPD489 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of SPD489. 
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1.2.1
Preclinical Information
Lisdexamfetamine is a pharmacologically inactive prodrug. After ingestion, it is converted in the 
blood to d-amphetamine (responsible for pharmacological activity) and l-lysine (a naturally 
occurring essential amino acid).  A comprehensive set of studies has been conducted to evaluate 
the pharmacological and toxicological properties associated with the parent compound 
lisdexamfetamine.  The safety profiles associated with d-amphetamine and l-lysine are well 
established.
All safety and toxicology studies, except the single dose acute toxicity study in rats, were 
conducted in compliance with Good Laboratory Practice.
Complete preclinical information is presented in the current SPD489 IB.
1.2.2
Clinical Information
The pharmacological profile of lisdexamfetamine and the pharmacologically active metabolite 
d-amphetamine have been well characterized in studies enrolling children, healthy adults, and 
adults with a history of stimulant abuse. These studies have demonstrated that oral administration 
of SPD489 resulted in a predictable d-amphetamine pharmacokinetic profile with low 
intra-subject and inter-subject variability. The d-amphetamine AUC0-∞ and Cmax generally 
behaved in a linear, dose-proportional manner. The weight-normalized d-amphetamine AUC0-∞ is 
similar for children and adults, with tmax and t½ consistent across age groups.
In the ADHD Clinical Development Program, the efficacy of SPD489 for the treatment of 
ADHD has been demonstrated for children, adolescents, and adults with ADHD. Substantial 
evidence of efficacy was provided in well-controlled studies, where SPD489 was shown to be 
effective compared to placebo. SPD489 was associated with a statistically significant, clinically 
meaningful improvement in ADHD symptoms, functional outcomes, and health-related quality 
of life compared to placebo, in studies that used a variety of study designs, a variety of validated 
assessments, and a variety of raters.
The well-characterized SPD489 safety profile was consistent with that of other stimulants used 
in the treatment of ADHD. When the safety results from the 35 completed Phase 2-4 clinical 
studies in the ADHD Clinical Development Program were examined, the majority of TEAEs 
were mild or moderate in severity, and no differences due to age or sex were noted. The most 
frequently reported AEs were those typically associated with stimulant therapy (including 
decreased appetite, insomnia, headache, dry mouth, irritability, upper abdominal pain, and 
weight decrease), or potentially attributable to intercurrent illnesses (eg, upper respiratory tract 
infection and nasopharyngitis). These TEAEs were generally non-serious and were considered 
by the investigator to have resolved during study participation.
Stimulant medications like SPD489 cause a modest increase in average blood pressure 
(approximately 2-4 mmHg) and average pulse (approximately 3-6 bpm). Individuals may have 
larger increases.
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Always refer to the latest version of the SPD489 IB for the overall risk/benefit assessment and 
the most accurate and current information regarding the drug metabolism, pharmacokinetics, 
efficacy and safety of SPD489.
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Based on IMS Health data and discussion at the FDA Pediatric Advisory Committee in 
September 2012, it has been noted that there is off-label use of SPD489 in children under 5 years 
old (4%, or approximately 100,000 patients between February 2007 and March 2012). The lack 
of controlled data regarding the safety and efficacy of SPD489 in the preschool ADHD 
population, along with the prevalence of off-label prescribing of SPD489 supports the need for 
SPD489 studies in the preschool ADHD population. Importantly, it is not known if the 
therapeutic effects of stimulant medications in school age children with ADHD can be 
extrapolated to preschool children with ADHD. There are some indications that the effect size 
may be reduced (Greenhill et al., 2006). There may also be differences in the safety and 
pharmacokinetic profiles (Wigal et al., 2007; Wigal et al., 2006).
However, recent data from Shire SPD489-211 study preschool aged children with ADHD 
suggests the safety and tolerability profile of SHP489 is similar to that observed in trials with 
children 6 to 12 years old, adolescents and adults. The efficacy results of the SPD489- 211 study, 
were also comparable to older subjects and revealed a mean decrease from baseline of -26.1 
(95% CI: -32.2, -20.0) in the ADHD-RS-IV Preschool Version total score, suggesting a robust 
similar improvement in ADHD symptoms. 
In summary given the abundance of information regarding the safety and efficacy of 
amphetamines; the very well-established PK profile of SPD489; the similar efficacy and safety 
findings between populations with ADHD covering the age span from 6 to 55 years; and the PK, 
safety, and efficacy data from Study SPD489-211 in preschoolers (aged 4-5 years) with ADHD, 
it is expected that findings from previous trials in older age groups can be extrapolated to 
preschool patients with ADHD.
Generating long-term safety data in this population will provide important information on the use 
of SPD489 in the preschool ADHD population.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to evaluate the long-term safety of SPD489 administered 
as a daily morning dose (5, 10, 15, 20, and 30 mg/day) in preschool children (4-5 years of age 
inclusive) diagnosed with ADHD.
The evaluation of safety and tolerability will be based on the occurrence of TEAEs, specific 
evaluation of blood pressure, pulse, weight, height, clinical laboratory evaluations and ECG 
results, and sleep assessments.
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3.2
Duration and Study Completion Definition
The duration of the evaluation phase (Dose Screening & Washout, Dose Optimization, Dose 
Maintenance, and Safety Follow-up) will be 57 weeks. The subject’s maximum duration of 
participation is expected to be approximately 399 days.  
The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment. Please note that this includes the follow-up visit or 
contact, whichever is later. The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
This study will be conducted in up to 60 sites in North America.
4
STUDY POPULATION
Each subject/parent or LAR must participate in the informed consent process and provide written 
informed consent and/or assent, as per IRB/EC requirements 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 criteria below 
(including test results):
1. Subject is male or female aged 4-5 years inclusive at the time of consent from antecedent 
studies SPD489-211 or SPD489-347 or at the time of consent if directly enrolled. 
2. Before completing any study-related procedures, subject’s parent(s) or LAR must provide 
signature of informed consent, and there must be documentation of assent (if applicable) by 
the subject indicating that the subject is aware of the investigational nature of the study. The 
subject’s parent(s) or LAR should understand that the required procedures and restrictions 
are being conducted in accordance with the International Council of Harmonisation (ICH) 
Good Clinical Practice (GCP) Guideline E6 (1996), any updates or revisions, and applicable 
federal or local regulations.
3. Subject and parent(s)/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 parent/LAR should be available at approximately 7:00AM (+2 hours) to dispense the 
dose of investigational product for the duration of the study.
4. Roll-over subject from antecedent SPD489-347 study:
a.
Subject completed the antecedent study (SPD489-347)
5. Direct enrolled subjects must meet antecedent study inclusion criteria, as listed below
a.
Subject must meet DSM-IV-TR criteria for a primary diagnosis of ADHD (any subtype) 
based on a detailed psychiatric evaluation conducted by a sponsor-approved clinician
b. Subject has an ADHD-RS-IV Preschool Version total score at the Baseline Visit (Visit 0) 
of 28 for boys and 24 for girls.  
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c.
Subject has a Clinical Global Impressions – Severity of Illness (CGI-S) score 4 at the 
Baseline Visit (Visit 0). 
d. Subject has a Peabody Picture Vocabulary Test, Fourth Edition standard score of 70 at 
the Screening Visit (Visit -1). 
e.
Subject has undergone an adequate course of non-pharmacological treatment based on 
investigator judgment OR the subject has a severe enough condition to consider 
enrollment without undergoing prior non-pharmacological treatment, based on 
investigator judgment.  
f.
Subject has, in the opinion of the investigator, participated in a structured group activity 
(eg, preschool, sports, Sunday school) so as to assess symptoms and impairment in a 
setting outside the home.
g. Subject has lived with the same parent(s) or guardian for 6 months.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1. Subject was terminated from an antecedent SPD489 study for non-compliance and/or 
experienced a serious adverse event (SAE) or AE resulting in termination.
2.
Subject is required to or anticipates the need to take medications that have central nervous 
system effects or affect performance, such as, but not limited to, sedating antihistamines and 
decongestant sympathomimetics, or monoamine oxidase inhibitors.  Stable use of 
bronchodilator inhalers is not exclusionary.
3.
Subject has a concurrent chronic or acute illness (such as, but not limited to, 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 Visit 0 
or a history of moderate or severe hypertension. 
7. Subject has a known history of symptomatic cardiovascular disease, unexplained syncope, 
exertional chest pain, advanced arteriosclerosis, structural cardiac abnormality, 
cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other serious 
cardiac problems placing them at increased vulnerability to the sympathomimetic effects of a 
stimulant drug.
8. Subject is taking any medication that is excluded per the protocol.
9. Subject had any clinically significant electrocardiogram (ECG) or clinical laboratory 
abnormalities at the Screening Visit (Visit -1).
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10. Subject has a history of hyperthyroidism, or current abnormal thyroid function, defined as 
abnormal thyroid stimulating hormone (TSH) and thyroxine (T4) at the Screening Visit 
(Visit -1) or Visit 0.  Treatment with a stable dose of thyroid medication for at least 3 months 
is permitted. 
11. Subject has taken another investigational product or has taken part in a clinical study within 
30 days prior to the Screening Visit (Visit -1).
12. Subject is well-controlled on his/her current ADHD medication with acceptable tolerability.
13. Subject has glaucoma.
14. Subject has failed to fully respond, based on investigator judgment, to an adequate course of 
amphetamine therapy.
15. Subject has a current, controlled (requiring medication or therapy) or uncontrolled, 
co-morbid psychiatric disorder including but not limited to any of the below co-morbid 
Axis I disorders and Axis II disorders:
a.
post-traumatic stress disorder (PTSD) or adjustment disorder
b. bipolar illness, psychosis, or family history of these disorders
c.
pervasive developmental disorder
d. obsessive-compulsive disorder (OCD) 
e.
psychosis/schizophrenia
f.
subject has a history of seizures (other than infantile febrile seizures) or a current 
diagnosis of Tourette’s disorder, or a chronic or current tic disorder that is judged by the 
investigator to be exclusionary 
g. 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 is currently demonstrating 
active suicidal ideation. Subjects with intermittent passive suicidal ideation are not 
necessarily excluded based on the assessment of the investigator 
h. a history of physical, sexual, or emotional abuse
i.
any other disorder or agitated state that in the opinion of the investigator, contraindicates 
SPD489 or lisdexamfetamine dimesylate treatment or confound efficacy or safety 
assessments.
16. Subject has initiated behavioral therapy within 1 month of the baseline visit (Visit 0).  
Subject may not initiate behavioral therapy during the study.
17. Subject has a height 5th percentile for age and sex at the screening visit (Visit -1).
18. Subject has a weight 5th percentile for age and sex at the screening visit (Visit -1).
19. Subject lives with anyone who currently abuses stimulants or cocaine.
20. Subject has a history of seizures (other than infantile febrile seizures).
4.3
Reproductive Potential
4.3.1
Female Contraception
Contraception is not applicable as no female subjects in this study are of child bearing potential. 
All female subjects in this study are pre-menarchal, less than age 9 years, and Tanner Stage 1.
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4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution. The investigator or sponsor may 
withdraw the subject at any time (eg, in the interest of subject safety). The investigator is 
encouraged to discuss withdrawal of a subject from investigational product with the medical 
monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for the 
Safety/Follow-up visit 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 source 
documents.  The reason for termination, date of stopping investigational product, and the total 
amount of investigational product taken must be recorded in the CRF and source documents.
4.4.1
Management of Blood Pressure and Pulse During the Study
Potential blood pressure and pulse increases must be further evaluated if they meet any of the 
criteria defined in Section 4.4.1.1 and Section 4.4.1.2. 
4.4.1.1
Systolic and Diastolic Blood Pressure
Blood pressure criteria for further evaluation have been developed based on the normative data 
presented in the National Institutes for Health Fourth Report on the Diagnosis, Evaluation, and 
Treatment of High Blood Pressure in Children and Adolescents (NIH, 2004). 
Increases in blood pressure (both systolic and diastolic) from the 50th to the 95th percentile 
(representative of a change of 2 standard deviations) range from 17-20 mmHg for both boys and 
girls in this age range.  Based on this range, an increase of >15mmHg from Visit 0 was selected 
for this protocol.
Prior to obtaining vital signs (blood pressure and pulse) the subject should be at rest for at least 
5 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 a dose reduction or potential 
discontinuation based upon the clinical judgment of the investigator and in conjunction with the 
medical monitor. If the dose has been previously decreased, or if the subject is already at the 
lowest dose, then the subject should be discontinued from the study. 
1. Elevations in the average (of 3 readings) sitting systolic blood pressure defined as an increase 
of >15 mmHg from the baseline visit (Visit 0) OR a value >95th percentile for age, sex, and 
height 
2. Elevations in average (of 3 readings) sitting diastolic blood pressure defined as an increase of 
>15 mmHg from the baseline visit (Visit 0) OR a value >95th percentile for age, sex, and 
height 
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4.4.1.2
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 (based on the average of 3 readings) 
and 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 
>126 bpm (based on the average of 3 readings) or if the subject is symptomatic then the subject’s 
investigator will discuss the findings with the medical monitor. A joint decision between the 
investigator and the medical monitor will be made regarding dose reduction and continued 
participation in the study. If the dose has been previously decreased, or if the subject is already at 
the lowest dose, then the subject will be discontinued from the study. If a visit cannot be 
scheduled the next day, the subject may be discontinued from the study. 
4.4.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the CRF.  If a subject is withdrawn for more than 1 reason, each reason 
should be documented in the source document and the most clinically relevant reason should be 
entered on the CRF.
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).  
4.4.3
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent(s) or LAR of any 
subject lost to follow-up at any time point prior to 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.
5
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy) received since the subject’s 
last visit in the antecedent study and through the final study contact (including protocol-defined 
follow-up period) must be recorded on the appropriate CRF page. 
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Table 2: Common Excluded Treatments and Associated Washout Period– Relative to 
Visit 0
Minimum Number of Days Before Visit 0
Treatment
7
14
30
Antihistamines (centrally and peripherally-active)
X
Herbal preparations (including melatonin)
X
Investigational compounds (other than the investigational 
compound received during participation in 1 of the respective 
antecedent SPD489 studies).
X
Sedatives, anxiolytics, antipsychotics a
X
Monoamine oxidase inhibitor (MAOIs) a
X
Antidepressants a
X
Clonidine and guanfacine
X
Selective noradrenaline reuptake inhibitors and noradrenaline 
reuptake inhibitors a
X
a These medications may signal that an exclusionary diagnosis is present. The medical monitor should be consulted prior to 
instructing a subject to discontinue one of these medications for this study.
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is SPD489, which will be provided in 5, 10, 15, 20, and 30 mg capsules. 
Additional information is provided in the current SPD489 IB.
6.1.1
Blinding the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product(s)
6.2.1
Interactive Response Technology (IRT) for Investigational Product 
Management
An IRT 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 IRT provider will provide a user manual and training to each site, with detailed instruction 
on the use of the IRT.
6.2.2
Allocation of Subjects to Treatment 
All subjects will receive open-label SPD489 during this study. 
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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 the 
antecedent study participation. 
6.2.3
Dosing
Dosing should begin at approximately 7:00AM (±2 hours) on the morning after Visit 0.  Subjects 
will be instructed to take 1 capsule 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. 
SPD489 will be administered one of the following ways: 

swallow SPD489 capsule whole, or

open capsule, empty and mix the entire contents with either yogurt, water, or orange juice. 
The contents should be mixed until completely dispersed. The subject must ingest the entire 
amount of mixture immediately within 3 minutes. The subject should not take anything less than 
one capsule per day and a single capsule cannot be split. The empty gelatinous capsule should be 
discarded. 
All subjects will begin dosing at 5 mg of SPD489 and should be titrated in a stepwise fashion 
until an optimal dose is reached.  
The objective of dose optimization during the first 6 weeks is to ensure that subjects are titrated 
to an optimal dose of study drug based on TEAEs and clinical criteria.
The investigator will categorize subject response into 1 of the 3 conditions, along with the 
associated actions, below.  Dose optimization should continue during the first 4 weeks until an 
“acceptable response” is achieved.

Intolerable response (ie, subject experiences intolerable side effects): This response 
suggests tapering the subject to a lower dose of investigational product (if available). 
However, 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-IV 
Preschool Version Total Score from Baseline (Visit 0) of the antecedent study and a CGI-I 
score of 1 or 2): This response suggests titrating the subject to the next available dose of 
investigational product (if available, provided there are no tolerability issues).

Acceptable response (ie, subject has achieved at least a 30% reduction in ADHD-RS-IV 
Preschool Version Total Score from Baseline (Visit 0) of the antecedent study 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.
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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 
product(s) 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 statements ‘For clinical trial use only’, and/or ‘CAUTION: New 
Drug - Limited by Federal (or US) 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. 
6.3.2
Packaging
Investigational product is packaged in the following labeled containers:
SPD489 capsules are packaged in 10-count and 35-count high density polyethylene bottles with 
child-resistant closures.  
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that 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.  
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Such a device (ie, certified min/max 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.
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 overall responsibility for administering/dispensing 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 his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to subjects included 
in this study following the procedures set out in the study protocol.  Each subject will be given 
only the investigational product carrying his/her treatment assignment.  All dispensed medication
will be documented on the CRFs and/or other investigational product record. The investigator is 
responsible for assuring the retrieval of all study supplies from subjects.  
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.
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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 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 prior to shipment from the site.  Validated electronic return systems (i.e., IRT) 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 prior to shipment.  Shipment of all returned investigational product must 
comply with local, state, and national laws.
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
All investigational product provided to pediatric subjects should be supervised by the 
parent(s)/legally-authorized representative/caregiver.
Subjects’ parent(s)/LAR must be instructed to bring their child’s 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/delegated person will record 
details on the drug accountability form. 
Subjects who have taken 80-100% of the investigational product are regarded as being compliant 
with the study protocol.  Compliance must be assessed by the investigator.
The calculation of medication compliance is as follows: 
Protocol
by
Prescribed
Capsules
100
Taken
Capsules
Total
Compliance


When performing the calculation of medication compliance for investigational product, the total 
capsules taken must also include number of capsules not returned by the subject to the site.
7
STUDY PROCEDURES
7.1
Study Schedule
The Schedule of Assessments (Table 1) details all procedures to be completed at each visit and 
should serve as the primary section of the protocol regarding visit-specific study procedures.
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Clinician-completed rating scales and assessments conducted by the site ie, ADHD-RS-IV 
Preschool Version, CGI-S, CGI-I, CSHQ and Columbia Suicide Rating Scale (C-SSRS)
Pediatric/Cognitively Impaired Version must be completed by the same rater whenever possible.
Throughout the Dose-Optimization Period of the study, visits should be scheduled as outlined 
(days), and throughout the Dose-Maintenance Period of the study, visits should be scheduled 
as outlined (5 days) with reference to Visit 0. The Follow-up Telephone Call should be 
scheduled 7 days post-last dose with a +3 day visit window.
Subjects will be required to visit the site up to 20 times over a 57-week period.
Additional unscheduled visits and/or assessments may occur as needed for safety 
(eg, unscheduled visits for blood pressure and/or pulse measurements will be conducted as 
described in Section 4.4.1) 
7.1.1
Screening and Washout Period
The principal investigator or his/her designee must obtain written informed consent from the 
subject’s parent(s)/LAR prior to any study-related procedures conducted during the Screening 
Visit (Visit -1). 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, prior to the performance of any study-related procedures.
A washout period may be required to discontinue any prohibited medication (see Table 2).  A 
subject cannot be instructed to wash out any medication for this study until after informed 
consent is obtained.
Screening assessments may take place across multiple days to allow enough time to complete all 
procedures and confirm initial study eligibility. Screening procedures and dates should be well 
documented in the source documents and CRF. The screening date is the date the parent(s)/LAR 
and/or subject has signed informed consent for this study. A screen failure is a subject who has 
given informed consent and failed to meet any of the inclusion and/or met at least 1 of the 
exclusion criteria and has not been administered investigational product.
For screen failure subjects, the investigator or assigned site staff designee will access the IWRS 
to record the subject as a screen failure. 
Subjects cannot be rescreened once they have been designated as a screen failure. Reassessment 
of subjects who failed specific inclusion/exclusion criteria is not allowed.
7.1.1.1
Screening Visit (Visit -1) 
Subjects will be screened at Visit -1 to establish eligibility for study participation. For roll-over 
subjects, the EOS visit in the antecedent SPD489-347 study will serve as the Screening visit for 
SPD489-348.
Some screening assessments (vital signs, height, weight, clinical laboratory tests, and ECGs) 
must be repeated prior to Baseline if more than 30 days have elapsed since collection.
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Table 1 details all procedures to be completed at the Screening Visit (Visit -1). Additional 
clarification on the procedures performed during the Screening Visit (Visit -1) is provided 
below:

All AEs occurring after signature of informed consent must be recorded in the source 
documents and CRF. Any AE ongoing at the time of the End of Study Visit from the 
antecedent study must be recorded on the CRF for this study. 

For roll-over subjects, document any new findings on the Medical History CRF with enough 
detail to permit detection of change over time.

Twelve-lead ECG will be performed after approximately 5 minutes of rest.  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.

After 5 minutes of rest, blood pressure and pulse will be collected 3 times (with 
approximately 2 minutes in between each collection) during the visit.  The average of each 
set of 3 measurements will be used to determine continued participation in the study (see 
Section 4.4.1).

The “Lifetime Recent” version of the C-SSRS will be administered at the Screening Visit 
(Visit -1) for direct-enrolled subjects.  The “Since Last Visit” version will be administered at 
the Screening Visit (Visit -1) for roll-over subjects.  Record historical/concomitant 
medications as follows:

All lifetime psychoactive medications and lifetime non-pharmacological interventions 
(behavioral therapy) for ADHD

Other medications used during the 30 days prior to the Screening Visit (Visit -1). 
7.1.1.2
Washout Telephone Call (Visit Phone Call) 
The Washout Period should be initiated after clinical laboratory test results and 12-lead ECG 
results have been received and reviewed by the investigator.  For roll-over subjects, the 
follow-up call for the antecedent SPD489-347 study will serve as the wash-out call for the 
SPD489-348 study.  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 a minimum of 5 times the half-life of the medication.  Washout periods for prohibited 
medications are defined in Table 2.
As part of the Washout Telephone Call, site personnel should perform the following procedures:

Schedule Visit 0

Review the inclusion/exclusion criteria
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
Ask about any concomitant medications that the subject is taking.  If any concomitant 
medications that require washout are noted, instructions for appropriate washout should be 
provided

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
Visit 0
The Baseline visit should be initiated after clinical laboratory test results and 12-lead ECG 
results have been received and reviewed by the investigator.  For subjects with more than 
30 days since the safety measurements at the Screening Visit (Visit -1) were collected, an 
abbreviated physical examination, clinical laboratory tests and 12-lead ECG must be repeated, 
and the results reviewed by the investigator prior to the subject being enrolled.
Inclusion/exclusion criteria must be reviewed during this visit to ensure subjects continue to 
meet all eligibility criteria.
Table 1 outlines all procedures to be conducted during Visit 0 with further clarification provided 
below:

After 5 minutes of rest, blood pressure and pulse will be collected 3 times (with 
approximately 2 minutes in between each collection) during the visit.  The average of each 
set of 3 measurements will be used to determine continued participation in the study (see 
Section 4.4.1). 

For eligible subjects, the investigator or assigned study center staff designee will access the 
IRT to enroll the subject and obtain an investigational medicinal product bottle number to 
dispense to the subject.  Subjects will be dispensed a 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 following Visit 0.

The C-SSRS “Since Last Visit” Version should be completed.
7.1.2
Treatment Period 
7.1.2.1
Dose-optimization Period (Visits 1 to 6) 
During the first 6 weeks of treatment, visits will be scheduled every 7 days (±3 days) to assess 
safety, efficacy, and tolerability and to allow investigators to titrate subjects to their optimal dose 
of SPD489 based on TEAEs and the dosing guidelines in Section 6.2.3. 
If the optimal dose is well tolerated and, in the opinion of the investigator, the subject would 
potentially receive additional symptom reduction, the subject may be titrated to the next allowed 
dose.
Throughout the Dose-optimization Period, subjects may attend the clinic for unscheduled visits 
to address any medical needs that arise between scheduled visits.
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See Table 1 for procedures that are completed at Visits 1 to 6.  Further clarification for these 
visits is outlined below:

At each visit during the Dose-optimization Period, subjects must return any empty or unused 
bottles to permit drug accountability and compliance to be assessed.

Subjects will be dispensed a 10-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 following each visit.

After 5 minutes of rest, blood pressure and pulse will be collected 3 times (with 
approximately 2 minutes in between each collection) during the visit.  The average of each 
set of 3 measurements will be used to determine continued participation in the study (see 
Section 4.4.1).

Scales should be completed by the same rater whenever possible.

The sleep diary is to be completed by the same parent/LAR, whenever possible.

The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired Version 
should be completed during the Optimization Period.
7.1.2.2
Dose Maintenance Period (Visits 7 to 18/ET) 
Following titration to an optimal dose of SPD489, subjects will continue daily morning treatment 
for an additional 48 weeks. Subjects will attend the clinic every 4 weeks for procedures to be 
performed. 
Throughout the Maintenance Period, subjects may attend the clinic for unscheduled visits to 
address any medical needs that arise between scheduled visits.
Table 1 outlines the procedures to be completed at each visit during the Maintenance Period.  
Additional clarification on the procedures to be performed during the Maintenance Period is 
provided below:

Scales are to be completed by the same rater whenever possible

At each visit during the Maintenance Period, subjects must return any empty or unused 
bottles to permit drug accountability and compliance to be assessed.

Subjects will be dispensed a 35-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 following each visit

After 5 minutes of rest, blood pressure and pulse will be collected 3 times (with 
approximately 2 minutes in between each collection) during the visit.  The average of each 
set of 3 measurements will be used to determine continued participation in the study (see 
Section 4.4.1).
7.1.2.3
End-of-Study Visit (Visit 18/Early Termination) 
All subjects who complete the study or discontinue early will complete the End-of-Study Visit.
Table 1 lists the procedures to be completed at Visit 18/ET and should serve as the primary point 
of reference regarding visit-specific study procedures.
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Further clarification on the procedures performed during the End-of-Study Visit is provided 
below:
Unused investigational product and empty containers will be collected to calculate medication
compliance.
Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in between 
each collection) during the visit.  The average of each set of 3 measurements will be used to 
determine if additional follow-up is needed (see Section 4.4.1).
7.1.3
Safety Follow-up Period 
The follow-up period for this protocol is 7 days +3 days from the last dose of investigational 
product.
At the end of this period there will be a telephone call initiated by the site to query for any SAE 
follow-up SAEs, AEs, and concomitant treatments.  All AEs and SAEs that are not resolved at 
the time of this contact will be followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects After the Study
There is no planned care for subjects after 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 below.  
Assessments are to be performed according to the schedule shown in Table 1.
Care must be taken by the site personnel or the investigator to fully explain the scale prior to 
completion.
If the subject terminates treatment early, all assessments listed in Table 1 for Visit 13/ET or 
Visit 18/ET and the Follow-up Telephone 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.
7.2.2
Screening Assessments
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7.2.2.1
Kiddie – Schedule for Affective Disorders and Schizophrenia for 
School-age Children – Present and Lifetime Version-Diagnostic Interview
The sponsor-approved clinician at the site who is trained and experienced in the evaluation of 
4- to 5-year-old children with ADHD, will determine a diagnosis of ADHD based on a 
psychiatric interview and mental status examination utilizing the K-SADS-PL using the 
DSM-IV-TR criteria for ADHD.
The K-SADS-PL is a semistructured diagnostic interview designed to assess current and past 
episodes of psychopathology in children and adolescents according to Diagnostic and Statistical 
Manual of Mental Disorders, Third Edition-Revised and DSM-IV-TR criteria. Probes and 
objective criteria are provided to rate individual symptoms. The primary diagnoses assessed with 
the K-SADS-PL include, but are not limited to: major depression, dysthymia, mania, bipolar 
disorders, schizoaffective disorders, panic disorder, agoraphobia, separation anxiety disorder, 
avoidant disorder of childhood and adolescence, simple phobia, social phobia, overanxious 
disorder, generalized anxiety, obsessive compulsive disorder, ADHD, conduct disorder, and 
oppositional defiant disorder.
The K-SADS-PL is administered by interviewing the parent(s)/LAR(s), the subject, and finally 
achieving summary ratings, which include all sources of information (parent/LAR, child, school, 
chart, and other). 
The K-SADS-PL will be administered by an individual experienced with the scale and qualified 
to establish a diagnosis. The site should maintain documentation of the K-SADS-PL training in 
the site’s files. All individuals performing this assessment must be pre-approved by the sponsor 
or delegated vendor. Based on the above criteria, suitable K-SADS-PL administrators may 
include physicians, nurse practitioners, or licensed psychologists.
7.2.2.2
Peabody Picture Vocabulary Test-Fourth Edition
The Peabody Picture Vocabulary Test measures an individual’s receptive (hearing) vocabulary 
for Standard American English and provides a quick estimate of verbal ability or scholastic 
aptitude (Dunn and Dunn, 1997). For purposes of this study, the Peabody Picture Vocabulary 
Test, Fourth Edition, will be used as a proxy for general cognitive ability. 
The Peabody Picture Vocabulary Test should be administered by site personnel with training and 
experience in general psychological testing. All individuals performing this assessment must be 
pre-approved by the sponsor or delegated vendor.
7.2.3
Efficacy
7.2.3.1
Attention-deficit/Hyperactivity Disorder Rating Scale – IV Preschool 
Version
The ADHD-RS-IV Preschool Version (McGoey et al., 2007), the secondary efficacy measure, is 
completed by the Sponsor approved clinician at the site and will be administered at Visit 1 and 
each subsequent visit up to and including the End of Study Visit  to capture the ADHD 
symptoms within each study period.  The ADHD-RS-IV Preschool Version was adapted from 
the ADHD Rating Scale-IV (DuPaul et al., 1998) and provides examples appropriate for the 
developmental level of preschool children.  
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The ADHD-RS-IV Preschool Version is an 18-item questionnaire that requires the respondent to 
rate the frequency of occurrence of ADHD symptoms as defined by DSM-IV-TR criteria.  Each 
item is scored on a 4-point scale ranging from 0 (never or rarely) to 3 (very often) with total 
scores ranging from 0-54.  The 18 items may be grouped into 2 subscales: 
hyperactivity/impulsivity (even numbered items 2-18) and inattentiveness (odd numbered 
items 1-17).
The ADHD-RS-IV Preschool Version will be completed by a clinician trained and experienced 
in the evaluation of preschool children with ADHD.  Since the ADHD-RS-IV Preschool Version 
is used to guide dosing decisions, if it is not completed by the principal investigator or 
subinvestigator who is medically/clinically responsible for the subject, it must be reviewed and 
signed by them. All individuals performing this assessment must be pre-approved by the Sponsor 
or delegated vendor.
The title, version, and date of the ADHD-RS-IV Preschool Version used in this study are 
included in Table 1.
7.2.3.2
Clinical Global Impressions
The CGI Scale (Guy, 1976) permits a global evaluation of the subject’s severity and 
improvement over time.  CGI has been used extensively in clinical studies of ADHD (Michelson 
et al., 2001; Weiss et al., 2005; Wilens et al., 2001).
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 Visit 0 
of the antecedent study or at Visit 0 of this study for directly enrolled subjects.  The investigator 
should establish 3 target areas of improvement with the subjects and the subject’s parent(s)/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.
At each visit from Visit 1 up to and including Visit 18/ET the investigator will assess the 
subject’s improvement relative to the 3 target areas of improvement recorded at Visit 0 of the 
antecedent study or Visit 0 of this study for directly enrolled subjects, on the CGI-I, a 7-point 
scale ranging from 1 (very much improved) to 7 (very much worse).
The CGI-S and the CGI-I should be completed by a clinician trained and experienced in the 
evaluation of preschool children with ADHD.  Since the CGI-I is used to guide dosing decisions, 
if it is not completed by the principal investigator or sub investigator who is medically/clinically 
responsible for the subject, it must be reviewed and signed by them. All individuals performing 
this assessment must be pre-approved by the Sponsor or delegated vendor.
The title, version, and date of the CGI-S and CGI-I used in this study are included in Table 1.
7.2.4
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.
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7.2.4.1
Medical and Medication History
Any new medical history, ie, medical conditions, which arose after the recording of the medical 
history in the antecedent study should be recorded at Visit 0 for roll-over subjects.
7.2.4.2
Physical Examination (Including Height and Weight)
A full physical examination will be performed at the Screening Visit (Visit -1).  Additionally, an 
abbreviated physical examination is required prior to Visit 0 if more than 30 days have elapsed 
since the physical examination was completed as part of the Screening Visit (Visit -1) was 
performed.
A physical examination will be performed by a qualified, licensed individual (eg, physician, 
physician assistant or a 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)

Musculoskeletal

Neurological.
If an abbreviated physical examination is required prior to Visit 0, a review of the body systems 
will include the following:

General Appearance

Respiratory

Cardiovascular.
Abnormalities identified at the Screening Visit (Visit -1) will be documented as AEs.  Changes 
after the Screening Visit (Visit -1) will be captured as AEs on the AE CRF page, as deemed by 
the investigator.
7.2.4.3
Adverse Event Collection
At each study visit, subjects 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. Any AE ongoing from 
the antecedent study must be entered. Any AE ongoing from the antecedent study must be 
recorded on the CRF for this study. (Please refer to Section 8, Adverse and Serious Adverse 
Events Assessment.)
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7.2.4.4
Vital Signs
Measurements of oral or tympanic temperature and sitting respiratory rate will be performed at 
the Screening Visit (Visit -1). 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 5 minutes.
Blood pressure will be determined by manual 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 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 a manual cuff and should be 
performed by the same study center personnel (if possible) throughout the study.  Three 
measurements should be obtained using the manual cuff while sitting and the subject has been at 
rest for a minimum of 5 minutes, with approximately 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 and CRF.
Any clinically significant deviations from Baseline (Visit 0) vital signs which are deemed 
clinically significant in the opinion of the investigator are to be recorded as an AE.
7.2.4.5
Height and Weight
Height will be captured at each 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.
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.
7.2.4.6
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 assessments will be performed at the Screening Visit (Visit -1), Visit 9, 
Visit 16, and Visit 18/ET.  Additionally, clinical laboratory tests are required to be repeated prior 
to Visit 0 with results reviewed before enrolling the subject in the study if more than 30 days 
have elapsed since the clinical laboratory assessments completed as part of the Screening Visit 
(Visit -1) were performed.
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Subjects will have the option for laboratory assessments to be collected by a home health care 
nurse, managed by United Biosource, LLC (UBC) at their residence. 
The following clinical laboratory assessments will be performed: 
Biochemistry and Endocrinology
A blood sample (~5mL) for biochemistry will be taken to assess the following parameters:
Total Cholesterol
Calcium
AST
Uric Acid
Phosphorus
Blood Urea Nitrogen
ALT
Total Bilirubin
Sodium
Creatinine
ALP
Glucose
Potassium
Albumin
GGT
Total Protein
TSH
Lactate Dehydrogenase
Free T4
Hematology
A blood sample (~4mL) for hematology will be taken to assess the following parameters:
Hemoglobin
Neutrophils
Hematocrit
Lymphocytes
RBC
Monocytes
Platelet count
Eosinophils
WBC count – total and differential 
Basophils
MCH
Bands
MCHC
MCV
Urinalysis
A urine sample (~10mL) for urinalysis will be collected to assess the following parameters:
Glucose
pH
Specific Gravity
Urobilinogen
Blood
Color
Ketones
Leukocyte Esterase
Protein
Nitrate
Bilirubin
If urinalysis detects protein and/or blood, a microscopic examination will be conducted.  The 
microscopic examination will consist of RBC, WBC, casts, and bacteria.
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7.2.4.7
Electrocardiogram
A 12-lead ECG will be performed at the Screening Visit (Visit -1), Visit 0, Visit 1-6, and Visit 8, 
Visit 11, Visit 14, Visit 17, and Visit 18/ET. Additionally, a 12-lead ECG is required to be 
repeated prior to Visit 0 with results reviewed before enrolling the subject in the study if more 
than 30 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.
The mean interval values of the 3 ECGs is used to establish the subject’s baseline intervals. All 
ECGs will be performed after 5 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 by the investigator.  The ECG tracing will then be 
evaluated by a cardiologist at the central ECG reading vendor (Cardiocore) for analysis and 
returned to the site with a determination of normal or abnormal.  Upon review of the report from 
Cardiocore, the investigator will reevaluate 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 must be transmitted to the central ECG reader and all ECGs 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 CRF 
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.
7.2.4.8
Children’s Sleep Habits Questionnaire and Sleep Diary 
The CSHQ is 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 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 completed at every visit to the site and will be completed by the 
subject’s parent/LAR. 
The subject’s parent/LAR will complete a sleep diary to log daytime napping, bedtime and wake 
time.
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7.2.4.9
Columbia-Suicide Severity Rating Scale- Pediatric/Cognitively Impaired 
Version
The C-SSRS (Posner, 2007) 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 2 required items pertaining to suicidal ideation, 4 required items pertaining 
to suicidal behavior, and 1 required item pertaining to non-suicidal self-injurious behavior.  
There are 8 additional suicidal ideation items and 2 additional suicidal behavior items which are 
completed in cases of positive responses for other items, as well as 2 items for completed suicide 
and suicide behavior present during the interview.  Thus, there is a maximum of 19 items to be 
completed.
The C-SSRS must be performed by an individual who is trained and certified and is preapproved 
by the sponsor or delegated vendor and the site investigator. 
The Pediatric/Cognitively Impaired Version of the scale will be used in the study. There are two 
versions of the C-SSRS. 
If the subject participated in an antecedent study:

The “Since Last Visit” version will be completed for all subjects at each visit in this study.
If the subject is directly enrolled in this study and did not participate in an antecedent study:

The “Lifetime recent” version will be administered at the Screening Visit (Visit -1).

The “Since Last Visit” version will be completed for all study visits after the Screening Visit 
(Visit -1).
The title, version, and date of the C-SSRS “Lifetime recent” version and the C-SSRS “Since Last 
Visit” version used in this study are included in Table 1.
7.2.4.10
Suitability of the Subject to Remain in the Study
At each visit (except for Visit 18/ET) starting with Visit 1, the investigator will assess the 
subject’s ability to continue in the study.  As part of the assessment of the subject’s suitability to 
remain in the study the investigator should assess the subject’s current potential for suicide, 
suicidal ideation, self-harm, or harm to others, 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.  The 
investigator should also ensure that there is appropriate documentation of this assessment in the 
subject’s source notes.  As part of this assessment, if appropriate, the investigator should discuss 
risk factors for suicide with the subject.  Where a subject has suffered an accidental injury, the 
investigator should ensure that this was a true accidental injury, rather than an episode of 
self-harming or a suicide attempt.
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The subject’s source notes should clearly document that the assessment of continued suitability 
including an assessment of the subject’s current potential risk of suicide, suicidal ideation, 
feelings of hopelessness, drug use, self-harm, or harm to others has taken place and should 
contain the decision on whether the subject is suitable to continue in the study.
Any subject who has 1 or more positive responses must undergo further evaluation to ensure that 
they are not in any way at risk.  The evaluation and decision should also be clearly documented 
in the subject’s source notes.
7.2.5
Volume of Blood to be Drawn From Each Subject
Table 3: Volume of Blood to be Drawn From Each Subject
Assessment
Sample Volume 
(mL)
Number of Samples 
Total Volume (mL) 
Safetya
Biochemistry 
5
5
25
Hematology
4
5
20
Total mL
45
aBiochemistry and hematology clinical laboratory tests will be performed prior to Baseline if 30 days or longer have 
elapsed since the Screening visit.
During this study, it is expected that approximately 45mL of blood will be drawn from each 
subject. Subjects will have the option for blood draws to be collected by a qualified home health 
care professional at their home. Routine laboratory home draws have a + 1 day window from the 
study visit date, with the exception of the last visit/early termination draw which has a -1 day 
window.
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 45mL.  When more than 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.  
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.  
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Where possible, a diagnosis rather than a list of symptoms should be recorded.  If a diagnosis has 
not been made, then each symptom should be listed individually.  All AEs should be captured on 
the appropriate AE pages in the CRF and in source documents.  In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on the 
AE CRF.
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 pre-treatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
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 CRF).
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.
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 document.
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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 CRF.  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
Clinical laboratory assessments, vital sign, and ECG assessments are performed at the Screening 
Visit (Visit 1) and Visit 8/ET. The Investigator is required to review these assessments prior to 
determining subject eligibility.  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 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 which were not present at the pre-treatment 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.
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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
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the sponsor 
according to the SAE reporting procedure whether or not they result in an AE/SAE as 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 categories below are not mutually exclusive; the event can meet more than 1 category.

Abuse – Persistent or sporadic intentional intake of investigational product when used for a 
non-medical 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 pre-specified total daily dose of 30 mg 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 below.
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 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/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the IB 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 
Pharmacovigilance Department (GlobalPharmacovigilance@shire.com) and the CRO/Shire 
medical monitor within 24 hours of the first awareness of the event.  
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Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors (see Section 8.1.6) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
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 
e-mail the form to the Shire Pharmacovigilance Department. A copy of the Shire Clinical Trial 
Serious Adverse Event 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 Pharmacovigilance Department and the CRO/Shire medical monitor within 24 hours 
of the first awareness of the event. 
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 
Pharmacovigilance Department within 24 hours of the first awareness of the event.
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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 
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, the 
action taken with the investigational product should be recorded as “dose not changed” or “not 
applicable” (if the subject never received investigational product).
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the 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 SPD489 program.  
The investigator is responsible for notifying the local IRB/EC/REB, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
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 CRF.  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 CRF entry within approximately 3 business days of the subject’s 
visit.
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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 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 prior to database lock.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis or adaptive design for this study.
A 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 
patients in the study and of those still to be entered. Data will be provided to the DMC by an 
independent statistical and reporting group not assigned to the study. The data provided to the 
DMC will not be considered ‘clean’ until the database is locked.
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product.  
9.6
Sample Size Calculation and Power Considerations
Approximately 100 subjects will be enrolled into this study to ensure that at least 50 subjects are 
exposed to SPD489 for one year and complete the study. 
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Subjects will enroll into this study from antecedent study SPD489-211 or SPD489-347 or 
directly enroll into this study without participating in either antecedent study. 
The sample size for this study is not based on statistical considerations. 
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Enrolled Set will consist of all subjects who have been dispensed SPD489 at the Baseline 
Visit (Visit 0). Screen failures will not be considered enrolled subjects and will not be included 
in the Enrolled Set.
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of 
investigational product. 
The FAS will consist of all subjects in the Safety Set who have at least 1 post-dose ADHD-RS-
IV Preschool Version Total Score assessment during the study.
9.8
Efficacy Analyses
The FAS will be used to summarize the efficacy data. 
9.8.1
Clinician-administered ADHD-RS-IV Preschool Version 
The efficacy endpoint for the ADHD-RS-IV Preschool Version is defined as the change from 
baseline on the clinician-administered ADHD-RS-IV Preschool Version Total Score. Where 
subjects that rolled over from an antecedent study, baseline is defined as the baseline from the 
antecedent study, and for subjects that directly enrolled into SPD489-348, baseline is defined as 
baseline of the SPD489-348 study. 
The observed and change from baseline ADHD-RS-IV Preschool Version Total Score will be 
summarized at each  visit as well as the last on-treatment visit using descriptive summary 
statistics of number of subjects, mean, standard deviation, median, minimum, and maximum 
values by treatment group of the antecedent studies, directly enrolled group and overall.
9.8.2
Clinical Global Impressions 
The efficacy endpoint for the CGI-I will be analyzed by a method similar to that used for the 
ADHD-RS-IV total scores. In addition, CGI-I, will also be analyzed using the proportion of 
subjects with an “improved” CGI-I measurement at the last on-treatment visit. The CGI-I 
categories of “very much improved” and “much improved” will be classified as “improved” and 
all other assessed categories will be grouped together as “not improved”.  
Descriptive summary statistics will be presented by treatment group of the antecedent studies, 
directly enrolled group and overall for the CGI-I scores at each visit as well as the last 
on-treatment assessment. 
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The change from baseline and observed dichotomized CGI-I values will be summarized at each 
visit as well as the last on-treatment visit using number of subjects and percentages.
9.8.3
Exploratory Efficacy Endpoints
Not applicable.
9.9
Safety Analyses
The Safety Analysis Set will be used to report the safety data. 
Safety analyses will be presented by treatment group of the antecedent studies, directly enrolled 
and overall for the occurrence of TEAEs, clinical laboratory results, vital signs, ECG results, and 
sleep assessments including sleep diary data and CSHQ. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  The 
number of events, incidence, and percentage of TEAEs will be calculated overall, by system 
organ class and, by preferred term.  Treatment-emergent adverse events 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 and overall. 
Potentially clinically important findings will also be summarized and listed.
The CSHQ will be summarized using appropriate descriptive statistics at each visit. 
The C-SSRS data will be listed for all subjects with any positive response. 
9.10
Other Analyses
No other analyses are planned in this study.
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH and any updates 
or revisions, 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), any updates or revisions, as well 
as all applicable national and local laws and regulations.
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Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
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 non-pediatric 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 
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), any updates or revisions, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
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The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification.  Curriculum vitae for investigators and 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 parent(s)/LAR consent, inform them 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), in compliance with Directive 2001/83/EC as amended by 
Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any subinvestigators 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.
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 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.
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The clinical research associate CRA/study monitor will verify the contents against the source 
data per the monitoring plan.  If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
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, subject sleep diary cards and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, 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 CRA/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 etc).  
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 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 
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; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
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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 and their parent(s)/LAR prior to any study-related procedures including screening 
assessments.  All consent and assent documentation must be in accordance with applicable 
regulations and GCP.  Each subject, parent(s), or the subject’s legally-authorized representative, 
as applicable, is requested to sign and date the subject informed consent form or a certified 
translation if applicable, after the subject, parent(s), or LAR 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, as 
applicable (ie, a complete set of subject information sheets and fully executed signature pages) 
must be given to the subject, parent(s) or the subject’s legally-authorized representative, as 
applicable.  This document may require translation into the local language.  Signed consent 
forms must remain in each subject’s study file and must be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent(s)/legally-authorized representative/caregiver 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, 
as applicable which was reviewed by the IRB/EC and which received their favorable 
opinion/approval.  A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action.  Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
It is the responsibility of the investigator to submit this protocol, the informed consent document 
(approved by the sponsor or their designee), relevant supporting information and all types of 
subject recruitment information to the IRB/EC for review, and all must be approved prior to site 
initiation.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
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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 apprised of the progress of the study and 
of any changes made to the protocol, but in any case at least once a year. The investigator must 
also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All sites and laboratories or entities providing support for this study, must, where applicable, 
comply with HIPAA of 1996 and any other local privacy requirements.  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 SPD489; 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).
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 2-4 and certain other studies as determined by Shire.  
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The purpose of the publication steering committee is to act as a non-commercial body that 
advises or decides on dissemination of scientific study data in accordance with the scope of this 
policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.  The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications.  To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results.  Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication.  If requested in writing by 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, or termination of the study at all sites, or after the sponsor confirms there shall be 
no multicenter study publication of the study results, an investigator may individually publish the 
study results from the specific site in accordance with this section.  The investigator must, 
however, acknowledge in the publication the limitations of the single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in which 
it is made, authorship will comply with the ICMJE current standards.  Participation as an 
investigator does not confer any rights to authorship of publications.
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11
REFERENCES
Centers for Disease Control and Prevention 2010. Increasing prevalence of parent-reported 
attention-deficit/hyperactivity disorder among children --- United States, 2003 and 2007. 
MMWR Morb Mortal Wkly Rep, 59, 1439-43.
Connor, D. F. 2002. Preschool attention deficit hyperactivity disorder: a review of prevalence, 
diagnosis, neurobiology, and stimulant treatment. J Dev Behav Pediatr, 23, S1-9.
Connor, D. F., Edwards, G., Fletcher, K. E., Baird, J., Barkley, R. A. & Steingard, R. J. 2003. 
Correlates of comorbid psychopathology in children with ADHD. J Am Acad Child 
Adolesc Psychiatry, 42, 193-200.
Dunn, L. M. & Dunn, L. M. 1997. Peabody Picture Vocabulary Test, third edition. J Psychoeduc 
Assess, 16, 334-8.
DuPaul, G., Power, T., Anastopoulos, A. & Reed, R. 1998. The ADHD rating scale IV: 
checklists, norms and clinical interpretation, New York, Guilford Press.
DuPaul, G. J., McGoey, K. E., Eckert, T. L. & VanBrakle, J. 2001. Preschool children with 
attention-deficit/hyperactivity disorder: impairments in behavioral, social, and school 
functioning. J Am Acad Child Adolesc Psychiatry, 40, 508-15.
Egger, H. L. & Angold, A. 2004. The preschool age psychiatric assessment (PAPA): a structured 
parent interview for diagnosing psychiatric disorders in preschool children. In:
DelCarmen-Wiggins, R. & Carter, A. (eds.) Handbook of infant, toddler, and preschool 
mental assessment. New York: Oxford University Press.
Egger, H. L., Erkanli, A., Keeler, G., Potts, E., Walter, B. K. & Angold, A. 2006a. Test-Retest 
Reliability of the Preschool Age Psychiatric Assessment (PAPA). J Am Acad Child 
Adolesc Psychiatry, 45, 538-49.
Egger, H. L., Kondo, D. & Angold, A. 2006b. The epidemiology and diagnostic issues in 
preschool attention-deficit/hyperactivity disorder: a review. Infants Young Child, 19, 109-
22.
Faraone, S. V. & Biederman, J. 1998. Neurobiology of attention-deficit hyperactivity disorder. 
Biol Psychiatry, 44, 951-8.
Ghuman, J. K., Arnold, L. E. & Anthony, B. J. 2008. Psychopharmacological and other 
treatments in preschool children with attention-deficit/hyperactivity disorder: current 
evidence and practice. J Child Adolesc Psychopharmacol, 18, 413-47.
Greenhill, L., Kollins, S., Abikoff, H., McCracken, J., Riddle, M., Swanson, J., McGough, J., 
Wigal, S., Wigal, T., Vitiello, B., Skrobala, A., Posner, K., Ghuman, J., Cunningham, C., 
Davies, M., Chuang, S. & Cooper, T. 2006. Efficacy and safety of immediate-release 
methylphenidate treatment for preschoolers with ADHD. J Am Acad Child Adolesc 
Psychiatry, 45, 1284-93.
Greenhill, L. L., Posner, K., Vaughan, B. S. & Kratochvil, C. J. 2008. Attention deficit 
hyperactivity disorder in preschool children. Child Adolesc Psychiatr Clin N Am, 17,
347-66, ix.
Guy, W. (ed.) 1976. Clinical Global Impression (CGI), Rockville, MD: US Department of 
Health, Education, and Welfare.
Hardman, J. G., Limbird, L. E. & Gilman, A. G. 2001. Goodman & Gillman’s The 
Pharmacological Basis of Therapeutics, 10th Edition, New York, NY, McGraw-Hill.
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Hinshaw, S. P. 2002. Preadolescent girls with attention-deficit/hyperactivity disorder: I. 
Background characteristics, comorbidity, cognitive and social functioning, and parenting 
practices. J Consult Clin Psychol, 70, 1086-98.
Lahey, B. B., Pelham, W. E., Loney, J., Kipp, H., Ehrhardt, A., Lee, S. S., Willcutt, E. G., 
Hartung, C. M., Chronis, A. & Massetti, G. 2004. Three-year predictive validity of DSM-
IV attention deficit hyperactivity disorder in children diagnosed at 4-6 years of age. Am J 
Psychiatry, 161, 2014-20.
McClelland, M. M., Acock, A. C., Piccinin, A., Rhea, S. A. & Stallings, M. C. 2013. Relations 
between Preschool Attention Span-Persistence and Age 25 Educational Outcomes. Early 
Child Res Q, 28, 314-324.
McGoey, K. E., DuPaul, G. J., Haley, E. & Shelton, T. L. 2007. Parent and teacher ratings of 
attention-deficit/hyperactivity disorder in preschool: the ADHD rating scale-IV preschool 
version. J Psychopathol Behav Assess, 29, 269-76.
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.
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.
Rappley, M. D., Mullan, P. B., Alvarez, F. J., Eneli, I. U., Wang, J. & Gardiner, J. C. 1999. 
Diagnosis of attention-deficit/hyperactivity disorder and use of psychotropic medication 
in very young children. Arch Pediatr Adolesc Med, 153, 1039-45.
Smith, K. G. & Corkum, P. 2007. Systematic review of measures used to diagnose attention-
deficit/hyperactivity disorder in research on preschool children. TEC, 27, 164-73.
Sonuga-Barke, E. J., Auerbach, J., Campbell, S. B., Daley, D. & Thompson, M. 2005. Varieties 
of preschool hyperactivity: multiple pathways from risk to disorder. Dev Sci, 8, 141-50.
Sonuga-Barke, E. J. & Halperin, J. M. 2010. Developmental phenotypes and causal pathways in 
attention deficit/hyperactivity disorder: potential targets for early intervention? J Child 
Psychol Psychiatry, 51, 368-89.
Subcommittee on ADHD, Management., S. C. o. Q. I. a., Wolraich, M., Brown, L., Brown, R. 
T., DuPaul, G., Earls, M., Feldman, H. M., Ganiats, T. G., Kaplanek, B., Meyer, B., 
Perrin, J., Pierce, K., Reiff, M., Stein, M. T. & Visser, S. 2011. ADHD: clinical practice 
guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity 
disorder in children and adolescents. Pediatrics, 128, 1007-22.
Szatmari, P., Offord, D. R. & Boyle, M. H. 1989. Ontario Child Health Study: prevalence of 
attention deficit disorder with hyperactivity. J Child Psychol Psychiatry, 30, 219-30.
Tandon, M., Si, X. & Luby, J. 2011. Preschool onset attention-deficit/hyperactivity disorder: 
course and predictors of stability over 24 months. J Child Adolesc Psychopharmacol, 21,
321-30.
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Tannock, R. 1998. Attention deficit hyperactivity disorder: advances in cognitive, 
neurobiological, and genetic research. J Child Psychol Psychiatry, 39, 65-99.
Thapar, A. 2002. Attention deficit hyperactivity disorder: new genetic findings, new directions, 
Washington, DC, US, American Psychological Association.
Wallis, D., Russell, H. F. & Muenke, M. 2008. Review: Genetics of attention 
deficit/hyperactivity disorder. J Pediatr Psychol, 33, 1085-99.
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.
Wigal, S. B., Gupta, S., Greenhill, L., Posner, K., Lerner, M., Steinhoff, K., Wigal, T., 
Kapelinski, A., Martinez, J., Modi, N. B., Stehli, A. & Swanson, J. 2007. 
Pharmacokinetics of methylphenidate in preschoolers with attention-deficit/hyperactivity 
disorder. J Child Adolesc Psychopharmacol, 17, 153-64.
Wigal, T., Greenhill, L., Chuang, S., McGough, J., Vitiello, B., Skrobala, A., Swanson, J., Wigal, 
S., Abikoff, H., Kollins, S., McCracken, J., Riddle, M., Posner, K., Ghuman, J., Davies, 
M., Thorp, B. & Stehli, A. 2006. Safety and tolerability of methylphenidate in preschool 
children with ADHD. J Am Acad Child Adolesc Psychiatry, 45, 1294-303.
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-IV-TR CRITERIA FOR ATTENTION-
DEFICIT/HYPERACTIVITY DISORDER
A. Either (1) or (2):
(1)
six (or more) of the following symptoms of inattention have persisted for at 
least 
6 months to a degree that is 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. 
Some hyperactive-impulsive or inattentive symptoms that caused impairment were 
present before age 7 years.
C. 
Some impairment from the symptoms is present in 2 or more settings (eg, at school 
[or work] and at home).
D. 
There must be 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, fourth Edition. Copyright 1994 
American Psychiatric Association
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APPENDIX 2.4
BOYS’ STATURE-FOR-AGE AND WEIGHT-FOR-AGE 
PERCENTILES
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APPENDIX 2.5
GIRLS’ STATURE-FOR-AGE AND WEIGHT-FOR-AGE 
PERCENTILES
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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 Rating Scale – IV Preschool Version
N/A
2007
Clinical Global Impressions – Global 
Improvement and Clinical Global 
Impressions – Severity of Illness 
N/A
1976
Columbia-Suicide Severity Rating Scale 
Baseline
Since Last Visit
Baseline 1/14/09 
Since Last Visit 1/14/09
Children’s Sleep Habits Questionnaire
N/A
2009
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. 
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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 Pharmacovigilance 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 fax or e-mail using the details below.
Fax:  
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:
Phone:
Fax:  
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 (e.g., inadequate or faulty closure, 
product contamination) or that the product did not meet the specifications defined in the 
application for the product (e.g., 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 below as applicable to report the Product Quality Complaint:
Origin of Product Quality Complaint
E-mail Address
North and South America
European Union and Rest of World
Telephone numbers (provided for reference if needed):
Shire, Wayne, PA (USA)
Shire, Basingstoke, Hampshire (UK)


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE............................................................................................2
EMERGENCY CONTACT INFORMATION ..........................................................................3
PRODUCT QUALITY COMPLAINTS ....................................................................................4
LIST OF TABLES....................................................................................................................10
LIST OF FIGURES..................................................................................................................10
LIST OF APPENDICES ..........................................................................................................10
ABBREVIATIONS..................................................................................................................11
STUDY SYNOPSIS.................................................................................................................13
STUDY SCHEDULE(S) ..........................................................................................................18
1.
BACKGROUND INFORMATION.............................................................................26
1.1
Indication and Current Treatment Options...................................................................26
1.2
Product Background and Clinical Information.............................................................28
1.2.1
Preclinical Information..........................................................................................29
1.2.2
Clinical Information ..............................................................................................29
2.
STUDY OBJECTIVES AND PURPOSE....................................................................30
2.1
Rationale for the Study.................................................................................................30
2.2
Study Objectives...........................................................................................................30
2.2.1
Primary Objectives ................................................................................................30
2.2.2
Secondary Objectives ............................................................................................31
3.
STUDY DESIGN.........................................................................................................31
3.1
Study Design and Flow Chart.......................................................................................31
3.2
Duration and Study Completion Definition..................................................................32


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3.3
Sites and Regions..........................................................................................................33
4.
STUDY POPULATION...............................................................................................33
4.1
Inclusion Criteria ..........................................................................................................33
4.2
Exclusion Criteria.........................................................................................................34
4.3
Reproductive Potential..................................................................................................35
4.3.1
Female Contraception............................................................................................35
4.4
Discontinuation of Subjects..........................................................................................35
4.4.1
Management of Blood Pressure and Pulse During the Study................................36
4.4.1.1
Systolic and Diastolic Blood Pressure.........................................................36
4.4.1.2
Pulse.............................................................................................................37
4.4.2
Reasons for Discontinuation..................................................................................37
4.4.3
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit..................................38
5.
PRIOR AND CONCOMITANT TREATMENT.........................................................38
5.1
Prior Treatment.............................................................................................................38
5.2
Concomitant Treatment ................................................................................................38
5.2.1
Permitted Treatment..............................................................................................39
5.2.2
Prohibited Treatment.............................................................................................39
6.
INVESTIGATIONAL PRODUCT ..............................................................................40
6.1
Identity of Investigational Product ...............................................................................40
6.1.1
Blinding the Treatment Assignment......................................................................40
6.2
Administration of Investigational Product(s) ...............................................................40
6.2.1
Interactive Response Technology for Investigational Product Management........40
6.2.2
Allocation of Subjects to Treatment......................................................................40
6.2.3
Dosing....................................................................................................................41
6.2.4
Unblinding the Treatment Assignment .................................................................42
6.3
Labeling, Packaging, Storage, and Handling................................................................42
6.3.1
Labeling.................................................................................................................42
6.3.2
Packaging ..............................................................................................................43
6.3.3
Storage...................................................................................................................43
6.4
Drug Accountability .....................................................................................................44


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6.5
Subject Compliance......................................................................................................45
7.
STUDY PROCEDURES..............................................................................................45
7.1
Study Schedule .............................................................................................................45
7.1.1
Screening and Washout Period..............................................................................46
7.1.1.1
Screening Visit (Visit -1) for “B” Subjects .................................................47
7.1.1.2
Washout Telephone Call (Visit Phone Call) for “B” Subjects ....................48
7.1.1.3
Visit 0 for “A” Subjects...............................................................................48
7.1.1.4
Visit 0 for “B” Subjects ...............................................................................49
7.1.2
Treatment Period ...................................................................................................50
7.1.2.1
Dose-optimization Period (Visits 1 to 6) for “B” Subjects..........................50
7.1.2.2
Dose Maintenance Period (Visits 1 to 13/ET) for “A” Subjects .................50
7.1.2.3
Dose Maintenance Period (Visits 7 to 18/ET) for “B” Subjects..................51
7.1.2.4
End-of-Study Visit (Visit 13/ Early Termination) for “A” Subjects ...........51
7.1.2.5
End-of-Study Visit (Visit 18/ Early Termination) for “B” Subjects ...........52
7.1.3
Safety Follow-up Period for “A” and “B” Subjects ..............................................52
7.1.4
Additional Care of Subjects After the Study.........................................................52
7.2
Study Evaluations and Procedures................................................................................52
7.2.1
Demographic and Other Baseline Characteristics.................................................53
7.2.2
Screening Assessments..........................................................................................53
7.2.3
Efficacy..................................................................................................................53
7.2.3.1
Attention-deficit/Hyperactivity Disorder Rating Scale IV Preschool 
Version.........................................................................................................53
7.2.3.2
Clinical Global Impressions.........................................................................54
7.2.4
Safety.....................................................................................................................54
7.2.4.1
Medical and Medication History .................................................................54
7.2.4.2
Physical Examination (Including Height and Weight)................................54
7.2.4.3
Adverse Event Collection ............................................................................55
7.2.4.4
Vital Signs....................................................................................................55
7.2.4.5
Height and Weight.......................................................................................56
7.2.4.6
Clinical Laboratory Evaluations ..................................................................56
7.2.4.7
Electrocardiogram........................................................................................58
7.2.4.8
Children’s Sleep Habits Questionnaire and Sleep Diary.............................59
7.2.4.9
Columbia-Suicide Severity Rating Scale- Pediatric/Cognitively 
Impaired Version .........................................................................................59
7.2.4.10
Suitability of the Subject to Remain in the Study........................................60


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7.2.5
Volume of Blood to be Drawn From Each Subject...............................................60
8.
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT..........................61
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events ...........................................................................................................................61
8.1.1
Severity Categorization .........................................................................................61
8.1.2
Relationship Categorization ..................................................................................62
8.1.3
Outcome Categorization........................................................................................62
8.1.4
Symptoms of the Disease Under Study.................................................................63
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................63
8.1.6
Abuse, Misuse, Overdose, and Medication Error..................................................63
8.2
Serious Adverse Event Procedures...............................................................................64
8.2.1
Reference Safety Information................................................................................64
8.2.2
Reporting Procedures ............................................................................................64
8.2.3
Serious Adverse Event Definition.........................................................................65
8.2.4
Serious Adverse Event Collection Time Frame ....................................................65
8.2.5
Serious Adverse Event Onset and Resolution Dates.............................................66
8.2.6
Fatal Outcome .......................................................................................................66
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting...............................................................................................................66
9.
DATA MANAGEMENT AND STATISTICAL METHODS.....................................66
9.1
Data Collection.............................................................................................................66
9.2
Clinical Data Management ...........................................................................................67
9.3
Data Handling Considerations......................................................................................67
9.4
Statistical Analysis Process ..........................................................................................67
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee ..........67
9.6
Sample Size Calculation and Power Considerations....................................................68
9.7
Study Population...........................................................................................................68
9.8
Efficacy Analyses .........................................................................................................68
9.8.1
Clinician-administered ADHD-RS-IV Preschool Version....................................68
9.8.2
Clinical Global Impressions ..................................................................................69
9.8.3
Exploratory Efficacy Endpoints ............................................................................69


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9.9
Safety Analyses ............................................................................................................69
9.10
Other Analyses..............................................................................................................69
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES.................................69
10.1
Sponsor’s Responsibilities............................................................................................70
10.1.1 Good Clinical Practice Compliance ......................................................................70
10.1.2 Public Posting of Study Information.....................................................................70
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees ..........................................70
10.1.4 Study Suspension, Termination, and Completion.................................................70
10.2
Investigator’s Responsibilities......................................................................................71
10.2.1 Good Clinical Practice Compliance ......................................................................71
10.2.2 Protocol Adherence and Investigator Agreement..................................................71
10.2.3 Documentation and Retention of Records.............................................................72
10.2.3.1
Case Report Forms.......................................................................................72
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents ...................................................................................................72
10.2.3.3
Audit/Inspection...........................................................................................73
10.2.3.4
Financial Disclosure ....................................................................................73
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation............................73
10.3
Ethical Considerations..................................................................................................73
10.3.1 Informed Consent ..................................................................................................73
10.3.2 Institutional Review Board or Ethics Committee..................................................74
10.4
Privacy and Confidentiality..........................................................................................75
10.5
Study Results / Publication Policy................................................................................75
11.
REFERENCES.............................................................................................................77
12.
APPENDICES..............................................................................................................80


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LIST OF TABLES
Table 1:
Schedule of Assessments for “A” Subjects ...........................................................18
Table 2:
Schedule of Assessments for “B” Subjects............................................................21
Table 3:
Common Excluded Treatments and Associated Washout Period Relative to 
Visit 0- ...................................................................................................................39
Table 4:
Volume of Blood to be Drawn From Each Subject...............................................60
LIST OF FIGURES
Figure 1:
Chemical Structure of the Active Pharmaceutical Ingredient ...............................28
Figure 2: 
Study Design Flow Chart for “A” Subjects...........................................................32
Figure 3:
Study Design Flow Chart for “B” Subjects ...........................................................32
LIST OF APPENDICES
Appendix 1
Protocol History...........................................................................................81
Appendix 2
Diagnostic Criteria/Disease Classification ..................................................82
Appendix 2.1
DSM-IV-TR Criteria for Attention- Deficit/Hyperactivity Disorder ..........83
Appendix 2.2
Blood Pressure Levels for Boys by Age and Height Percentiles.................85
Appendix 2.3
Blood Pressure Levels for Girls by Age and Height Percentile ..................86
Appendix 3
Scales and Assessments...............................................................................87


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ABBREVIATIONS
AAP
American Academy of Pediatrics
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS_IV
attention-deficit/hyperactivity disorder rating scale- IV
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase 
AST
aspartate transaminase
CGI-I
clinical global impressions-global improvement
CGI-S
clinical global impressions-severity of illness
CNS
central nervous system
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
CSHQ
children’s sleep habits questionnaire
C-SSRS
Columbia-suicide severity rating scale
DBP
diastolic blood pressure
DMC
data monitoring committee
DSM-IV
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
EC
ethics committee
ECG
Electrocardiogram
EMA
European Medicines Agency
ET
early termination
EU
European Union
FAS
full analysis set
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GGT
gamma glutamyl transferase
HIPAA
Health Insurance Portability and Accountability Act
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
ICMJE
International Committee of Medical Journal Editors
IRB
Institutional Review Board


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IRT
interactive response technology
IWRS
interactive web response system
LAR
legally authorized representative
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
PAPA
preschool age psychiatric assessment
PATS
Preschool ADHD Treatment Study
RBC
red blood cell
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
T4
thyroxine
TEAE
treatment-emergent adverse event
TSH
thyroid stimulating hormone
UK
United Kingdom
US
United States
WBC
white blood cell


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STUDY SYNOPSIS
Protocol number:  SPD489-348
Drug: Lisdexamfetamine dimesylate
Title of the study:  A Phase 3, Open-label, Multicenter, 12-Month Safety and Tolerability Study of SPD489 in 
Preschool Children Aged 4-5 Years Diagnosed with Attention-deficit/Hyperactivity Disorder
Number of subjects:
Approximately 100 subjects will be enrolled into this study. Subjects will enroll into this study from antecedent 
study, SPD489-211 or SPD489-347. If a decision is made to enroll subjects directly, the study procedures and 
definition of baseline for directly enrolled subjects will be described in the amended protocol.
The sample size was established to provide long-term safety data in this population.
Investigator(s):  Multicenter
Site(s) and Region(s): 
Approximately 20 sites in the United States (US)
Study period (planned):
2014-2021
Clinical phase:
3
Objectives:
Primary:  To evaluate the long-term safety of SPD489 administered as a daily morning dose (5, 10, 15, 20, and 
30mg/day) in preschool children (4-5 years of age 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), specific evaluation of blood pressure, pulse, weight, height, clinical laboratory evaluations,
electrocardiogram (ECG) results, and sleep assessments.
Secondary: 
1.
To describe
the long-term efficacy of SPD489 using the clinician
administered Attention-
deficit/Hyperactivity Disorder Rating Scale-IV Preschool Version (ADHD-RS-IV Preschool Version).
2.
To describe the long-term efficacy of SPD489 using global clinical measures of improvement, as measured 
by the Clinical Global Impressions – Global Improvement (CGI-I).
Rationale:
The purpose of the study is to evaluate the long-term safety of SPD489 in preschool children who are diagnosed 
with ADHD. Based on IMS Health data and discussion at the Food and Drug Administration (FDA) Pediatric 
Advisory Committee in September 2012, it has been noted that there is off-label use of SPD489 in children 
under 5 years old (4%, or approximately 100 000 patients between February 2007 and March 2012).  The lack 
of controlled data regarding the safety and efficacy of SPD489 in the preschool ADHD population, along with 
the prevalence of off-label prescribing of SPD489 supports the need for SPD489 studies in the preschool ADHD 
population.  Importantly, it is not known if the therapeutic effects of stimulant medications in school age 
children with ADHD can be extrapolated to preschool children with ADHD.  There are some indications that the 
effect size may be reduced (Greenhill 2006).  There may also be differences in the safety and pharmacokinetic 
profiles (Wigal 2007; Wigal 2006).
Generating long-term safety data in this population will provide important information on the use of SPD489 in 
the preschool ADHD population.


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Investigational product, dose, and mode of administration:
The sponsor will provide SPD489 as 5, 10, 15, 20, and 30mg strength capsules.
All subjects will be instructed to take 1 capsule daily throughout the study at approximately 7:00AM (+/-2 
hours). SPD489 will be administered one of the following ways: 
•
swallow SPD489 capsules whole, or
•
open capsules, empty and mix the entire contents either with yogurt, water, or orange juice.
The contents should be mixed until completely dispersed. The subject must ingest the entire amount of the 
mixture immediately within 3 minutes. The subject should not take anything less than one capsule per day and a 
single capsule can not be split. The empty gelatinous capsule should be discarded. 
Methodology:
This study is a Phase 3 long-term, open-label, safety and tolerability study in preschool children (4-5 years of 
age inclusive at the time of entry into antecedent study or at the time of enrollment if directly enrolled) with 
Attention-deficit/Hyperactivity Disorder (ADHD).
The study will enroll two types of subjects; Subjects “A” and Subjects “B”. The “A” Subjects will have 2 
periods: (1) Dose Maintenance and (2) Safety Follow-up. The “B” Subjects will have 4 periods: (1) Screening 
and Washout; (2) Dose-optimization; (3) Dose Maintenance; and (4) Safety Follow-up.
The duration of the evaluation phase for “A” Subjects (Dose Maintenance) and “B” Subjects (Dose-optimization 
and Maintenance) will be 52 weeks. 
SPD489 will be provided in 5, 10, 15, 20, and 30mg capsules.
Visit 0 procedures for “A” Subjects will be performed at the final dose maintenance visit of the antecedent 
study. 
Subjects will be required to visit the site up to 20 times over a 57-week period, depending on their assignment.
“A” Subjects may visit the site up to 13 times while “B” Subjects may visit the site up to 18 times. 


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Inclusion and exclusion criteria
Inclusion Criteria:
The subject will not be considered eligible for the study without meeting all of the criteria below (including test 
results).
1.
Subject is male or female aged 4-5 years inclusive at the time of consent for an antecedent SPD489 trial in 
the preschool ADHD population.
2.
For “A” Subjects: Subject is on a known dose of SPD489 and completed the final visit of the treatment 
phase of an unblinded antecedent study without experiencing any clinically significant adverse events 
(AEs) that would preclude exposure to SPD489 and can directly enter this study without gap between the 
antecedent study and this study (defined as ≤3 days since last dose in the prior study), OR
For “B” Subjects: Subject requires dose titration and completed at least the dose optimization and follow up 
of a blinded antecedent study without experiencing any clinically significant adverse events (AEs) that 
would preclude exposure to SPD489, OR
For “B” Subjects: Subject completed the final visit of the treatment phase of an unblinded antecedent study 
without experiencing any clinically significant adverse events (AEs) that would preclude exposure to 
SPD489, and did not enroll in this study within 3 days (i.e. >3 days since last dose in the prior study). 
3.
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 indicating that the subject is aware 
of the investigational nature of the study and the required procedures and restrictions in accordance with the 
International Conference on Harmonisation (ICH) GCP Guideline E6 (1996) and applicable regulations, 
before completing any study-related procedures.
4.
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 study duration.
5.
For “A” Subjects: Subject has a satisfactory medical assessment with no clinically significant or relevant 
abnormalities as determined by physical examination findings or vital sign results that would preclude 
treatment with SPD489.
For “B” Subjects: Subject has a satisfactory medical assessment with no clinically significant or relevant 
abnormalities as determined by physical examination findings, clinical laboratory test results, ECG results, 
or vital sign results that would preclude treatment with SPD489.
6.
Subject has lived with the same parent or guardian for ≥6 months.
Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met at Visit 0 for “A” 
Subjects or at Screening (Visit -1) and/or Baseline (Visit 0) for “B” Subjects. These criteria apply to all subjects 
regardless of duration since participation in an antecedent trial:
1.
Subject was terminated from an antecedent SPD489 trial for non-compliance and/or experienced a serious 
adverse event (SAE) or AE resulting in termination from any previous SPD489 trial.
2.
Subject experienced any clinically significant AEs in any previous SPD489 trial that, in the opinion of the 
investigator, would preclude further exposure to SPD489.
3.
Subject is required to or anticipates the need to take medications that have central nervous system effects or 
affect performance, such as sedating antihistamines and decongestant sympathomimetics, or are 
monoamine oxidase inhibitors.  Stable use of bronchodilator inhalers is not exclusionary.
4.
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 


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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.
5.
Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in 
the investigational product.
6.
Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
7.
Subject has a blood pressure measurement ≥95th percentile for age, sex, and height at Visit 0.
8.
Subject has a known history of symptomatic cardiovascular disease, advanced arteriosclerosis, structural 
cardiac abnormality, cardiomyopathy, serious heart rhythm abnormalities, coronary artery disease, or other 
serious cardiac problems placing them at increased vulnerability to the sympathomimetic effects of a 
stimulant drug.
9.
Subject has a current diagnosis of adjustment disorder, autism, psychosis, or bipolar disorder.
10. Subject is currently considered at risk for suicide in the opinion of the investigator, has previously made a 
suicide attempt, or is currently demonstrating active suicidal ideation.  Subjects with intermittent passive 
suicidal ideation are not necessarily excluded based on the assessment of the investigator.
11. Subject has a history of seizures (other than infantile febrile seizures) or a current diagnosis of Tourette’s 
Disorder.
12. Subject has a chronic or current tic disorder that is judged by the investigator to be exclusionary.
13. Subject is taking any medication that is excluded per the protocol.
14. For “B” Subjects only: Subject had any clinically significant electrocardiogram (ECG) or clinical laboratory 
abnormalities at the Screening Visit (Visit -1).
15. For “B” Subjects only: Subject has current abnormal thyroid function, defined as abnormal thyroid 
stimulating hormone (TSH) and thyroxine (T4) at the Screening Visit (Visit -1) or Visit 0.  Treatment with 
a stable dose of thyroid medication for at least 3 months is permitted.
Maximum duration of subject involvement in the study:
•
Planned duration of screening period: 
For “A” Subjects: Visit 0 procedures will be assessed at the final dose maintenance visit of the antecedent 
study. 
For “B” Subjects: 28 days
•
Planned duration of treatment period: 
For “A” Subjects: 52 week period
For “B” Subjects: 52 week period
•
Planned duration of safety follow-up period: 
For “A” Subjects: 7 days
For “B” Subjects: 7 days
Endpoints and statistical analysis:
Subject Populations
•
The Screened Set will consist of all subjects who have signed informed consent. 
•
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of investigational 


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product.
•
The Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at least 1 post-
dose ADHD-RS-IV Preschool Version Total Score assessment during the study.
Safety Endpoints
Safety assessments include the occurrence of treatment emergent adverse events (TEAEs), specific evaluation of 
blood pressure, pulse, height, weight, clinical laboratory evaluations and electrocardiogram (ECG) results, and 
sleep assessments [(including sleep diary data, and Children’s Sleep Habits Questionnaire (CSHQ)].
Additional safety rating scales utilized in the study will include:
Columbia Suicide Rating Scale (C-SSRS)- Pediatric/Cognitively Impaired Version
Efficacy Endpoint(s)
The efficacy endpoint is defined as the change from baseline on the clinician-administered ADHD-RS-IV 
Preschool Version Total Score, where baseline is defined as the baseline from the antecedent study.
The additional efficacy endpoint is the Clinical Global Impression-Improvement Scale (CGI-I): The CGI-I will 
be used to determine the proportion of subjects with an “improved” measurement. 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 Endpoint(s)
Safety analyses will be summarized using the Safety Analysis Set, and presented by treatment group of the 
antecedent studies and overall for AEs, clinical laboratory results, vital signs, ECGs, CSHQ, and sleep diaries.  
A listing of the C-SSRS will be provided for subjects with any positive responses.
Statistical Methodology for Efficacy Endpoint(s)
The FAS will be used to report the efficacy data. Descriptive summary statistics will be presented by treatment 
group of the antecedent studies and overall for the observed efficacy variables. Change from baseline in total 
score for the ADHD-RS-IV Preschool Version 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 post-dose visit. 


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STUDY SCHEDULE(S)
Table 1:
Schedule of Assessments for “A” Subjects
Period
Dose Maintenance Period
Safety
Follow-up
Visit a
Visit 0b  
1
2
3
4
5
6
7
8
9
10
11
12
13/ET
Telephone
Call
Assessment 
Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
Assessment Day
0
28
56
84
112
140
168
196
224
252
280
308
336
364
371
Informed 
consent/assent

Inclusion/exclusio
n criteriac

Demographicsd

Medical and 
medication 
history

Physical 
examination

Vital signs e














Height f














Body weight
















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Table 1:
Schedule of Assessments for “A” Subjects
Period
Dose Maintenance Period
Safety
Follow-up
Visit a
Visit 0b  
1
2
3
4
5
6
7
8
9
10
11
12
13/ET
Telephone
Call
Assessment 
Week
0
4
8
12
16
20
24
28
32
36
40
44
48
52
53
Assessment Day
0
28
56
84
112
140
168
196
224
252
280
308
336
364
371
Clinical 
laboratory testg 



12 lead ECGh






ADHD RS IV i













CGI I i













CSHQ i














C SSRS j














Sleep diary k














Suitability of 
subject to remain 
in study












Investigator dose 
assessment












Access IWRS














Investigational 
product 
distributed















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Investigational 
product returned













Investigational 
product 
compliance













Concomitant 
medications















Adverse events 















a Visit Window for Visits 1 6 is ± 2 days, and Visit Window for Visits 7 17 is ±5 days [in reference to the Visit 0 date]; Visit Window for Visit 18 is +5 days;  Visit Window  for 
Safety Follow up Telephone call is + 2 days. 
b Visit 0 is the same day as the End of Study Visit for the antecedent study
c Inclusion/exclusion criteria must be reviewed at the Washout Telephone Call and at Visit 0.
d Demographic data will be pulled programmatically from antecedent study.
eIncludes oral or tympanic temperature, sitting blood pressure, pulse, and respiratory rate. Measurement of temperature and respiratory rate will be performed as part of the End of 
Study Visit of the antecedent study .  Measurement of blood pressure and pulse will be collected 3 times (with approximately 2 minutes in between each collection) using the 
provided automated cuff. The average of each set of 3 measurements will be used to determine continued participation in the study. Blood pressure, pulse and respiratory rate will be 
determined after subjects have remained seated for approximately 5 minutes. Refer to Section 4.4.1.
f Height to be measured without shoes.
g  Clinical laboratory tests will include hematology, chemistry, endocrinology, and urinalysis.
h A single ECG will be collected at, Visits 0, 3, 6, 9, 12, 15and 18/ET 
i Scales to be completed by same rater whenever possible.
j C SSRS pediatric/cognitively impaired “Since Last Visit” version is completed for all visits. The scale will be compared to the C SSRS pediatric/cognitively impaired “Baseline” 
from the antecedent study.
k Sleep diary to be completed by parent/LAR. Sleep diaries will be dispensed at Visits 0 17 and collected at Visits 1 18. 
ADHD RS IV ADHD Rating Scale IV; CGI I Clinical Global Impressions Global Improvement; CGI S Clinical Global Impressions Severity of Illness; CSHQ Children’s Sleep 
Habits Questionnaire; C SSRS Columbia Suicide Severity Rating Scale Pediatric/Cognitively Impaired; ECG electrocardiogram; ET early termination; IWRS Interactive Web 
Response System












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1.
BACKGROUND INFORMATION
Lisdexamfetamine dimesylate capsules (SPD489, previously referred to as NRP104) were 
developed for the once-daily treatment of ADHD.
SPD489 capsules contain 5, 10, 15, 20, or 30mg of lisdexamfetamine dimesylate, a new 
chemical entity designed for once-daily oral administration.  Lisdexamfetamine itself is a 
pharmacologically inactive prodrug.  After ingestion it is converted to l-lysine (a naturally 
occurring essential amino acid) and dextroamphetamine (d-amphetamine, responsible for 
pharmacological activity) primarily in the blood.
Amphetamine is a chiral compound that exists as 2 stereoisomers: dextro (d)- and levo (l)-
amphetamine. Lisdexamfetamine is the l-lysine conjugate of the dextro stereoisomer.  After 
oral administration, lisdexamfetamine is rapidly absorbed from the gastrointestinal tract and 
converted primarily in the blood to l-lysine (a naturally occurring amino acid) and d-
amphetamine, which is responsible for the drug’s pharmacological activity.
Lisdexamfetamine is classified as a psychomotor stimulant.  
Amphetamine appears to exert its pharmacological effects in the CNS by increasing the 
availability of naturally occurring amines that have important functions in nerve terminals. 
Amphetamine increases synaptic levels of dopamine (DA), norepinephrine (NE), and 
serotonin (5-HT) through multiple mechanisms (Hardman et al. 2001). It promotes the release 
of DA, NE, and 5-HT into the extraneuronal space, and also inhibits the reuptake of DA and 
NE into the pre-synaptic nerve terminal resulting in prolonged residency of these 
neurotransmitters in the synaptic cleft. In addition to producing a CNS response, 
amphetamine treatment is also associated with cardiovascular effects such as an increase in 
SBP and DBP, and pulse. Amphetamine may also suppress the appetite.
In addition to the approved indication of ADHD, other indications have been explored.
Additional information can be found in the current IB for SPD489.
1.1
Indication and Current Treatment Options 
Attention-deficit/hyperactivity disorder
is a heterogeneous neurobehavioral
disorder 
characterised by a pattern of developmentally inappropriate inattentiveness, impulsivity, and 
hyperactivity resulting in clinically significant impairment in social, academic, or 
occupational functioning.  Although ADHD was originally thought to be a disorder primarily 
affecting elementary school age children; it has become clear that ADHD may persist across a 
lifetime, and that ADHD symptoms may manifest several years prior to entry into elementary 
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While there are hundreds of studies investigating the treatment of ADHD in school-age 
children, there are very few studies exploring the treatment of ADHD in preschoolers.  
Although diagnosing ADHD in a preschool child can be challenging, reliable diagnostic tools 
and age-appropriate assessments are available, and it is therefore possible to conduct 
scientifically rigorous ADHD studies in this population.  It would be beneficial to provide 
additional evidence-based support for ADHD treatment decisions in the preschool population.  
Estimates of the prevalence of ADHD in the preschool population vary depending on the 
referral source and the method used to diagnose ADHD; however it appears that 
approximately 4-5% of preschool children are considered to have ADHD.  Using the PAPA, 
an assessment validated for use in the preschool population, the prevalence of ADHD in a 
sample of 1 073 children aged 2-5 years was reported to be 3.9-5.1% (Egger et al. 2006a; 
Egger 2004; Greenhill 2008).  In 2007, the National Survey of Children’s Health obtained 
information from parents of 73,123 children aged 4-17 years (MMWR 2010).  Parents 
reported a current diagnosis of ADHD in 5.5% of 4-10 year olds (MMWR 2010).  Prevalence 
in males aged 4-11 is roughly 3 times greater than in females (Szatmari 1989).
Attention-deficit/hyperactivity disorder is characterized by symptoms of inattention, 
hyperactivity, and impulsivity that are “maladaptive and inconsistent with developmental 
level” (DSM-IV).   Preschool children, ages 3-5 years, often exhibit symptoms of 
hyperactivity and impulsivity, so it may be challenging to delineate what is “inconsistent with 
developmental level” for this population (Smith 2007).  Nevertheless, it is possible to 
diagnose ADHD in the preschool population in a reliable fashion (Egger et al. 2006a; Egger et 
al. 2006b; McGoey et al. 2007).
The presence of ADHD symptoms that are frequent, severe, and developmentally 
inappropriate, can be used to define ADHD in this population (Connor 2002; Smith 2007).  In 
addition, impairment in 2 or more settings establishes that the constellation of ADHD 
symptoms is maladaptive and not confined to a specific environment.  The severity of ADHD 
symptoms in a preschool child can be reliably measured using scales such as the PAPA and 
the ADHD-RS-IV Preschool Version that have been validated for this population and include 
age-appropriate questions and prompts (Egger et al. 2006a; McGoey et al. 2007).  
It is appropriate to consider whether an ADHD diagnosis in a preschool child will endure or 
resolve as the child matures.  ADHD has been described in terms of a developmental 
trajectory that can be modified by biologic or environmental factors (Sonuga-Barke and 
Halperin 2010; Sonuga-Barke et al. 2005).  Potential risk factors such as severity of ADHD 
symptoms, the presence of oppositional defiant symptoms, and neuropsychological 
impairment may affect the course of ADHD (Sonuga-Barke and Halperin 2010).  Although 
some children may not retain the ADHD diagnosis as they grow older, for many children the 
diagnosis endures beyond their preschool years (Lahey et al. 2004; Tandon et al. 2011).  In a 
sample of 96 children aged 4-6 years with ADHD, 79% of the children continued to have an 
ADHD diagnosis 3 years later as compared to 3% of the non-ADHD control children (Lahey
et al. 2004).  This finding was replicated in a sample of 48 children aged 4-6 years with 


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ADHD who were followed for 2 years (Tandon et al. 2011).  These results suggest that when 
an ADHD diagnosis is first made in a preschool child, it is likely to be stable over time. 
The constellation of impairments associated with an ADHD diagnosis in preschool children 
suggests a characteristic profile similar to that for individuals diagnosed after the preschool 
period.  Preschool children with ADHD demonstrate impairments in social functioning and 
pre-academic skills (Dupaul et al. 2001; Ghuman et al. 2008).  They are also more likely to be 
aggressive towards others and to sustain an injury (Greenhill et al. 2008; Rappley et al. 1999;
Connor et al. 2003).  In a longitudinal study which followed children from ages 4-21 years, 
the attention span at age 4 years predicted math and reading skills at age 21 years and 
completion of college at age 25 years (McClelland et al. 2013).
Currently, the lack of a robust body of evidence derived from controlled clinical studies in 
preschool children makes it difficult to create reliable treatment recommendations. The AAP 
ADHD Clinical Practice guideline suggests that preschool children with ADHD initiate 
treatment with behavioral therapy prior to using pharmacotherapy (Subcommittee on ADHD 
2011); however the PATS results indicates that (13%) preschool children have a satisfactory 
response to behavioral therapy (Greenhill et al. 2006). If the preschool child with ADHD 
does not respond to behavioral therapy, the guideline then suggests the use of 
methylphenidate. Of note, methylphenidate does not have an indication for a population less 
than 6 years old (Subcommittee on ADHD 2011).
Immediate-release Adderall 
(dextroamphetamine saccharate, amphetamine aspartate, dextroamphetamine sulfate, and 
amphetamine sulfate) and dextroamphetamine are approved for children with ADHD as 
young as 3 years old. As a result, if a preschool child does not respond to methylphenidate, a 
trial of an amphetamine product is recommended by the AAP. However, the lack of data for 
amphetamines in preschool children with ADHD is acknowledged.
Clearly, the 
implementation of additional studies in preschool children with ADHD would provide 
additional evidence in order to inform treatment decisions. 
1.2
Product Background and Clinical Information
The active pharmaceutical ingredient of SPD489 is (2S)-2, 6-diamino-N-[(1S)-1-methyl-
2-phenylethyl] hexanamide dimethanesulfonate.
Figure 1 shows the chemical structure of the active pharmaceutical ingredient: 
Figure 1:
Chemical Structure of the Active Pharmaceutical Ingredient
H
N
NH2
O
CH3
NH2
H3C S OH
O
O
2
·


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Always refer to the latest version of the SPD489 investigator’s brochure for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics, efficacy and safety of SPD489. 
1.2.1
Preclinical Information
Lisdexamfetamine is a pharmacologically inactive prodrug. After ingestion, it is converted in 
the blood to d-amphetamine (responsible for pharmacological activity) and l-lysine (a 
naturally occurring essential amino acid). A comprehensive set of studies has been conducted 
to evaluate the pharmacological and toxicological properties associated with the parent 
compound lisdexamfetamine.  The safety profiles associated with d-amphetamine and l-lysine 
are well established.
All safety and toxicology studies, except the single dose acute toxicity study in rats, were 
conducted in compliance with Good Laboratory Practice.
Complete preclinical information is presented in the current SPD489 IB.
1.2.2
Clinical Information
The pharmacological profile of lisdexamfetamine and the pharmacologically active metabolite 
d-amphetamine have been well characterized in studies enrolling children, healthy adults, and 
adults with a history of stimulant abuse. These studies have demonstrated that oral 
administration of SPD489 resulted in a predictable d-amphetamine pharmacokinetic profile 
with low intra-subject and inter-subject variability. The d-amphetamine AUC0 ∞ and Cmax
generally behaved in a linear, dose-proportional manner. The weight-normalized d-
amphetamine AUC0 ∞ is similar for children and adults, with tmax and t½ consistent across age 
groups.
In the ADHD Clinical Development Program, the efficacy of SPD489 for the treatment of
ADHD has been demonstrated for children, adolescents, and adults with ADHD. Substantial 
evidence of efficacy was provided in well-controlled studies, where SPD489 was shown to be 
effective compared to placebo. SPD489 was associated with a statistically significant, 
clinically meaningful improvement in ADHD symptoms, functional outcomes, and health-
related quality of life compared to placebo, in studies that used a variety of study designs, a 
variety of validated assessments, and a variety of raters.
The well-characterized SPD489 safety profile was consistent with that of other stimulants 
used in the treatment of ADHD. When the safety results from the 15 completed Phase 2-4 
clinical studies in the ADHD Clinical Development Program were examined, the majority of 
TEAEs were mild or moderate in severity, and no differences due to age or sex were noted. 
The most frequently reported AEs were those typically associated with stimulant therapy 
(including decreased appetite, insomnia, headache, dry mouth, irritability, upper abdominal 
pain, and weight decrease), or potentially attributable to intercurrent illnesses (e.g., upper 


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respiratory tract infection and nasopharyngitis). These TEAEs were generally non-serious and 
were considered by the investigator to be resolved during study participation.
Stimulant medications like SPD489 cause a modest increase in average blood pressure (about
2-4 mmHg) and average pulse (about 3-6 bpm). Individuals may have larger increases.
Always refer to the latest version of the SPD489 IB for the overall risk/benefit assessment and 
the most accurate and current information regarding the drug metabolism, pharmacokinetics, 
efficacy and safety of SPD489.
2.
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
Based on IMS Health data and discussion at the FDA Pediatric Advisory Committee in 
September 2012, it has been noted that there is off-label use of SPD489 in children under 5 
years old (4%, or approximately 100 000 patients between February 2007 and March 2012).  
The lack of controlled data regarding the safety and efficacy of SPD489 in the preschool 
ADHD population, along with the prevalence of off-label prescribing of SPD489 supports the 
need for SPD489 studies in the preschool ADHD population.  Importantly, it is not known if 
the therapeutic effects of stimulant medications in school age children with ADHD can be 
extrapolated to preschool children with ADHD.  There are some indications that the effect 
size may be reduced (Greenhill et al. 2006).  There may also be differences in the safety and 
pharmacokinetic profiles (Wigal et al. 2007; Wigal et al. 2006).
Generating long-term safety data in this population will provide important information on the 
use of SPD489 in the preschool ADHD population.
2.2
Study Objectives
2.2.1
Primary Objectives
The primary objective of this study is to evaluate the long-term safety of SPD489 
administered as a daily morning dose (5, 10, 15, 20, and 30mg/day) in preschool children (4-5 
years of age inclusive) diagnosed with ADHD.
The evaluation of safety and tolerability will be based on the occurrence of TEAEs, specific 
evaluation of blood pressure, pulse, weight, height, clinical laboratory evaluations and ECG 
results, and sleep assessments.


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2.2.2
Secondary Objectives
•
To describe the long-term efficacy of SPD489 using the clinician-administered Attention-
deficit/Hyperactivity Disorder Rating Scale-IV Preschool Version.
•
To describe the long-term efficacy of SPD489 using global clinical measures of 
improvement, as measured by the CGI-I.
3.
STUDY DESIGN
3.1
Study Design and Flow Chart
Approximately 100 subjects will be enrolled in this long-term, open-label study to evaluate 
safety and tolerability of SPD489, administered as a daily morning dose in the treatment of 
children 4-5 years of age with ADHD. SPD489 will be provided in 5, 10, 15, 20, and 30mg 
capsules. 
This study will enroll subjects who participated in an antecedent SPD489 study (SPD489-211 
or SPD489-347). Subjects entering into this study will be classified as either an “A” Subject 
or a “B” Subject, determined by the need to retitrate the SPD489 dose, defined as follows: 
•
“A” Subjects are subjects on a known dose of SPD489, classified as subjects who 
completed the final visit of the treatment phase of an unblinded antecedent study 
(SPD489-211) who are directly entering this study ≤3 days after the last dose of study 
medication in the previous study.  
•
“B” Subjects are subjects who require dose titration, classified as subjects who completed 
at least the dose optimization and follow up of the blinded antecedent study (SPD489-347) 
OR those subjects who completed the final visit of the treatment phase of the unblinded 
antecedent study (SPD489-211) and did not enroll in this study within 3 days.  
For “B” Subjects, screening assessments (physical examination, vital signs, height, weight, 
clinical laboratory tests, and ECGs) must be repeated for this study if more than 30 days have 
elapsed since the conclusion of the antecedent study.  
During the Dose Maintenance Period for both “A” and “B” Subjects, the investigator may 
make further dose adjustments based upon TEAEs and clinical judgment.  




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The Study Completion Date is defined as the date the final subject, across all sites, completes 
their final protocol-defined assessment.  Please note that this includes the follow-up visit or 
contact, whichever is later.  The Study Completion Date is used to ascertain timing for study 
results posting and reporting.
3.3
Sites and Regions
This study will be conducted in approximately 20 sites in US.
4.
STUDY POPULATION
Each subject/parent or LAR 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 criteria 
below (including test results):
1. Subject is male or female aged 4-5 years inclusive at the time of consent for an antecedent 
SPD489 trial in the preschool ADHD population. 
2. For “A” Subjects: Subject is on a known dose of SPD489 and completed the final visit of 
the treatment phase of an unblinded antecedent study without experiencing any clinically 
significant AEs that would preclude exposure to SPD489 and can directly enter this study 
without gap between the antecedent study and this study (defined as ≤3 days since last 
dose in the prior study), OR
For “B” Subjects: Subject requires dose titration and completed at least the dose 
optimization and follow up of a blinded antecedent study without experiencing any 
clinically significant AEs that would preclude exposure to SPD489, OR
For “B” Subjects: Subject completed the final visit of the treatment phase of an unblinded 
antecedent study without experiencing any clinically significant AEs that would preclude 
exposure to SPD489, and did not enroll in this study within 3 days (i.e., >3 days since last 
dose in the prior study). 
3. Subject’s parent or LAR must provide signature of informed consent, and there must be 
documentation of assent (if applicable) by the subject indicating that the subject is aware 
of the investigational nature of the study and the required procedures and restrictions in 
accordance with the ICH GCP Guideline E6 (1996) and applicable regulations, before 
completing any study-related procedures.
4. 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, 


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the same parent/LAR should be available to dispense the dose of investigational product 
for the study duration.
5. For “A” Subjects: Subject has a satisfactory medical assessment with no clinically 
significant or relevant abnormalities as determined by physical examination findings or 
vital sign results that would preclude treatment with SPD489.
For “B” Subjects: Subject has a satisfactory medical assessment with no clinically 
significant or relevant abnormalities as determined by physical examination findings 
clinical laboratory test results, ECG results, or vital sign results that would preclude 
treatment with SPD489.
6. Subject has lived with the same parent or guardian for ≥6 months.
4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following criteria are met at Visit 0 for “A” 
Subjects or at Screening (Visit -1) and/or Visit 0 for “B” Subjects. These criteria apply to all 
subjects regardless of duration since participation in an antecedent trial.
1. Subject was terminated from an antecedent SPD489 trial for non-compliance and/or 
experienced a SAE or AE resulting in termination from any previous SPD489 trial.
2. Subject experienced any clinically significant AEs in any previous SPD489 trial that, in 
the opinion of the investigator, would preclude further exposure to SPD489.
3. Subject is required to or anticipates the need to take medications that have central nervous 
system effects or affect performance, such as sedating antihistamines and decongestant 
sympathomimetics, or are monoamine oxidase inhibitors.  Stable use of bronchodilator 
inhalers is not exclusionary.
4. 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.
5. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to 
any excipients in the investigational product.
6. Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
7. Subject has a blood pressure measurement ≥95th percentile for age, sex, and height at 
Visit 0.
8. Subject has a known history of symptomatic cardiovascular disease, advanced 
arteriosclerosis, structural cardiac abnormality, cardiomyopathy, serious heart rhythm 


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abnormalities, coronary artery disease, or other serious cardiac problems placing them at 
increased vulnerability to the sympathomimetic effects of a stimulant drug.
9. Subject has a current diagnosis of adjustment disorder, autism, psychosis, or bipolar 
disorder.
10. Subject is currently considered at risk for suicide in the opinion of the investigator, has 
previously made a suicide attempt, or is currently demonstrating active suicidal ideation.  
Subjects with intermittent passive suicidal ideation are not necessarily excluded based on 
the assessment of the investigator.
11. Subject has a history of seizures (other than infantile febrile seizures) or a current 
diagnosis of Tourette’s Disorder.
12. Subject has a chronic or current tic disorder that is judged by the investigator to be 
exclusionary.
13. Subject is taking any medication that is excluded per the protocol.
14. For “B” Subjects only: Subject had any clinically significant ECG or clinical laboratory 
abnormalities at the Screening Visit (Visit -1).
15. For “B” Subjects only: Subject has current abnormal thyroid function, defined as 
abnormal TSH and T4 at the Screening Visit (Visit -1) or Visit 0.  Treatment with a stable 
dose of thyroid medication for at least 3 months is permitted.
4.3
Reproductive Potential
4.3.1
Female Contraception
Contraception is not applicable as no female subjects in this study are of child bearing 
potential. All female subjects in this study are pre-menarchal, less than age 9 years, and 
Tanner Stage 1.
4.4
Discontinuation of Subjects
A subject may withdraw from the study at any time for any reason without prejudice to their 
future medical care by the physician or at the institution.  The investigator or sponsor may 
withdraw the subject at any time (e.g., 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 
the Safety/Follow-up visit 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 source 


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documents.  The reason for termination, date of stopping investigational product, and the total 
amount of investigational product taken must be recorded in the CRF and source documents.
Subjects who discontinue will not be replaced.
4.4.1
Management of Blood Pressure and Pulse During the Study
To ensure that potential blood pressure and pulse increases associated with the use of SPD489 
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 4.4.1.1 and 4.4.1.2. 
4.4.1.1
Systolic and Diastolic Blood Pressure
Blood pressure criteria for further evaluation have been developed based on the normative 
data presented in the National Institutes for Health Fourth Report on the Diagnosis, 
Evaluation, and Treatment of High Blood Pressure in Children and Adolescents (2005).
Increases in blood pressure (both systolic and diastolic) from the 50th to the 95th percentile 
(representative of a change of 2 standard deviations) range from 17-20 mmHg for both boys 
and girls in this age range.  Based on this range, an increase of >15mmHg from Visit 0 was 
selected for this protocol.
If there are elevations in the average (of 3 readings with approximately 2 minutes between 
readings) systolic and/or diastolic blood pressure based on the criteria defined below further 
assessment will be required:  
•
Elevations in average (of 3 readings) sitting systolic blood pressure defined as an increase 
of >15 mmHg from Visit 0 of the antecedent study for “A” Subjects or Visit 0 for “B” 
Subjects or an average (of 3 readings) sitting systolic blood pressure value ≥95th 
percentile for age, sex, and height percentile
•
Elevations in average (of 3 readings) sitting diastolic blood pressure defined as an increase 
of >15 mmHg from Visit 0 of the antecedent study for “A” Subjects or Visit 0 for “B” 
Subjects or an average (of 3 readings) sitting diastolic blood pressure value ≥95th 
percentile for age, sex, and height percentile
The investigator will discuss each subject meeting any criterion with the medical monitor, and 
a joint decision between the investigator and the medical monitor will be made regarding dose 
reduction and continued participation in the study. If the dose has been previously decreased, 
or if the subject is already at the lowest dose, then the subject will be immediately 
discontinued from the study.
If the subject is allowed to remain in the study, an unscheduled visit will be conducted the 
next business day. If a visit cannot be conducted the next day, the subject may be 
discontinued from the study.


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At the unscheduled visit, 3 individual measurements will be obtained and the average of the 3 
blood pressure measurements for each parameter will be reported. The investigator will notify 
the medical monitor of the results and if the previously met criteria remain, the subject will be 
discontinued from the study. 
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.
4.4.1.2
Pulse
The resting pulse rate criterion for further evaluation has been defined based on the normative 
data presented in the National Health Statistics Reports “Resting Pulse Rate Reference Data 
for Children, Adolescents, and Adults: United States, 1999-2008.”
Elevations in the average (of 3 readings) sitting pulse, defined as 126 beats per minute (bpm) -
equivalent to the 99th percentile for this age range, require further assessment. 
The investigator will discuss each subject meeting this criterion with the medical monitor, and 
a joint decision between the investigator and the medical monitor regarding dose reduction 
and continued participation in the study. If the dose has been previously decreased, or if the 
subject is already at the lowest dose, then the subject will be immediately discontinued from 
the study.  
If the subject is allowed to remain in the study, an unscheduled visit will be conducted the 
next business day.  If a visit cannot be scheduled the next day, the subject must be 
discontinued from the study.
At the unscheduled visit, the investigator will notify the medical monitor of the result and if 
the pulse is still >126 bpm, the subject will be discontinued from the study.
Any subject with a pulse rate ≤126 bpm may be discontinued from the study upon the clinical 
judgment of the investigator regarding the subject’s safety.
4.4.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the 
subject’s medical record and on the CRF.  If a subject is withdrawn for more than 1 reason, 
each reason should be documented in the source document and the most clinically relevant 
reason should be entered on the CRF.
Reasons for discontinuation include but are not limited to:
•
Adverse event


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•
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).  
4.4.3
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact the parent or LAR of any 
subject lost to follow-up at any time point prior to 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.
5.
PRIOR AND CONCOMITANT TREATMENT
All non-study treatment (including but not limited to herbal treatments, vitamins, behavioral 
treatment, non-pharmacological treatment, such as psychotherapy) received since the 
subject’s last visit in the antecedent study and through the final study contact (including 
protocol-defined follow-up period) must be recorded on the appropriate CRF page. 
5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
behavioral treatment, non-pharmacological treatment, such as psychotherapy) received within 
30 days (or pharmacokinetic equivalent of 5 half-lives, whichever is longer) prior to the date 
of first dose of investigational product. Prior treatment information must be recorded on the 
appropriate CRF page.
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 on the appropriate CRF page.


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5.2.1
Permitted Treatment
Medications permitted during the study are listed below:
•
Stable dose of thyroid medication, provided the same dose had been used during the 
antecedent study  Stable dose of bronchodilator inhalers (however, beta-agonists and 
chronic use of oral corticosteroids is prohibited)
•
Any medications that do not affect blood pressure, heart rate, or the CNS, and which are 
considered necessary for the subject’s welfare, may be administered at the discretion of 
the Investigator
•
Non-sedating antihistamines such as fexofenadine (ALLEGRA®, Sanofi), loratadine 
(CLARITIN®, Schering-Plough), and cetirizine hydrochloride (ZYRTEC®, McNeil-PPC)
•
Over-the-counter non-stimulant cold remedies
Concomitant psychotherapy must also be recorded in the appropriate section of the source 
documents and in the appropriate CRF page.
5.2.2
Prohibited Treatment
Table 3 details the washout period, relative to Visit 0, for treatments that are excluded during 
this study. Subjects can only be instructed to discontinue a medication for this study after the 
informed consent has been obtained. 
Table 3:
Common Excluded Treatments and Associated Washout Period– Relative to 
Visit 0-
Minimum Number of Days Before Visit 0
Treatment
7
14
30
Psychostimulants, Amphetamines, and Amphetamine-like 
agents
X
Antihypertensives a
X
Antihistamines (centrally and peripherally-active)
X
Herbal preparations (including melatonin)
X
Investigational compounds (other than the investigational 
compound received during participation in 1 of the respective 
antecedent SPD489 studies).
X
Sedatives, anxiolytics, antipsychotics a
X
Monoamine oxidase inhibitor (MAOIs) a
X
Antidepressants a
X
Clonidine and guanfacine
X
Selective noradrenaline reuptake inhibitors and noradrenaline 
reuptake inhibitors a
X


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Table 3:
Common Excluded Treatments and Associated Washout Period– Relative to 
Visit 0-
Minimum Number of Days Before Visit 0
Treatment
7
14
30
a These medications may signal that an exclusionary diagnosis is present. The medical monitor should be consulted prior to 
instructing a subject to discontinue one of these medications for this study.
6.
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is SPD489, which will be provided in 5, 10, 15, 20, and 30mg capsules. 
Additional information is provided in the current SPD489 IB.
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 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 SPD489 during this study. 
Subject numbers are assigned to all subjects as they consent to take part in the antecedent 
study.  Within each site (numbered uniquely within a protocol), the subject number is 
assigned to subjects according to the sequence of presentation for the antecedent study 
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6.2.3
Dosing
Dosing should begin at approximately 7:00AM (+/-2 hours) on the morning after Visit 0. 
Subjects will be instructed to take 1 capsule 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. 
SPD489 will be administered one of the following ways: 
•
swallow SPD489 capsule whole, or
•
open capsule, empty and mix the entire contents with either yogurt, water or orange juice.
The contents should be mixed until completely dispersed. The subject must ingest the entire 
amount of mixture immediately within 3 minutes. The subject should not take anything less 
than one capsule per day and a single capsule cannot be split. The empty gelatinous capsule 
should be discarded. 
A subject from the open-label antecedent study (SPD489-211) will enter this study on their 
optimal dose, if entering this study within 3 days. However, if a subject is entering this study 
from the double-blind antecedent study (SPD489-347), or the subject does not immediately 
enter following the dose maintenance period of the unblinded study (SPD489-211), then the 
subject will begin dosing at 5mg of SPD489 and should be titrated in a stepwise fashion until 
an optimal dose is reached. 
The objective of dose optimization during the first 6 weeks for “B” Subjects is to ensure that 
subjects are titrated to an optimal dose of study drug based on TEAEs and clinical criteria.
The Investigator will categorize subject response into 1 of the 3 conditions, along with the 
associated actions, below. Dose optimization should continue during the first 4 weeks until 
an “acceptable response” is achieved.
•
Intolerable response (i.e., subject experiences intolerable side effects): This response 
suggests tapering the subject to a lower dose of investigational product (if available).
However, if this lower dose also produces an intolerable effect, the subject should be 
discontinued from the study.
•
Ineffective response (i.e., subject has not achieved at least a 30% reduction in 
ADHD-RS-IV Preschool Version Total Score from Baseline (Visit 0) of the antecedent 
study and a CGI-I score of 1 or 2): This response suggests titrating the subject to the next 
available dose of investigational product (if available, provided there are no tolerability 
issues).
•
Acceptable response (i.e., subject has achieved at least a 30% reduction in ADHD-RS-IV 
Preschool Version Total Score from Baseline (Visit 0) of the antecedent study 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.


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Further, if the “acceptable” dose is well tolerated and, in the opinion of the clinician, the 
subject may potentially receive additional symptom reduction, the dose may be increased to 
the next dose strength.
Dosing will continue at the protocol specified doses of 5, 10, 15, 20, and 30mg for all subjects 
for the duration of the trial.  Subjects who turn 6 years old during the course of the trial will 
be expected to remain on a protocol specified dose.  Higher doses of SPD489, consistent with 
the approved product labeling for children ages 6 and older will not be provided as part of this 
protocol.  If the Investigator believes a subject who turns 6 during the course of the trial 
requires a higher dose of SPD489, the subject must be discontinued from the trial.
Investigators have the option to down-titrate a subject in the event the dose is not tolerated. If 
the subject experiences unacceptable tolerability on the 5mg dose, the subject will be 
discontinued.  Additionally, the Investigator should not decrease or increase the dose by more 
than 1 dose level at any 1 visit. During the Maintenance Period, the investigator may make 
further dose adjustments based upon TEAEs and clinical judgment.  
Subjects who are unable to tolerate investigational product 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 
product(s) 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 statements ‘For clinical trial use only’, and/or ‘CAUTION: New 
Drug - Limited by Federal (or US) 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. 


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Additional labels (e.g., 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
•
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:
SPD489 capsules are packaged in 9-count and 30-count high density polyethylene bottles 
with child-resistant closures.  
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement 
in advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that 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 
(i.e., certified min/max 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.


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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), e.g., 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.
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 overall responsibility for administering/dispensing investigational 
product.  Where permissible, tasks may be delegated to a qualified designee (e.g., 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 his/her designee (as documented by the investigator in the applicable 
study delegation of authority form) will dispense the investigational product only to subjects 
included in this study following the procedures set out in the study protocol.  Each subject 
will be given only the investigational product carrying his/her treatment assignment.  All 
dispensed medication will be documented on the CRFs and/or other investigational product 
record. The investigator is responsible for assuring the retrieval of all study supplies from 
subjects.  
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 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 


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labeled amount is to be documented in lieu of counting.  Shipment return forms, when used, 
must be signed prior to shipment from the site.  Validated electronic return systems (i.e., IRT) 
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 prior to shipment.  Shipment of all returned investigational 
product must comply with local, state, and national laws.
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
Subjects 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 (e.g., 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.
Subjects who have taken 80-100% of the investigational product are regarded as being 
compliant with the study protocol.  Compliance must be assessed by the Investigator.
The calculation of medication compliance is as follows: 
Protocol
by
Prescribed
Capsules
100
Taken
Capsules
Total
Compliance
×
When performing the calculation of medication compliance for investigational product, the 
total capsules taken must also include number of capsules not returned by the subject to the 
site.
7.
STUDY PROCEDURES
7.1
Study Schedule
The Schedule of Assessments (Table 1 and Table 2) details 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 i.e., ADHD-RS-IV
Preschool Version, CGI-S, CGI-I, CSHQ and Columbia Suicide Rating Scale (C-SSRS)


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Pediatric/Cognitively Impaired Version must be completed by the same rater whenever 
possible.
For “A” Subjects, throughout the Dose Maintenance Period of the study, visits should be 
scheduled as outlined (±5 days) with reference to Visit 0.  The Follow-up Telephone Call 
should be scheduled 7 days post-last dose with a +2 day visit window.
Subjects will be required to visit the site up to 14 times over a 53-week period.
For “B” Subjects, throughout the Dose-Optimization Period of the study, visits should be 
scheduled as outlined (±2 days), and throughout the Dose-Maintenance Period of the study, 
visits should be scheduled as outlined (±5 days) with reference to Visit 0.  The Follow-up 
Telephone Call should be scheduled 7 days post-last dose with a +2 day visit window.
Subjects will be required to visit the site up to 20 times over a 57-week period.
Additional unscheduled visits and/or assessments may occur as needed for safety (e.g., 
unscheduled visits for blood pressure and/or pulse measurements will be conducted as 
described in Section 4.4.1) 
7.1.1
Screening and Washout Period
The Principal Investigator or his/her designee must obtain written informed consent from the 
subject’s parent/LAR prior to any study-related procedures conducted during the Screening 
Visit (Visit -1). 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, prior to the performance of any study-related procedures.
A washout period may be required to discontinue any prohibited medication (see Table 2).  A 
subject cannot be instructed to wash out any medication for this study until after informed 
consent is obtained.
Screening assessments may take place across multiple days to allow enough time to complete 
all procedures and confirm initial study eligibility.  Screening procedures and dates should be 
well documented in the source documents and CRF. The screening date is the date the 
parent/LAR has signed informed consent for this study. Subjects requiring washout must have 
an abbreviated physical examination, clinical laboratory tests, and 12-lead ECG repeated if 
more than 30 days have elapsed since the safety measurements at the Screening Visit 
(Visit -1) were collected.  
A screen failure is a subject who has given informed consent and failed to meet any of the 
inclusion and/or met at least 1 of the exclusion criteria and has not been administered 
investigational product.


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For screen failure subjects, the investigator or assigned site staff designee will access the 
IWRS to record the subject as a screen failure.
Subjects cannot be rescreened once they have been designated as a screen failure.
Reassessment of subjects who failed specific inclusion/exclusion criteria is not allowed.
7.1.1.1
Screening Visit (Visit -1) for “B” Subjects
All “B” Subjects will be screened at Visit -1 to establish eligibility for study participation. 
Some screening assessments (vital signs, height, weight, clinical laboratory tests, and ECGs) 
must be repeated if more than 30 days have elapsed since the End of Study Visit of the 
antecedent study. 
Table 2 details all procedures to be completed at the Screening Visit (Visit -1). Additional 
clarification on the procedures performed during the Screening Visit (Visit -1) is provided 
below:
•
All AEs occurring after signature of informed consent must be recorded in the source 
documents and CRF. Any AE ongoing at the time of the End of Study Visit from the 
antecedent study must be recorded on the CRF for this study. 
•
Document any new findings on the Medical History CRF with enough detail to permit 
detection of change over time.
•
Twelve-lead ECG will be performed after approximately 5 minutes of rest.  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.
•
Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in 
between each collection) during the visit. The average of each set of 3 measurements will 
be used to determine continued participation in the study (see Section 4.4.1).
•
The “Since Last Visit” version of the Pediatric/Cognitively Impaired Version C-SSRS 
should be completed.
•
Record historical/concomitant medications as follows:
All lifetime psychoactive medications and lifetime non-pharmacological 
interventions (behavioral therapy) for ADHD
Other medications used during the 30 days prior to the Screening Visit (Visit -1). 


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7.1.1.2
Washout Telephone Call (Visit Phone Call) for “B” Subjects 
The Washout Period should 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 a minimum of 5 times the half-life of the 
medication.  Washout periods for prohibited medications are defined in Table 2.
All “B” Subjects requiring washout must have an abbreviated physical examination, clinical 
laboratory tests, and 12-lead ECG repeated if more than 30 days have elapsed since these
safety measurements at the Screening Visit (Visit -1) were collected.  The results of these 
assessments must be reviewed by the Investigator prior to the subject being enrolled.
As part of the Washout Telephone Call, site personnel should perform the following 
procedures:
•
Schedule Visit 0
•
Review the inclusion/exclusion criteria
•
Ask about any concomitant medications that the subject is taking.  If any concomitant 
medications that require washout are noted, instructions for appropriate washout should be 
provided
•
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
Visit 0 for “A” Subjects
Visit 0 for “A” Subjects is the same day as the End-of-Study Visit for the antecedent study.  
Subjects will be screened for eligibility for the SPD489-348 during this visit. 
The Principal Investigator or his/her designee must obtain written informed consent from the 
subject’s parent/LAR prior to any SPD489-348 study-related procedures conducted during 
Visit 0. 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, prior to the performance of any SPD489-348 study-related procedures.
Inclusion/exclusion criteria must be reviewed during this visit to ensure subjects continue to 
meet all eligibility criteria.
Table 1 outlines all procedures to be conducted during Visit 0 with further clarification 
provided below:


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•
Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in 
between each collection) during the visit.  The average of each set of 3 measurements will 
be used to determine continued participation in the study (see Section 4.4.1).
•
For eligible subjects, the investigator or assigned study center staff designee will access 
the IWRS to enroll the subject and obtain an investigational medicinal product bottle 
number to dispense to the subject.  Subjects will be dispensed a 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 following Visit 0.
•
The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired Version 
should be completed.
7.1.1.4
Visit 0 for “B” Subjects
Once all screening results, including clinical laboratory tests and ECGs, have been obtained in 
addition to repeat assessments (if required), and reviewed and after the subject has completed 
any required washout period (if applicable), subjects will return to the study center for their 
Visit 0.
Inclusion/exclusion criteria must be reviewed during this visit to ensure subjects continue to 
meet all eligibility criteria.
Table 2 outlines all procedures to be conducted during Visit 0 with further clarification 
provided below:
•
For subjects with more than 30 days since the safety measurements at the Screening Visit 
(Visit -1) were collected, an abbreviated physical examination and clinical laboratory tests
must be repeated, and the results reviewed by the Investigator prior to the subject being 
enrolled.
•
Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in 
between each collection) during the visit.  The average of each set of 3 measurements will 
be used to determine continued participation in the study (see Section 4.4.1).
•
For eligible subjects, the investigator or assigned study center staff designee will access 
the IWRS to enroll the subject and obtain an investigational medicinal product bottle 
number to dispense to the subject.  Subjects will be dispensed a 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 following Visit 0.
•
The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired Version 
should be completed.


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7.1.2
Treatment Period 
7.1.2.1
Dose-optimization Period (Visits 1 to 6) for “B” Subjects 
During the first 6 weeks of treatment, visits will be scheduled every 7 days (±2 days) to assess 
safety, efficacy, and tolerability and to allow investigators to titrate subjects to their optimal 
dose of SPD489 based on TEAEs and the dosing guidelines in Section 6.2.3. 
If the optimal dose is well tolerated and, in the opinion of the investigator, the subject would 
potentially receive additional symptom reduction, the subject may be titrated to the next 
allowed dose.
Throughout the Dose-optimization Period, subjects may attend the clinic for unscheduled 
visits to address any medical needs that arise between scheduled visits.
See Table 2 for procedures that are completed at Visits 1 to 6.  Further clarification for these 
visits is outlined below:
•
At each visit during the Dose-optimization 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 following each visit.
•
Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in 
between each collection) during the visit.  The average of each set of 3 measurements will 
be used to determine continued participation in the study (see Section 4.4.1).
•
Scales should be completed by the same rater whenever possible.
•
The sleep diary is to be completed by the parent/LAR.
•
The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired Version
should be completed during the Optimization Period.
7.1.2.2
Dose Maintenance Period (Visits 1 to 13/ET) for “A” Subjects
Following Visit 0 subjects will continue daily morning treatment for an additional 48 weeks.
Subjects will attend the clinic every 4 weeks for procedures to be performed. 
Throughout the Maintenance Period, subjects may attend the clinic for unscheduled visits to 
address any medical needs that arise between scheduled visits.
Table 1 outlines the procedures to be completed at each visit during the Maintenance Period.  
Additional clarification on the procedures to be performed during the Maintenance Period is 
provided below:


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•
Scales are to be completed by the same rater whenever possible
•
At each visit during the Maintenance Period, subjects must return any empty or unused 
bottles to permit drug accountability and compliance to be assessed.
•
Subjects will be dispensed a 35-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 following each visit.
•
Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in 
between each collection) during the visit.  The average of each set of 3 measurements will 
be used to determine continued participation in the study (see Section 4.4.1).
7.1.2.3
Dose Maintenance Period (Visits 7 to 18/ET) for “B” Subjects
Following titration to an optimal dose of SPD489, subjects will continue daily morning 
treatment for an additional 48 weeks. Subjects will attend the clinic every 4 weeks for 
procedures to be performed. 
Throughout the Maintenance Period, subjects may attend the clinic for unscheduled visits to 
address any medical needs that arise between scheduled visits.
Table 2 outlines the procedures to be completed at each visit during the Maintenance Period.  
Additional clarification on the procedures to be performed during the Maintenance Period is 
provided below:
•
Scales are to be completed by the same rater whenever possible
•
At each visit during the Maintenance Period, subjects must return any empty or unused 
bottles to permit drug accountability and compliance to be assessed.
•
Subjects will be dispensed a 35-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 following each visit
•
Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in 
between each collection) during the visit.  The average of each set of 3 measurements will 
be used to determine continued participation in the study (see Section 4.4.1).
7.1.2.4
End-of-Study Visit (Visit 13/ Early Termination) for “A” Subjects 
All subjects who complete the study or discontinue early will complete the End-of-Study 
Visit.
Table 1 list the procedures to be completed at Visit 13/ET and should serve as the primary 
point of reference regarding visit-specific study procedures.
Further clarification on the procedures performed during the End-of-Study Visit is provided 
below:


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•
Unused investigational product and empty containers will be collected to calculate 
medication compliance.
•
Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in 
between each collection) during the visit.  The average of each set of 3 measurements will 
be used to determine if additional follow-up is needed (see Section 4.4.1).
7.1.2.5
End-of-Study Visit (Visit 18/ Early Termination) for “B” Subjects 
All subjects who complete the study or discontinue early will complete the End-of-Study 
Visit.
Table 2 list the procedures to be completed at Visit 18/ET and should serve as the primary 
point of reference regarding visit-specific study procedures.
Further clarification on the procedures performed during the End-of-Study Visit is provided 
below:
•
Unused investigational product and empty containers will be collected to calculate 
medication compliance.
•
Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in 
between each collection) during the visit.  The average of each set of 3 measurements will 
be used to determine if additional follow-up is needed (see Section 4.4.1).
7.1.3
Safety Follow-up Period for “A” and “B” Subjects
The follow-up period for this protocol is 7 days +2 days from the last dose of investigational 
prodect.
At the end of this period there will be a telephone call initiated by the site to query for any 
SAE follow-up SAEs, AEs, and concomitant treatments.  All AEs and SAEs that are not 
resolved at the time of this contact will be followed to closure (see Section 8.1).
7.1.4
Additional Care of Subjects After the Study
There is no planned care for subjects after 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 below.  
Assessments are to be performed according to the schedule shown in Table 1 and Table 2.


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Care must be taken by the site personnel or the Investigator to fully explain the scale prior to 
completion.
If the subject terminates treatment early, all assessments listed in Table 1 and Table 2 for Visit 
13/ET or Visit 18/ET and the Follow-up Telephone 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 and Table 2.
7.2.2
Screening Assessments
Not applicable. 
7.2.3
Efficacy
7.2.3.1
Attention-deficit/Hyperactivity Disorder Rating Scale IV Preschool Version
The ADHD-RS-IV Preschool Version (McGoey et al. 2007), the secondary efficacy measure, 
is completed by the Sponsor approved clinician at the site and will be administered at Visit 1 
and each subsequent visit up to and including the End of Study Visit to capture the ADHD 
symptoms within each study period.  The ADHD-RS-IV Preschool Version was adapted from 
the ADHD Rating Scale-IV (DuPaul et al. 1998) and provides examples appropriate for the 
developmental level of preschool children.  The ADHD-RS-IV Preschool Version is an 18-
item questionnaire that requires the respondent to rate the frequency of occurrence of ADHD 
symptoms as defined by DSM-IV-TR criteria.  Each item is scored on a 4-point scale ranging 
from 0 (never or rarely) to 3 (very often) with total scores ranging from 0-54.  The 18 items 
may be grouped into 2 subscales: hyperactivity/impulsivity (even numbered items 2-18) and 
inattentiveness (odd numbered items 1-17).
The ADHD-RS-IV Preschool Version will be completed by a clinician trained and 
experienced in the evaluation of preschool children with ADHD.  Since the ADHD-RS-IV 
Preschool Version is used to guide dosing decisions, if it is not completed by the Principal 
Investigator or Sub-Investigator who is medically/clinically responsible for the subject, it 
must be reviewed and signed by them. All individuals performing this assessment must be 
pre-approved by the Sponsor or delegated vendor.
The title, version, and date of the ADHD-RS-IV Preschool Version used in this study are 
included in Table 1 and Table 2.


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7.2.3.2
Clinical Global Impressions
The CGI Scale (Guy 1976) permits a global evaluation of the subject’s severity and 
improvement over time.  The CGI has been used extensively in clinical studies of ADHD 
(Michelson et al. 2001; Weiss et al. 2005; Wilens et al. 2001).
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 Visit 0 of the antecedent study.  Ratings will be completed with respect to ADHD 
symptoms.
At each visit from Visit 1 up to and including Visit 13/ET (for “A” Subjects) and Visit 18/ET
(for “B” Subjects), the Investigator will assess the subject’s improvement relative to the 3 
target areas of improvement recorded at Visit 0 of the antecedent study, on the CGI-I, a 
7-point scale ranging from 1 (very much improved) to 7 (very much worse).
The CGI-I should be completed by a clinician trained and experienced in the evaluation of 
preschool children with ADHD.  Since the CGI-I is used to guide dosing decisions, if it is not 
completed by the Principal Investigator or Sub-Investigator who is medically/clinically 
responsible for the subject, it must be reviewed and signed by them. All individuals 
performing this assessment must be pre-approved by the Sponsor or delegated vendor.
The title, version, and date of the CGI-I used in this study are included in Table 1 and Table 2.
7.2.4
Safety
The name and address of each third party vendor (e.g., clinical laboratory) used in this study 
will be maintained in the investigator’s and sponsor’s files.
7.2.4.1
Medical and Medication History
Any new medical history, i.e., medical conditions, which arose after the recording of the 
medical history in the antecedent study, should be recorded at Visit 0 for “A” Subjects and 
Screening Visit (Visit -1) for “B” Subjects.
7.2.4.2
Physical Examination (Including Height and Weight)
A full physical examination will be performed at Visit 0 for “A” Subjects and at the Screening 
Visit (Visit -1) for “B” Subjects. Additionally, for “B” Subjects, an abbreviated physical 
examination is required at Visit 0 if more than 30 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 (e.g., physician, physician assistant or a nurse practitioner).


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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)
•
Musculoskeletal
•
Neurological.
If an abbreviated physical examination is required for “B” Subjects at Visit 0, a review of the 
body systems will include the following:
•
General Appearance
•
Respiratory
•
Cardiovascular.
Abnormalities identified at the Screening Visit (Visit -1) will be documented in the subject’s 
source documents and on the medical history CRF.  Changes after the Screening Visit 
(Visit -1) will be captured as AEs on the AE CRF page, as deemed by the investigator.
7.2.4.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain if AEs have 
occurred since the previous visit (e.g., “Have you had any health problems since your last 
visit?”).  Adverse events are collected from the time informed consent is signed. Any AE 
ongoing from the antecedent study must be entered. Any AE ongoing from the antecedent 
study must be recorded on the CRF for this study. (Please refer to Section 8, Adverse and 
Serious Adverse Events Assessment.)
7.2.4.4
Vital Signs
Measurements of oral or tympanic temperature and sitting respiratory rate will be performed 
at the Screening Visit (Visit -1) for “B” Subjects only. For subjects who enter this study 
within 7 days of completing the antecedent study, vital signs are collected at the End of Study 
Visit of the antecedent study. 


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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 5 minutes.
Blood pressure will be determined by automated cuff (the same unit 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 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 unit 
provided by the central ECG vendor.  The automated cuff will obtain 3 measurements with 
approximately 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 and CRF.
Any clinically significant deviations from Baseline (Visit 0) vital signs which are deemed 
clinically significant in the opinion of the investigator are to be recorded as an AE.
7.2.4.5
Height and Weight
Height will be captured at each 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.
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.
7.2.4.6
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 assessments for “A” Subjects will be performed at Visit 0, Visit 6, and 
Visit 13/ET. While the Clinical Laboratory assessments for “B” Subjects will be performed at 
the Screening Visit (Visit -1), Visit 9, Visit 16, and Visit 18/ET.  Additionally, clinical 
laboratory tests are required to be repeated prior to Visit 0 with results reviewed before 
enrolling the subject in the study if more than 30 days have elapsed since the clinical 
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The following clinical laboratory assessments will be performed: 
Biochemistry and Endocrinology
A blood sample (~5mL) for biochemistry will be taken to assess the following parameters:
Total Cholesterol
Calcium
AST
Uric Acid
Phosphorus
Blood Urea Nitrogen
ALT
Total Bilirubin
Sodium
Creatinine
ALP
Glucose
Potassium
Albumin
GGT
Total Protein
TSH
Lactate Dehydrogenase
Free T4
Hematology
A blood sample (~4mL) for hematology will be taken to assess the following parameters:
Hemoglobin
Neutrophils
Hematocrit
Lymphocytes
RBC
Monocytes
Platelet count
Eosinophils
WBC count total and differential 
Basophils
MCH
Bands
MCHC
MCV
Urinalysis
A urine sample (~10mL) for urinalysis will be collected to assess the following parameters:
Glucose
pH
Specific Gravity
Urobilinogen


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Blood
Color
Ketones
Leukocyte Esterase
Protein
Nitrate
Bilirubin
If urinalysis detects protein and/or blood, a microscopic examination will be conducted. The 
microscopic examination will consist of RBC, WBC, casts, and bacteria.
7.2.4.7
Electrocardiogram
For “A” Subjects a 12-lead ECG will be performed at Visit 0, Visit 3, Visit 6, Visit 9, Visit 12 
and Visit 13/ET. For “B” Subjects a 12-lead ECG will be performed at the Screening Visit 
(Visit -1), Visit 0, Visit 1-6, and Visit 8, Visit 11, Visit 14, Visit 17, and Visit 18/ET. 
Additionally, for “B” Subjects, a 12-lead ECG is required to be repeated prior to Visit 0 with 
results reviewed before enrolling the subject in the study if more than 30 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.
All ECGs will be performed after 5 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 CRF 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.


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7.2.4.8
Children’s Sleep Habits Questionnaire and Sleep Diary 
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 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 completed at every visit to the site starting with 
the Screening Visit (Visit -1) for “B” Subjects and Visit 0 for “A” Subjects and will be 
completed by the subject’s parent/LAR. 
The subject’s parent/LAR will complete a sleep diary to log daytime napping and nighttime 
sleep. 
7.2.4.9
Columbia-Suicide Severity Rating Scale- Pediatric/Cognitively Impaired Version
The C-SSRS (Posner 2007) 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 2 required items pertaining to suicidal ideation, 4 required items 
pertaining to suicidal behavior, and 1 required item pertaining to non-suicidal self-injurious 
behavior.  There are 8 additional suicidal ideation items and 2 additional suicidal behavior 
items which are completed in cases of positive responses for other items, as well as 2 items 
for completed suicide and suicide behavior present during the interview.  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 pre-approved by the sponsor or delegated 
vendor.
The Pediatric/Cognitively Impaired Version of the scale will be used in the study. There are 
two versions of the C-SSRS:
•
The “Baseline” version will be administered at the Screening Visit (Visit -1) for all 
subjects as part of the antecedent study visit procedures. 
•
The “Since Last Visit” version will be completed for all subjects at each visit in this study.
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 Table 1 and Table 2.


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7.2.4.10 Suitability of the Subject to Remain in the Study
At each visit (except for Visit 13/ET or Visit 18/ET) starting with the Visit 1, the Investigator 
or a medically qualified designee should assess whether it remains in the best interest of the 
subject to continue in the study and that it is safe for the subject to do so.  As part of the 
assessment of the subject’s suitability to remain in the study the Investigator should assess the 
subject’s current potential for suicide, suicidal ideation, self-harm, or harm to others, 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.  The Investigator should also ensure that there is appropriate 
documentation of this assessment in the subject’s source notes.  As part of this assessment, if 
appropriate, the Investigator should discuss risk factors for suicide with the subject.  Where a 
subject has suffered an accidental injury, the Investigator should ensure that this was a true 
accidental injury, rather than an episode of self-harming or a suicide attempt.
The subject’s source notes should clearly document that the assessment of continued 
suitability including an assessment of the subject’s current potential risk of suicide, suicidal 
ideation, feelings of hopelessness, drug use, self-harm, or harm to others has taken place and 
should contain the decision on whether the subject is suitable to continue in the study.
The Investigator should pay particular attention to:
•
Any “yes” response to items 2, 3, 4, or 5 on the C-SSRS or any suicidal behavior.
Any subject who has 1 or more positive responses must undergo further evaluation to ensure 
that they are not in any way at risk.  The evaluation and decision should also be clearly 
documented in the subject’s source notes.
7.2.5
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)
Safetya
Biochemistry 
5
2
10
Hematology
4
2
8
Total mL
18
a Biochemistry and hematology clinical laboratory tests will be repeated at Baseline if 30 days or longer have elapsed since the
Screening Visit. 
During this study, it is expected that approximately 18mL 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 


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laboratory for an individual assessment; however, the total volume drawn over the course of 
the study should be approximately 18mL.  When more than 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.  
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 on 
the appropriate AE pages in the CRF and in source documents.  In addition to untoward AEs, 
unexpected benefits outside the investigational product indication should also be captured on 
the AE CRF.
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 pre-treatment events, after initiation of investigational product, 
must be recorded as new AEs (for example, if a subject experiences mild intermittent 
dyspepsia prior to 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 CRF).


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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.
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 document.
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 CRF.  Outcomes 
are as follows:
•
Fatal
•
Not Recovered/Not Resolved


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•
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 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 which were not present at the pre-treatment 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 (e.g., 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
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (as defined below) must be reported to the 
sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
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 categories below are not mutually exclusive; the event can meet more than 1 category.


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•
Abuse
Persistent or sporadic intentional intake of investigational product when used 
for a non-medical purpose (e.g., 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 pre-specified total daily dose of 30mg 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 below.
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 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/legally-authorized representative/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the IB 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 
Pharmacovigilance 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 8.1.6) unless 
they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
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 
e-mail the form to the Shire Pharmacovigilance Department. A copy of the Shire Clinical 


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Trial Serious Adverse Event 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 Pharmacovigilance Department and the CRO/Shire Medical Monitor 
within 24 hours of the first awareness of the event. 
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 
Pharmacovigilance Department within 24 hours of the first awareness of the event.


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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 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 (i.e., 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, the 
action taken with the investigational product should be recorded as “dose not changed” or 
“not applicable” (if the subject never received investigational product).
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the 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 SPD489
program.  
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.
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 CRF.  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.  


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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 CRF entry within approximately 3 business 
days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management 
plan.  Quality control and data validation procedures are applied to ensure the validity and 
accuracy of the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures.  Data queries requiring clarification 
are to be communicated to the site for resolution.  Only authorized personnel will make 
corrections to the clinical database, and all corrections are documented in an auditable 
manner.
9.3
Data Handling Considerations
Not applicable. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.  
The SAP will provide the statistical methods and definitions for the analysis of the efficacy 
and safety data, as well as describe the approaches to be taken for summarizing other study 
information such as subject disposition, demographics and baseline characteristics, 
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 prior to database lock.
All statistical analyses will be performed using SAS® (SAS Institute, Cary, NC 27513). 
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis or adaptive design for this study.


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A 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 
patients in the study and of those still to be entered. Data will be provided to the DMC by an 
independent statistical and reporting group not assigned to the study. The data provided to the 
DMC will not be considered ‘clean’ until the database is locked.
Further details regarding the DMC can be found in the DMC charter, which will be available 
prior to the administration of investigational product.  
9.6
Sample Size Calculation and Power Considerations
Approximately 100 subjects will be enrolled into this study to ensure that at least 50 subjects 
are exposed to SPD489 for one year. Subjects will enroll directly into this study from an
antecedent SPD489 study (SPD489-211 or SPD489-347).
The sample size for this study is not based on statistical considerations. 
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Safety Analysis Set will consist of all subjects who have taken at least 1 dose of 
investigational product. 
The FAS will consist of all subjects in the Safety Set who have at least 1 post-dose ADHD-
RS-IV Preschool Version Total Score assessment during the study.
9.8
Efficacy Analyses
The FAS will be used to summarize the efficacy data. 
Rules for handling of missing data will be described in the SAP. 
9.8.1
Clinician-administered ADHD-RS-IV Preschool Version 
The efficacy endpoint for the ADHD-RS-IV Preschool Version is defined as the change from 
baseline on the clinician-administered ADHD-RS-IV Preschool Version Total Score, where 
baseline is defined as the baseline from the antecedent study for all subjects. 
The observed and change from baseline ADHD-RS-IV Preschool Version Total Score will be 
summarized at each applicable visit using the number of subjects, mean, standard deviation, 
median, minimum, and maximum values.  


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9.8.2
Clinical Global Impressions 
The efficacy endpoint for the CGI-I is defined as the proportion of subjects who had an 
“improved” CGI-I measurement.  The CGI-I categories of “very much improved” and “much 
improved” will be classified as “improved” and all other assessed categories will be grouped 
together as “not improved”.
The observed dichotomized CGI-I values will be summarized at each applicable visit using 
number of subjects and percentages.
9.8.3
Exploratory Efficacy Endpoints
Not applicable.
9.9
Safety Analyses
The Safety Analysis Set will be used to report the safety data. 
Safety analyses will be presented by treatment group of the antecedent studies and overall for 
the occurrence of TEAEs, clinical laboratory results, vital signs, ECG results, and sleep 
assessments including sleep diary data and CSHQ. 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities.  The 
number of events, incidence, and percentage of TEAEs will be calculated overall, by system 
organ class and, by preferred term.  Treatment-emergent adverse events 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 and 
overall. Potentially clinically important findings will also be summarized or listed.
The CSHQ will be summarized using appropriate descriptive statistics at each visit. 
The C-SSRS data will be listed for all subjects with any positive response.
9.10 Other Analyses
No other analyses are planned in this study.
10.
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements.  


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The name and address of each third party vendor (e.g., 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), EU 
Directive 2001/20/EC, as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and
(inter)national government regulations and guidelines.  Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of 
the study. 
The sponsor (or a nominated designee) is responsible for the preparation, 
submission, and confirmation of receipt of any regulatory authority approvals required prior 
to release of 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 non-pediatric 
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, 


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regulatory agencies and IRBs/ECs are notified as appropriate.  Additionally, the 
discontinuation of a registered clinical study which has been posted to a designated public 
website will be updated accordingly.
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), EU Directive 2001/20/EC, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study.  The 
investigator should also be able to estimate or demonstrate a potential for recruiting the 
required number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the 
investigator has delegated significant study-related tasks, and shall, upon request of the 
sponsor, provide documented evidence of any licenses and certifications necessary to 
demonstrate such qualification.  Curriculum vitae for investigators and sub-investigators 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 them 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), in compliance with Directive 2001/83/EC as 
amended by Directive 2003/63/EC and ICH Guidance E3 (1995). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document.  The investigator 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.


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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.
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 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 CRA/study monitor will verify the contents against the source 
data per the monitoring plan.  If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
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, subject sleep diary cards and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective 
national, local, or foreign regulatory authorities, 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 CRA/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 (e.g., subject’s medical 
file, appointment books, original laboratory reports, X-rays etc).  


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These records must be made available within reasonable times for inspection and duplication, 
if required, by a properly authorized representative of any regulatory agency (e.g., the US 
FDA, EMA, UK Medicines and Healthcare products Regulatory Agency) or an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be 
available for inspection upon request by representatives of, for example, the US FDA (as well 
as other US national and local regulatory authorities), the EMA, the Medicines and Healthcare 
products Regulatory Agency, other regulatory authorities, the sponsor or its representatives, 
and the IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator 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; any significant equity interest in the sponsor or subsidiaries as 
defined in 21 CFR 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 prior to any study-related procedures including screening assessments.  All 
consent and assent documentation must be in accordance with applicable regulations and 
GCP.  Each subject or the subject’s legally-authorized representative, as applicable, is 


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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 (i.e., a complete 
set of subject information sheets and fully executed signature pages) must be given to the 
subject or the subject’s legally-authorized representative, as applicable.  This document may 
require translation into the local language.  Signed consent forms must remain in each 
subject’s study file and must be available for verification at any time.
Within the source documents, site personnel should document instruction of and 
understanding by the parent/legally-authorized representative/caregiver of the safe, 
responsible storage and administration of investigational product to the study subject.
The principal investigator provides the sponsor with a copy of the consent form and assent
form which was reviewed by the IRB/EC and which received their favorable 
opinion/approval.  A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (i.e., sponsor or coordinating principal investigator) is responsible for this 
action.  Additionally, if the IRB/EC requires modification of the sample subject information 
and consent document provided by the sponsor, the documentation supporting this 
requirement must be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
For sites outside the EU, it is the responsibility of the investigator to submit this protocol, the 
informed consent document (approved by the sponsor or their designee), relevant supporting 
information and all types of subject recruitment information to the IRB/EC for review, and all 
must be approved prior to site initiation.
For sites within the EU, the applicant for an EC opinion can be the sponsor, the investigator, 
or for multicenter studies the coordinating principal investigator or sponsor, according to 
national provisions.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the CRO has received written 
IRB/EC approval of and copies of revised documents.


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For sites outside the EU, the investigator is responsible for keeping the IRB/EC apprised of 
the progress of the study and of any changes made to the protocol, but in any case at least 
once a year; for sites within the EU, this can be done by the sponsor, the investigator or for 
multicenter studies 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 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 SPD489; 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 (e.g., to 
confirm that laboratory results have been assigned to the correct subject).
The results of studies containing subjects’ unique identifying number, relevant medical 
records, and 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 
(e.g., Good Publication Practices 2) when forming a publication steering committee, which is 
done for large, multicenter Phase 2-4 and certain other studies as determined by Shire.  The 


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purpose of the publication steering committee is to act as a non-commercial body that advises 
or decides on dissemination of scientific study data in accordance with the scope of this 
policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information.  
The review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study.  To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) 
the copyright on his/her publications.  To the extent that the principal investigator has such 
sole, joint or shared rights, the principal investigator grants the sponsor a perpetual, 
irrevocable, royalty-free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, 
review articles, oral presentations, abstracts and posters at medical congresses, journal 
supplements, letters to the editor, invited lectures, opinion pieces, book chapters, electronic 
postings on medical/scientific websites, or other disclosure of the study results, in printed, 
electronic, oral or other form.
Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results.  Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication.  If requested in writing by 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, or termination of the study at all sites, or after the sponsor confirms 
there shall be no multicenter study publication of the study results, an investigator may 
individually publish the study results from the specific site in accordance with this section.  
The investigator must, however, acknowledge in the publication the limitations of the 
single-site data being presented.
Unless otherwise required by the journal in which the publication appears, or the forum in 
which it is made, authorship will comply with the ICMJE current standards.  Participation as 
an investigator does not confer any rights to authorship of publications.


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11.
REFERENCES
21 CFR 54 2(b) December 1998. Financial Disclosure by Clinical Investigators.
Connor DF 2002. Preschool attention deficit hyperactivity disorder: a review of prevalence, 
diagnosis, neurobiology, and stimulant treatment.  JDBP. 23: S1-S9.
Connor DF, Edwards G, Fletcher KE, et al. 2003. Correlates of comorbid psychopathology in 
children with ADHD. J Am Acad Child Adolesc Psychiatry.42(2):193 200.
DuPaul GJ, Power T, Anastopoulos A, Reed R 1998. ADHD rating scale IV checklists, norms 
and clinical interpretation: Guilford Press: New York, NY.
DuPaul GJ, McGoey KE, Eckert TL et. al. 2001. Preschool children with attention-
deficit/hyperactivity disorder: impairments in behavioral, social, and school functioning.  
JAACAP; 40(5): 508-515.
Egger HL, Angold A 2004. The preschool age psychiatric assessment (PAPA): a structured 
parent interview for diagnosing psychiatric disorders in preschool children. In: DelCarmen-
Wiggins, R, Carter A, editors. Handbook of infant, toddler, and preschool mental assessment. 
New York: Oxford University Press.
Egger HL, Erkanli A, Keeler G et. al. 2006a. Test-retest reliability of the preschool age 
psychiatric assessment (PAPA).  JAACAP; 45(5): 538-549.
Egger HL, Kondo D, Angold A  2006b. The epidemiology and diagnostic issues in preschool 
attention-deficit/hyperactivity disorder: a review. Infants and Young Children; 19(2): 109-
122.
Ghuman JK, Arnold LE and Anthony BJ 2008. Psychopharmacological and other treatments 
in preschool children with attention-deficit/hyperactivity disorder: current evidence and 
practice. JCAP; 18(5): 413-447.
Greenhill L, Kollins S, Abikoff H et. al. 2006. Efficacy and safety of immediate-release 
methylphenidate treatment for preschoolers with ADHD.  JAACAP 45(11): 1284-1293.
Greenhill LL, Posner K. Vaughan BS et. al. 2008. Attention deficit hyperactivity disorder in 
preschool children.  Child Adol Psych Clin N Am; 17: 347-366.
Guy W, (ed) 1976. Clinical global impressions (CGI). In: ECDEU assessment manual for 
psychopharmacology. Rockville (MD): US Department of Health, Education, and Welfare, 
125-126.
Hardman JG, Limbird LE, Gilman AG 2001. Goodman & Gillman’s The Pharmacological 
Basis of Therapeutics, 10th Edition. McGraw-Hill: New York, NY.


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“Increasing Prevalence of Parent-Reported Attention-Deficit/Hyperactivity Disorder Among 
Children 
United States, 2003 and 2007” Morbidity and Mortality Weekly Report 2010; 
59(44): 1439-1443.
Lahey BB, Pelham WE, Loney J et. al. 2004. Three-Year Predictive validity of DSM-IV 
attention deficit hyperactivity disorder in children diagnosed at 4 6 years of age.  Am J Psych; 
161: 2014-2020.
McClelland MM. Acock, AC. Piccinin, A. Rhea, SA. Stallings, MC 2013. Relations between 
preschool attention span-persistence and age 25 educational outcomes, Early Childhood 
Research Quarterly, 28(2), 314-324. 
McGoey K.E., DuPaul, G.J., Haley, E., and Shelton, TL 2007. Parent and teacher ratings of  
Attention-deficit/hyperactivity disorder in preschool: The ADHD Rating Scale-IV Preschool 
Version. Journal of Psychopathology and Behavioral Assessment; 29, 269-276.  
Michelson D, Faries D, Wenicke J, Kelsey D, Kendrick K, Sallee FR et al. 2001.
Atomoxetine in the treatment of children and adolescents with attention-deficit/hyperactivity 
disorder: a randomized, placebo-controlled, dose-response study. Pediatrics; 108(5): E83.
National Institutes of Health 2005.  The Fourth Report the Diagnosis, Evaluation, and 
Treatment of High Blood Pressure in Children and Adolescents. Bethesda, MD
Ostchega Y, Porter KS, Hughes J, Dillon CF, Nwankwo T 2011. Resting pulse rate reference 
data for children, adolescents, and adults: United States, 1999-2008. Natl Health Stat Report;
(41):1-16.
Posner K 2007. 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.
Rappley MD, Mullan PB, Alvarez FJ, et al. 1999. Diagnosis of attention-deficit/hyperactivity 
disorder and use of psychotropic medication in very young children. Arch Pediatr Adolesc 
Med;153(10):1039 45.
Smith KG and Corkum P 2007. Systematic review of measures used to diagnose attention-
deficit/hyperactivity disorder in research on preschool children. TECSE; 27(3): 164-173.
Sonuga-Barke EJS et.al. 2005. Varieties of preschool hyperactivity: multiple pathways from 
risk to disorder. Developmental Science; 8(2): 141-150.
Sonuga-Barke EJS and Halperin JM 2010. Developmental phenotypes and causal pathways in 
attention deficit/hyperactivity disorder: potential targets for early intervention? J Child 
Psychol Psych; 51(4): 368-389.


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Subcommittee on Attention-Deficit/Hyperactivity Disorder; Steering Committee on Quality 
Improvement and Management, (2011). ADHD: clinical practice guideline for the diagnosis, 
evaluation, and treatment of attention-deficit/hyperactivity disorder in children and 
adolescents. Pediatrics. 128: 1007 1022.
Szatmari P, Offord DR, Boyle MH 1989. Ontario child health study: prevalence of attention 
deficit disorder with hyperactivity.  J Child Psychol Psychiatry 30:219-230
Tandon M, Si X and Luby J 2011. Preschool onset attention-deficit/hyperactivity disorder:  
course and predictors of stability over 24 months. JCAP; 21(4): 321-330.
Weiss M, Tannock R, Kratochvil C, Dunn D, Velez-Borras J, Thomason C, et al. 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(7): 647-55.
Wigal T, Greenhill L, Chuang S et al. 2006. Safety and tolerability of methylphenidate in 
preschool children with ADHD.  JAACAP; 45(11): 1294-1303.
Wigal SB, Gupta S, Greenhill L et al. 2007. Pharmacokinetics of methylphenidate in 
preschoolers with attention-deficit/hyperactivity disorder.  JCAP; 17(2): 153-164.
Wilens TE, Spencer TJ, Biederman J, Girard K, Doyle R, Prince J, et al. 2001. A controlled 
clinical trial of bupropion for attention deficit hyperactivity disorder in adults. Am J 
Psychiatry; 158(2): 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-IV-TR CRITERIA FOR ATTENTION-
DEFICIT/HYPERACTIVITY DISORDER
A. Either (1) or (2):
(1)
six (or more) of the following symptoms of inattention have persisted for at 
least 6 months to a degree that is 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. 
Some hyperactive-impulsive or inattentive symptoms that caused impairment were 
present before age 7 years.
C. 
Some impairment from the symptoms is present in 2 or more settings (eg, at school 
[or work] and at home).
D. 
There must be 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, fourth Edition. Copyright 
1994 American Psychiatric Association






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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 Rating Scale IV Preschool 
Version
N/A
2007
Clinical Global Impressions Global 
Improvement and Clinical Global 
Impressions Severity of Illness 
N/A
1976
Columbia-Suicide Severity Rating Scale 
Baseline
Since Last Visit
Baseline 1/14/09 
Since Last Visit 1/14/09
Children’s Sleep Habits Questionnaire
N/A
2009
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.