Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Keywords: SPD489 Lisdexamfetamine dimesylate ADHD hyperactivity Neurobehavioral disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 199
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if an investigational treatment is effective in improving the total score on the ADHD-RS-IV Preschool Version in children 4-5 years old diagnosed with ADHD.

Detailed description:

Arms:
arm 1: Participant will receive placebo matching to SPD489 (Lisdexamfetamine dimesylate) capsule for 6 weeks. arm 2: Participants will be randomized to receive SPD489 capsule in a 5:5:5:5:6 ratio to SPD489 5, 10, 20, 30 milligram (mg) orally once daily for 6 weeks. Dosing will begin with the lowest strength of SPD489 (5 mg), and will be titrated until the randomly assigned fixed-dose is reached.

Interventions: intervention 1: Placebo intervention 2: SPD489 (Lisdexamfetamine dimesylate) intervention 3: SPD489
Intervention descriptions: intervention 1: Placebo matching to SPD489 (Lisdexamfetamine dimesylate) capsule for 6 weeks. intervention 2: SPD489 capsule in a 5:5:5:5:6 ratio to 5, 10, 20, 30 mg orally once daily for 6 weeks. intervention 3: SPD489

Protocol document:
Prot_000.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).
Shire Pharmacovigilance SAE Fax Number:
or 
For protocol- or safety-related issues during normal business hours 9:00 AM to 5:00 PM 
Eastern Standard Time, the investigator must contact the PPD Medical Monitor:
, MD, MPH
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 (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 America
Telephone numbers (provided for reference if needed):
Shire, Lexington, MA (USA)


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................4
PRODUCT QUALITY COMPLAINTS..........................................................................................5
TABLE OF CONTENTS.................................................................................................................6
LIST OF TABLES.........................................................................................................................11
LIST OF FIGURES .......................................................................................................................11
ABBREVIATIONS .......................................................................................................................12
STUDY SYNOPSIS ......................................................................................................................14
STUDY SCHEDULE(S) ...............................................................................................................24
1
BACKGROUND INFORMATION.......................................................................................27
1.1
Indication and Current Treatment Options...............................................................27
1.2
Product Background and Clinical Information ........................................................29
1.2.1
Preclinical Information......................................................................................30
1.2.2
Clinical Information..........................................................................................30
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................31
2.1
Rationale for the Study.............................................................................................31
2.2
Study Objectives ......................................................................................................31
2.2.1
Primary Objectives............................................................................................31
2.2.2
Secondary Objectives........................................................................................31
3
STUDY DESIGN ...................................................................................................................32
3.1
Study Design and Flow Chart ..................................................................................32
3.2
Duration and Study Completion Definition .............................................................33
3.3
Sites and Regions .....................................................................................................33
4
STUDY POPULATION.........................................................................................................33
4.1
Inclusion Criteria......................................................................................................33
4.2
Exclusion Criteria.....................................................................................................34
4.3
Reproductive Potential .............................................................................................36
4.3.1
Female Contraception .......................................................................................36
4.4
Discontinuation of Subjects .....................................................................................36
4.4.1
Management of Blood Pressure and Pulse During the Study...........................37
4.4.1.1
Systolic and Diastolic Blood Pressure ...................................................37
4.4.1.2
Pulse .......................................................................................................37
4.4.2
Reasons for Discontinuation .............................................................................38
4.4.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit ............................38
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................38


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5.1
Prior Treatment ........................................................................................................38
5.2
Concomitant Treatment............................................................................................39
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)...........................................................41
6.2.1
Interactive Response Technology for Investigational Product 
Management......................................................................................................41
6.2.2
Allocation of Subjects to Treatment .................................................................41
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
6.5
Subject Compliance..................................................................................................45
7
STUDY PROCEDURES........................................................................................................45
7.1
Study Schedule.........................................................................................................45
7.1.1
Screening and Washout Period .........................................................................45
7.1.1.1
Screening Visit (Visit -1) .......................................................................46
7.1.1.2
Other Medications Used During the 30 Days Prior to the Screening 
Visit (Visit -1) Washout Telephone Call................................................47
7.1.1.3
Baseline Visit (Visit 0)...........................................................................47
7.1.2
Double-blind Evaluation Periods......................................................................48
7.1.2.1
Fixed-dose Titration Period (Visits 1 to 3).............................................48
7.1.2.2
Dose-maintenance Period (Visits 4 to 6)................................................49
7.1.2.3
End-of-Study Visit (Visit 6/Early Termination) ....................................50
7.1.3
Safety Follow-up Period ...................................................................................50
7.1.4
Additional Care of Subjects After the Study ....................................................50
7.2
Study Evaluations and Procedures ...........................................................................50
7.2.1
Demographic and Other Baseline Characteristics.............................................50
7.2.2
Screening Assessments .....................................................................................51
7.2.2.1
Kiddie–Schedule for Affective Disorders and Schizophrenia for 
School-age Children–Present and Lifetime Version–Diagnostic 
Interview.................................................................................................51


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7.2.2.2
Peabody Picture Vocabulary Test ..........................................................51
7.2.3
Efficacy.............................................................................................................52
7.2.3.1
Attention-deficit/Hyperactivity Disorder Rating Scale – IV 
Preschool Version ..................................................................................52
7.2.3.2
Clinical Global Impressions...................................................................52
7.2.4
Safety.................................................................................................................53
7.2.4.1
Medical and Medication History............................................................53
7.2.4.2
Physical Examination.............................................................................53
7.2.4.3
Adverse Event Collection.......................................................................54
7.2.4.4
Vital Signs..............................................................................................54
7.2.4.5
Height and Weight .................................................................................55
7.2.4.6
Clinical Laboratory Evaluations.............................................................55
7.2.4.7
Electrocardiogram ..................................................................................56
7.2.4.8
Children’s Sleep Habits Questionnaire and Sleep Diary .......................57
7.2.4.9
Columbia-Suicide Severity Rating Scale ...............................................57
7.2.4.10
Suitability of the Subject to Remain in the Study..................................58
7.2.4.11
Volume of Blood to be Drawn From Each Subject................................58
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................59
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................59
8.1.1
Severity Categorization.....................................................................................59
8.1.2
Relationship Categorization..............................................................................60
8.1.3
Outcome Categorization....................................................................................60
8.1.4
Symptoms of the Disease Under Study.............................................................61
8.1.5
Clinical Laboratory and Other Safety Evaluations ...........................................61
8.1.6
Abuse, Misuse, Overdose, and Medication Error .............................................61
8.2
Serious Adverse Event Procedures ..........................................................................62
8.2.1
Reference Safety Information ...........................................................................62
8.2.2
Reporting Procedures........................................................................................62
8.2.3
Serious Adverse Event Definition.....................................................................62
8.2.4
Serious Adverse Event Collection Timeframe..................................................63
8.2.5
Serious Adverse Event Onset and Resolution Dates ........................................63
8.2.6
Fatal Outcome...................................................................................................63
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and 
Site Reporting ...................................................................................................64
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................64
9.1
Data Collection.........................................................................................................64
9.2
Clinical Data Management.......................................................................................64


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9.3
Data Handling Considerations..................................................................................64
9.4
Statistical Analysis Process......................................................................................65
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......65
9.5.1
Interim Analysis................................................................................................65
9.5.2
Sample Size Re-estimation ...............................................................................66
9.5.3
Data Monitoring Committee .............................................................................67
9.6
Sample Size Calculation and Power Considerations................................................67
9.7
Study Population ......................................................................................................68
9.8
Efficacy Analyses.....................................................................................................68
9.8.1
Primary Efficacy Endpoint................................................................................68
9.8.2
Key Secondary Efficacy Endpoints ..................................................................69
9.8.3
Secondary Efficacy Endpoints..........................................................................69
9.9
Safety Analyses........................................................................................................70
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................70
10.1
Sponsor’s Responsibilities .......................................................................................70
10.1.1
Good Clinical Practice Compliance..................................................................70
10.1.2
Public Posting of Study Information.................................................................71
10.1.3
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees...................71
10.1.4
Study Suspension, Termination, and Completion.............................................71
10.2
Investigator’s Responsibilities .................................................................................71
10.2.1
Good Clinical Practice Compliance..................................................................71
10.2.2
Protocol Adherence and Investigator Agreement .............................................72
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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Appendix 1
Protocol History ................................................................................................81
Appendix 2
Diagnostic Criteria/Disease Classification........................................................84
Appendix 2.1
DSM-IV-TR Criteria for Attention-Deficit/Hyperactivity Disorder......84
Appendix 2.2
Boys’ Stature-for-Age and Weight-for-Age Percentiles........................86
Appendix 2.3
Blood Pressure Levels for Boys by Age and Height Percentile.............87
Appendix 2.4
Girls’ Stature-for-Age and Weight-for-Age    Percentiles .....................88
Appendix 2.5
Blood Pressure Levels for Girls by Age and Height Percentile.............89
Appendix 3
Scales and Assessments ....................................................................................90


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LIST OF TABLES
Table 1
Schedule of Assessments...............................................................................24
Table 2
Common Excluded Treatments and Associated Washout Period –
Relative to Baseline Visit (Visit 0)................................................................39
Table 3
Volume of Blood to be Drawn From Each Subject.......................................58
LIST OF FIGURES
Figure 1
Chemical Structure of the Active Pharmaceutical Ingredient .......................29
Figure 2
Study Design Flow Chart ..............................................................................33


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ABBREVIATIONS
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS-IV
Attention-deficit/Hyperactivity Disorder Rating Scale-IV
ADHD-RS-IV 
Preschool Version
Attention-deficit/Hyperactivity Disorder Rating Scale-IV Preschool Version
AE
adverse event
ALP
alkaline phosphatase
ALT
alanine transaminase (SGPT)
AST
aspartate transaminase (SGOT)
BMI
body mass index
bpm
beats per minute
CGI
Clinical Global Impressions
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
d-amphetamine
dextroamphetamine
DBP
diastolic blood pressure
DMC
data monitoring committee
DRAS
Dose Response Analysis Set
DSM-IV-TR
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text Revision
EC
ethics committee
ECG
electrocardiogram
EOS
end of study
ET
early termination
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
K-SADS-PL
Kiddie–Schedule for Affective Disorders and Schizophrenia for School-age Children–
Present and Lifetime Version–Diagnostic Interview
LAR
legally authorized representative
MAOI
monoamine oxidase inhibitor
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MED
minimum effective dose
MMRM
mixed-effects model for repeated measures
PAPA 
Preschool Age Psychiatric Assessment
PK
pharmacokinetic
RBC
red blood cell
SAE
serious adverse event
SBP
systolic blood pressure
SAP
statistical analysis plan
T4
thyroxine
TEAE
treatment-emergent adverse event
TSH
thyroid stimulating hormone
US
United States
WBC
white blood cell


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STUDY SYNOPSIS
Protocol number:  SPD489-347
Drug: Lisdexamfetamine dimesylate
Title of the study:  A Phase 3, Randomized, Double-blind, Multicenter, Parallel-group, Placebo-controlled, 
Fixed-dose Safety and Efficacy Study of SPD489 Compared with Placebo in Preschool Children Aged 
4-5 Years with Attention-deficit/Hyperactivity Disorder
Number of Subjects (total and for each treatment arm):
Approximately 245 subjects will be screened to randomize approximately 195 subjects in a 5:5:5:5:6 ratio to 
SPD489 5, 10, 20, 30 mg  or placebo to achieve 156 completers for the study (30 in each active treatment group 
and 36 in the placebo group) and 85% power for the primary efficacy analysis. The sample size planned at study 
initiation is estimated based on the primary comparison of the change from baseline in the total score on the 
ADHD-RS-IV Preschool Version between those who received SPD489 10, 20, 30 mg pooled vs. those 
randomized to placebo, using a group sequential design with 1 interim analysis, using the Lan-DeMets alpha 
spending function with O'Brien-Fleming boundary for the primary efficacy endpoint. Assumptions for the 
calculation include the true mean difference of 8.4 with the common standard deviation of 14 for the primary 
efficacy endpoint, for an effect size of 0.6, and a dropout rate of 20%. 
A blinded sample size re-estimation is planned to ensure sufficient study power to detect a clinically meaningful 
drug effect for the primary efficacy endpoint. This re-estimation will be performed after approximately 75% of 
the 195 randomized subjects have either completed or discontinued from the study. The proposed blinded 
sample size re-estimation will only be conducted if the study does not meet the primary efficacy criterion at the 
interim analysis, when approximately 60% of randomized subjects having completed or discontinued from the 
study. In this case, cumulative primary efficacy data will be used to estimate a pooled common standard 
deviation (SD) to ensure that the variability hypothesized at the design stage (SD = 14) is not underestimated. 
Together with the assumed treatment difference of 8.4, the final total number of subjects to be enrolled will be 
calculated using the re-estimated pooled SD. If the re-estimated pooled common SD is larger than 14, the 
sample size will be increased. Otherwise, the sample size will remain the same. The total number of planned 
completers could remain at 156, or could potentially be as high as 218, which corresponds to the 97.5% 
percentile of the distribution of the estimator on the assumed true common standard deviation of 14. Note that 
the total of 218 completers is not considered a cap. As the final sample size is data driven, a higher number, 
though unlikely, is possible. 
The dose-response relationship will be measured by the ADHD-RS-IV Preschool Version Total Score change 
from baseline. Assuming the maximum difference in change from baseline in ADHD-RS-IV Preschool Version 
Total Score between 0 mg (placebo) and SPD489 (5, 10, 20 or 30 mg) is 13.0 points, and has a standard 
deviation of 14 for the change, then in order to detect a plausible dose-response curve at 85% power and a 
significance level of 0.05 (2-sided) using MCP-Mod with equal allocation to the treatment groups, it is 
necessary to have 18 completers for each arm. Assuming a 20% dropout rate, a total of 24 subjects for each 
treatment group are required to be randomized. Therefore, the overall sample size of the study will be sufficient 
for dose-response analysis. 
Approximately 25% of the subjects enrolled will be female.
Investigator(s):  Multicenter, 
, MD (Lead PI)
Site(s) and Region(s):
Up to 60 sites in North America
Study period (planned):
2017-2019
Clinical phase:
3


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Objectives:
Primary:  To evaluate the efficacy of SPD489 compared to placebo in preschool children (4-5 years of age 
inclusive at the time of consent) with Attention-deficit/Hyperactivity Disorder (ADHD). The primary measure 
of efficacy will be the clinician-administered ADHD Rating Scale Preschool Version (ADHD-RS-IV Preschool 
Version) Total Score.
Secondary:  

Key Secondary:  To evaluate the efficacy of SPD489 compared to placebo, using a global clinical 
measure of improvement, the Clinical Global Impression- Global Improvement (CGI-I) Scale.

Secondary: 
o
To evaluate the dose-response relationship in preschool children with ADHD, using the 
ADHD-RS Preschool Version Total Score.
o
To evaluate the safety and tolerability of SPD489 based on the occurrence of treatment-emergent 
adverse events (TEAEs), specific evaluation of vital signs (systolic and diastolic blood pressure 
and pulse), height, weight, and body mass index, clinical laboratory evaluations, electrocardiogram 
(ECG) results, sleep assessment, and the Columbia Suicide Rating Scale (C-SSRS). 
Rationale:
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, in concert 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 controlled data in this population will provide practicing physicians with information on the safety 
and efficacy profiles of SPD489 in preschool children with ADHD.
Investigational product, dose, and mode of administration:
The sponsor will provide SPD489 as 5, 10, 20, and 30 mg strength capsules. The sponsor will also provide 
placebo, which will appear identical to the investigational product. 
All subjects will be instructed to take 1 capsule daily throughout the study at approximately 7:00AM. SPD489 
will be administered by means of the capsule being swallowed whole or opened, the entire contents of the 
capsule mixed with orange juice, water, or yogurt and the mixture administered to the subject. The subject must 
ingest the entire amount of the mixture immediately within 3 minutes. The empty gelatinous capsule will be 
discarded.
Methodology:
This study is a Phase 3 randomized, double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy 
of SPD489 compared to placebo in preschool children (4-5 years of age inclusive at the time of consent) with 
ADHD.
The study will have 4 periods: 
(1) Screening and Washout 28 days 
(2) Fixed-dose titration 3 weeks 
(3) Dose-maintenance 3 weeks 
(4) Safety Follow-up- 7 days


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Subjects will be required to visit the site about 8 times over a 10-week period. The Schedule of Assessments 
(Table 1) details all procedures to be completed at each visit and should serve as the primary section regarding 
visit-specific study procedures.
Screening Procedures
Subjects will be screened at Visit -1 to establish eligibility for study participation. Screening procedures may 
take place across multiple days to allow enough time to complete all procedures and to confirm the subject’s 
initial eligibility.
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.

Eligibility will be established per inclusion and exclusion criteria, including documentation of any prior 
non-pharmacological treatment, and specified ADHD and Clinical Global Impressions – Severity of 
Illness (CGI-S) severity criteria. Areas of impairment will be recorded for all subjects for assessing the 
severity of the subject’s condition.

All AEs occurring after signature of informed consent must be recorded in the source documents and 
case report form (CRF).

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 contract research organization 
(CRO) medical monitor, will confirm the subject’s eligibility to participate in this study.

Blood pressure and pulse will be collected 3 times after resting for 5 minutes (with approximately 
2 minutes in between each collection) using a manual cuff during the visit. The average of each set of 
3 measurements will be used to determine continued participation in the study.  

The “Lifetime Recent” version of the Pediatric/Cognitively Impaired Version C-SSRS should be 
completed.

Record historical/concomitant medications as follows:
o
All lifetime psychoactive medications and lifetime non-pharmacological interventions 
(behavioral therapy) for ADHD
o
Other medications used during the 30 days prior to the screening visit (Visit -1)
Rating Scales and Assessments
Clinician-completed rating scales and assessments conducted by the site must be completed by the same rater 
with input from the same parent(s)/LAR whenever possible. The rating scales and assessments are described 
below. 
Screening Assessments
Kiddie – Schedule for Affective Disorders and Schizophrenia for School age Children – Present and Lifetime 
Version-Diagnostic Interview (K-SADS-PL)
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 semi-structured diagnostic interview designed to assess current and past episodes of 
psychopathology in children and adolescents according to Diagnostic and Statistical Manual of Mental 
Disorders (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.


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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[s]/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.
Peabody Picture Vocabulary Test-Third Edition
The Peabody Picture Vocabulary Test, Third Edition, 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, Third Edition, will be used as a 
proxy for general cognitive ability. 
The Peabody Picture Vocabulary Test, Third Edition, will 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.
Efficacy
Attention-deficit/Hyperactivity Disorder Rating Scale-IV Preschool Version 
The ADHD-RS-IV Preschool Version (McGoey et al. 2007) is completed by the clinician and will be 
administered at the baseline visit (Visit 0) and each subsequent visit up to and including Visit 6/ET 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. 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.
Clinical Global Impressions (CGI)
The Clinical Global Impressions Scale (Guy 1976) permits a global evaluation of the subject’s severity and 
improvement over time. The Clinical Global Impressions Scale 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 the baseline visit (Visit 0). 
Additionally, at the baseline visit (Visit 0), the investigator should establish 3 target areas of improvement with 
the subject 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 6ET, the investigator will assess the subject’s overall 
improvement relative to the 3 target areas of improvement recorded at the baseline visit (Visit 0), on the CGI-I, 
a 7-point scale ranging from 1 (very much improved) to 7 (very much worse).  
The CGI-S and CGI-I should be completed by a clinician trained and experienced in the evaluation of preschool 
children with ADHD. 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 designee.


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Safety
Children’s Sleep Habits Questionnaire (CSHQ) 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 conducted at each visit to the site starting 
with the baseline visit (Visit 0) and will be completed by the subject’s parent(s)/LAR. 
The subject’s parent(s)/LAR will complete a sleep diary to log daytime napping and nighttime sleep. 
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS (Posner 2007) is a semistructured interview that captures the occurrence, severity, and frequency 
of suicide-related thoughts and behaviors during the assessment period. The interview includes definitions and 
suggested questions to solicit the type of information needed to determine if a suicide-related thought or 
behavior occurred. 
The C-SSRS contains 2 required items pertaining to suicidal ideation, 4 required items pertaining to suicidal 
behavior, and 1 required item pertaining to non-suicidal but self-injurious behavior. In situations where there is 
a positive response to the screening questions, there are 8 additional suicidal ideation items and 4 additional 
suicidal behavior items which are completed. Thus, there is a maximum of 19 items to be completed.
The C-SSRS must be performed by an individual who is medically responsible for the subject. All individuals 
performing this assessment must be pre-approved by the sponsor or delegated vendor.
The Pediatric/Cognitively Impaired Version of the scale will be used in the study. Two time point versions of 
the C-SSRS are used in this study:

The “Lifetime Recent” version will be administered at the screening visit (Visit -1). 

The “Since Last Visit” version will be completed at all study visits after the screening visit (Visit -1). 
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 a male or female aged 4-5 years inclusive at the time of consent.
2.
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 the International 
Council on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 (1996), any updates or 
revisions, and applicable regulations, before completing any study related procedures.
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(s)/LAR must be available at 
approximately 7:00AM (±2 hours) to dispense the dose of investigational product for the duration of the 
study.
4.
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.
5.
Subject has an ADHD-RS-IV Preschool Version Total Score at the baseline visit (Visit 0) of ≥28 for boys, 
and 24 for girls.
6.
Subject has a CGI-S score 4 at the baseline visit (Visit 0).


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7.
Subject has a Peabody Picture Vocabulary Test standard score of 70 at the screening visit (Visit -1).
8.
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.
9.
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.
10. 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 is required to or anticipates the need to take any prohibited medications or medications that have 
central nervous system (CNS) effects or have an effect on performance, such as sedating antihistamines and 
decongestant sympathomimetics, or other monoamine oxidase inhibitors. Stable use of bronchodilator 
inhalers is not exclusionary.
2.
Subject has taken another investigational product or has taken part in a clinical study within 30 days prior to 
the screening visit (Visit -1).
3.
Subject is well-controlled on his/her current ADHD medication with acceptable tolerability.
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 conditions 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 glaucoma.
6.
Subject has failed to fully respond, based on investigator judgment, to an adequate course of amphetamine 
therapy.
7.
Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in 
the investigational product.
8.
Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
9.
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
10. 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

other serious cardiac problems placing them at increased vulnerability to the sympathomimetic effects 
of a stimulant drug.


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11. Subject has any clinically significant laboratory abnormalities at the screening visit (Visit -1) or clinically 
significant ECG at the screening visit (Visit -1) or baseline visit (Visit 0) based on investigator judgment.
12. 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). Treatment with a stable 
dose of thyroid medication for at least 3 months is permitted.
13. 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:
i.
post-traumatic stress disorder or adjustment disorder
ii.
bipolar illness, psychosis, or a family history of these disorders
iii.
pervasive developmental disorder
iv.
obsessive-compulsive disorder (OCD) 
v.
psychosis/schizophrenia
vi.
a serious tic disorder, or a family history of Tourette’s disorder
vii.
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. 
viii.
a history of physical, sexual, or emotional abuse
ix.
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.
14. Subject has initiated behavioral therapy within 1 month of the baseline visit (Visit 0). Subject may not 
initiate behavioral therapy during the study.
15. Subject has a height 5th percentile for age and sex at the screening visit (Visit -1).
16. Subject has a weight 5th percentile for age and sex at the screening visit (Visit -1).
17. Subject lives with anyone who currently abuses stimulants or cocaine.
18. Subject has a history of seizures (other than infantile febrile seizures).
19. Subject is taking any medication that is excluded per the protocol.
Duration of subject involvement in the study:

Planned duration of screening period: 28 days

Planned duration of treatment period: 42 days

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 an informed consent.
The Randomized Set will consist of all subjects in the Screened Set for whom a randomization number has 
been assigned.
The Safety Analysis Set will consist of all subjects in the Randomized Set 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-baseline ADHD-RS-IV-Preschool Version Total Score assessment, where baseline is defined as the last 
valid assessment prior to taking the first dose of investigational product.


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The Dose Response Analysis Set (DRAS) will consist of all subjects in the Safety Analysis Set who have at 
least 1 valid primary efficacy measurement (ADHD-RS total score) on the randomized target dose strength of 
the investigational product.
The above analysis sets are similarly defined for both the interim and the complete study analyses.
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as the change from baseline in clinician-administered ADHD-RS-IV 
Preschool Version Total Score at Visit 6 (Week 6). 
Key Secondary Efficacy Endpoint
The key secondary efficacy endpoint is the improvement status based on CGI-I measurement at Visit 6
(Week 6).
Secondary Efficacy Endpoint
A secondary efficacy endpoint is the dose response relationship of SHP489 for randomized fixed-dose strength 
(placebo, SHP489 5, 10, 20, and 30 mg), as measured by the change from baseline for ADHD-RS Preschool 
Version Total Score at study stop (at interim analysis or end of study).
Safety Endpoints
Safety assessments include the occurrence of TEAEs, specific evaluation of blood pressure, pulse, height, 
weight, and body mass index, clinical laboratory evaluations and ECG results, sleep assessments (including 
sleep diary data and CSHQ), and C-SSRS. 
Statistical Methodology for Primary Efficacy Endpoint(s)
For the primary and key secondary efficacy analyses the SPD489 10, 20, and 30 mg dose strengths will be 
pooled together to compare with placebo group in change from baseline. For these analyses the SDP489 5 mg 
data will not be used.   
Primary efficacy endpoint will be analyzed using the linear mixed-effects model for repeated measures 
(MMRM) with treatment group, visit, and the interaction of treatment group with visit as factors, baseline 
ADHD-RS-IV Preschool Version Total Score as a covariate, and the interaction of the baseline ADHD-RS-IV 
Preschool Version Total Score with visit adjusted in the model. The primary contrast of interest will be pooled 
10, 20, and 30 mg dose treatment assessment at Visit 6 (Week 6) for SPD489 compared with placebo. The 
2-sided overall significance level for the primary endpoint analysis is 0.05. The nominal significance levels used 
at the interim and final analysis are described in the Interim Analysis section below.
Interim Analysis
The study implements a group sequential design with one interim analysis. The interim analysis is proposed at 
approximately 60% of planned subjects who either complete or discontinue the study.
The interim analysis will be conducted on the interim analysis dataset, which is defined as all data from 60% of 
initially planned subjects who have either completed or discontinued the study, together with data for subjects in 
the study up to the interim analysis data cut time point. The efficacy, safety, and sensitivity on missing data 
mechanisms analyses at the interim analysis will primarily be conducted using this dataset.
The Lan-DeMets alpha spending function with O’Brien-Fleming boundary will be used for alpha spending 
between the interim and end of study analysis for the primary endpoint. The Lan-DeMets alpha spending 
function with Pocock boundary will be applied to analyze the key secondary efficacy endpoint.
If the hypothesis for the primary efficacy endpoint is rejected at the interim analysis, then the study will be 
stopped for efficacy and all ongoing subjects from the study (SPD489-347) will be immediately rolled over to 
the open-label extension study (Study SPD489-348). In this case, using the same data cut point that contains the 
same information fractions as the primary efficacy interim analysis, the key secondary efficacy endpoint will be 
tested. In addition, the incremental data collected during the interim analysis process, i.e., the overrun, together 
with the interim analysis dataset will be used for primary and key secondary sensitivity analysis and all safety 


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analysis. Otherwise, if the primary efficacy criterion is not met at the interim analysis, then the hypothesis for 
the key secondary endpoint will not be tested at this time, and the study will continue to its completion, then the 
primary efficacy endpoint will be tested. If the primary efficacy test is rejected, then the key secondary efficacy 
endpoint will be tested. This testing procedure strongly protects the overall alpha level. In addition, all other 
efficacy and safety analyses will be conducted at this time.    
At the interim or final efficacy analysis, only the primary efficacy result will be used to determine if the study 
meets the efficacy criterion. The nominal significance level for the interim or final primary and key secondary 
efficacy endpoints for a 2-sided at a 0.05 significant level are specified below, calculated using East® 6.4. The 
calculations are based on 60% of planned sample size, and will be updated based on the actual information 
fraction at the interim analysis. 
Efficacy Boundary p-value Scale
Interim Analysis
Final Analysis
Primary Endpoint
0.0074
0.0477
Key Secondary 
Endpoint
0.0354
0.0257
Separately, if the primary efficacy criterion is met at the interim analysis, the interim analysis dataset together 
with overrun data will be used to evaluate the dose-response relationship with the DRAS. If the primary efficacy 
criterion is not met at the interim analysis and study continues to its completion, dose-response evaluation will 
be conducted using the end of study data. 
If the primary efficacy criterion is not met at the interim analysis, and the blinded sample size re-estimation 
causes a sample size increase, the nominal significance levels at the end of the study will be recalculated, such 
that the overall alpha level is not greater than 0.05 for the primary and key secondary analyses together. The 
calculations will be based on the new increased sample size, the actual information ratio, and the alpha already 
spent. 
It is estimated that the interim analysis will take up to 8 weeks from data cutoff to its completion. If the 
recruitment rate is high and the remaining 40% planned subjects are projected to be all or nearly all enrolled 
within those 8 weeks, the interim analysis will be waived with reasons documented. In this case, the end of study 
analysis will be conducted at the 2-sided significance level of 0.05 with primary and key secondary endpoints 
tested sequentially. Furthermore, the dose-response relationship will be evaluated. 
Statistical Methodology for Secondary Efficacy Endpoints

The key secondary efficacy endpoint, CGI-I score, will be analyzed using the same analysis method 
(MMRM) as for the primary efficacy endpoint. The baseline CGI-S score will be used as the covariate. 
The contrast of interest will be at Visit 6 (Week 6) for SPD489 compared with placebo.

The dose-response relationship of SPD489 as measured by the change from baseline for ADHD-RS 
Preschool Version Total Score for the randomized fixed-dose arms (placebo, SHP489 5, 10, 20, and 
30 mg) will be evaluated using the MCP-Mod methodology with DRAS.  
Safety Analyses
The Safety Analysis Set will be used to report the safety data. 
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group and visit using 
appropriate descriptive statistics. Potentially clinically important findings will also be summarized or listed by 
treatment group.


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Adverse events will be coded using the Medical Dictionary for Regulatory Activities. Treatment-emergent 
adverse events are defined as adverse events (AEs) that start or deteriorate on or after the date of the first dose 
of investigational product and no later than 3 days following the last dose of investigational product in the 
double-blind phase. 
Treatment-emergent AEs will be summarized. The number and percent of subjects with TEAEs will be 
calculated for each system organ class, by preferred term, and by treatment. The severity of the TEAEs, the 
relationship to the investigational product, TEAEs causing study discontinuation, serious AEs and death will 
also be presented. 
The CSHQ will also be summarized using appropriate descriptive statistics.  
Sleep diary data will be descriptively summarized.
A summary and listing of the C-SSRS data will be provided for subjects with a positive response only. 
Data Monitoring Committee
An external independent 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 this Pediatric Written Request program, 
which includes studies SPD489-211, SPD489-347, and SPD489-348. The same DMC will evaluate the efficacy 
analysis results and supportive safety summaries to determine if the interim efficacy criteria are met for this 
study. Confidentiality of the unblinded DMC analyses is a critical concern, and to address this, an un-blinded 
independent reporting team will be identified within a CRO. The independent reporting team will have no 
involvement in the conduct of the study.
Sample Size Re-estimation
In order to have sufficient study power to detect a clinically meaningful treatment effect for the primary efficacy 
endpoint, a blinded sample size re-estimation is planned as described in the section “Number of Subjects”.  


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STUDY SCHEDULE(S)
Table 1
Schedule of Assessments
Period
Screening and  Washout
Dose-titration 
Dose-maintenance 
Safety
Follow-up
Visita
-1
(Screening)
Washout 
Telephone 
Call
0
(Baseline)
1
2
3
4
5
6/ ET
Telephone Call
Assessment Week
-4 to -1
-1 
0
1
2
3
4
5
6
7
Assessment Day 
-28 to -1
0
7
14
21
28
35
42
49
Informed consent/assent

Psychiatric evaluation (utilizing 
the K-SADS-PL)

Peabody Picture Vocabulary Test

Inclusion/exclusion criteria

b
b
Demographics

Randomization

Medical and medication historyc

Physical examination

d

Vital signse








Heightf


Body weight f








Calculate BMI g

Clinical laboratory testsh, i

d

12-lead ECG j

d






ADHD-RS-IV Preschool Versionk







CGI-S l



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Table 1
Schedule of Assessments
Period
Screening and  Washout
Dose-titration 
Dose-maintenance 
Safety
Follow-up
Visita
-1
(Screening)
Washout 
Telephone 
Call
0
(Baseline)
1
2
3
4
5
6/ ET
Telephone Call
Assessment Week
-4 to -1
-1 
0
1
2
3
4
5
6
7
Assessment Day 
-28 to -1
0
7
14
21
28
35
42
49
CGI-I k






CSHQ k







Sleep diary l







C-SSRS k








Suitability of subject to remain in 
study m






Access IWRS








Investigational product distributed 






Investigational product returned 






Investigational product 
compliance 






Concomitant medications










Adverse events 










ADHD-RS-IV=ADHD Rating Scale-IV; BMI=body mass index; 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; ECG=Electrocardiogram; ET=early termination; IWRS= Interactive Web 
Response System; K-SADS-PL=Kiddie-Schedule for Affective Disorders and Schizophrenia for School-age Children-Present and Lifetime Version-Diagnostic Interview
a Visit windows are 3 days [in reference to the baseline visit (Visit 0) date] during the Fixed-dose titration and Dose-maintenance Periods. Safety Follow-up Telephone Call 
window is +3 days.
b Inclusion/exclusion criteria must be reviewed at the Washout Telephone Call and at the baseline visit (Visit 0).
c Medication history will include a lifetime history of pharmacologic and non-pharmacologic therapies for ADHD.
d An abbreviated physical examination, 12-lead ECG, and all clinical laboratory tests must be repeated and results reviewed by the investigator prior to the baseline visit (Visit 0) if 
more than 30 days have elapsed since the safety measurements at the screening visit (Visit -1) were collected. Results must be obtained and reviewed prior to determining 
eligibility. 


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Table 1
Schedule of Assessments
Period
Screening and  Washout
Dose-titration 
Dose-maintenance 
Safety
Follow-up
Visita
-1
(Screening)
Washout 
Telephone 
Call
0
(Baseline)
1
2
3
4
5
6/ ET
Telephone Call
Assessment Week
-4 to -1
-1 
0
1
2
3
4
5
6
7
Assessment Day 
-28 to -1
0
7
14
21
28
35
42
49
e Includes oral or tympanic temperature, sitting blood pressure, pulse, and respiratory rate. Measurements of blood pressure and pulse will be performed at each visit to the site. 
Measurements of temperature and respiratory rate will be performed at the screening visit (Visit -1) and Visit 6/ET only. Blood pressure, pulse, and respiratory rate will be 
determined after subjects have remained seated for a minimum of 5 minutes. Measurement of blood pressure and pulse will be collected 3 times (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 
measurements should be taken prior to the collection of blood draws.
f Height and weight to be measured without shoes.
g BMI will be recorded at Screening for eligibility. BMI will be derived from height and weight during the course of the study for analysis. 
h Clinical laboratory tests will include hematology, chemistry, endocrinology, and urinalysis.
i 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 the study visit date, with 
the exception of the 6/ET home draw which has a -1 day window. 
j Three ECGs, taken approximately 5 minutes apart, are to be collected so that appropriate baseline intervals are established. Results must be reviewed prior to determining 
eligibility.
k Scales to be completed by same rater with input from the same parent/LAR whenever possible.
l Sleep diary to be completed by parent(s)/LAR. Sleep diaries will be dispensed at Visits 0-5 and collected at Visits 1-6. 
m C-SSRS “Lifetime Recent” version completed at the screening visit (Visit -1). C-SSRS “Since Last Visit” version completed for all subsequent visits. Include assessment of 
decreased appetite.


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1
BACKGROUND INFORMATION
Lisdexamfetamine dimesylate capsules (SPD489, previously referred to as NRP104) were 
developed for the once-daily treatment of attention-deficit/hyperactivity disorder (ADHD).
SPD489 capsules contain 5, 10, 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: 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 central nervous system (CNS) 
by increasing the availability of naturally occurring amines that have important functions in 
nerve terminals. Amphetamine increases synaptic levels of dopamine, norepinephrine, and 
serotonin through multiple mechanisms (Hardman et al. 2001). It promotes the release of 
dopamine, norepinephrine, and serotonin into the extraneuronal space, and also inhibits the 
reuptake of dopamine and norepinephrine 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 systolic blood pressure and diastolic blood pressure, 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 investigator's brochure (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 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 (Centers 
for Disease Control and Prevention 2010). Parents reported a current diagnosis of ADHD in 
5.5% of 4- to 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” 
(Diagnostic and Statistical Manual of Mental Disorders [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 Preschool-age Psychiatric 
Assessment and the ADHD-Rating Scale-IV Preschool Version (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). 


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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 
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). In 
a longitudinal study which followed children 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 
American Academy of Pediatrics (AAP) ADHD Clinical Practice guideline suggests that 
preschool children with ADHD initiate treatment with behavioral therapy prior to using 
pharmacotherapy (Subcommitte on ADHD et al. 2011); however the Preschool ADHD 
Treatment Study results indicates that only 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 
(Subcommitte 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. Therefore 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 IB for the most accurate and current 
information regarding the 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 
intrasubject and intersubject 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 adverse events (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 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.


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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 Food and Drug Administration (FDA) Pediatric 
Advisory Committee in September 2012 (Mistry and Chai 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, in concert 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.
2.2
Study Objectives
2.2.1
Primary Objectives
To evaluate the efficacy of SPD489 compared to placebo in preschool children (4-5 years of age 
inclusive at the time of consent) with ADHD. The primary measure of efficacy will be the 
clinician-administered ADHD Rating Scale Preschool Version (ADHD-RS-IV Preschool 
Version) Total Score.
2.2.2
Secondary Objectives

Key secondary: To evaluate the efficacy of SPD489 compared to placebo, using the global 
clinical measure of improvement, the Clinical Global Impression-Global Improvement 
(CGI-I) Scale.


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
Secondary: 
o
To evaluate the dose response relationship in preschool children with ADHD, using the 
ADHD-RS Preschool Version Total Score.
o
To evaluate the safety and tolerability of SPD489 based on the occurrence of 
treatment-emergent adverse events (TEAEs), specific evaluation of vital signs (systolic 
and diastolic blood pressure and pulse), height, weight, and body mass index (BMI), 
clinical laboratory evaluations, and electrocardiogram (ECG) results, sleep assessment, 
and the Columbia Suicide Rating Scale (C-SSRS).
3
STUDY DESIGN
3.1
Study Design and Flow Chart
Approximately 245 subjects will be screened to randomize approximately 195 subjects in a 
5:5:5:5:6 ratio to SPD489 5, 10, 20, 30 mg dose strength or placebo to achieve 156 completers 
for this Phase 3 double-blind, placebo-controlled, fixed-dose study to evaluate the efficacy of 
SPD489 10, 20, and 30 mg pooled together compared to placebo, administered as a daily 
morning dose in the treatment of preschool children 4-5 years of age with ADHD. 
Approximately 25% of the subjects enrolled will be female, consistent with the literature-defined 
gender distribution in ADHD clinic samples (Szatmari et al. 1989; Wallis et al. 2008; Thapar 
2002).
A randomized fixed-dose design is used to avoid baseline characteristics selection bias for 
different treatment groups on the part of the participants and investigators. Blinded treatment is 
used to reduce potential bias during data collection and evaluation of clinical results. The 
placebo arm is used to control the subject’s expectation that a treatment would have an effect, to 
optimize sensitivity, to maintain the scientific rigor of the study, and to validate the study 
internally.
The study will have 4 periods as outlined below and in Figure 2:
(1) Screening and Washout
(2) Fixed-dose titration
(3) Dose-maintenance
(4) Safety Follow-up.
The duration of the double-blind evaluation period (Fixed-dose titration and Dose-maintenance 
Periods) will be 6 weeks. 
SPD489 will be provided in dose strengths of 5, 10, 20, and 30 mg. Matching placebo will also 
be provided.


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Figure 2
Study Design Flow Chart
ET=early termination; V=visit; W=week, WO=washout.
3.2
Duration and Study Completion Definition
The subject’s maximum duration of participation is expected to be approximately 11 weeks. The 
study will be completed in approximately 24 months.
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 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).


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1. Subject is a male or female aged 4-5 years inclusive at the time of consent.
2. 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 Council on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guideline E6 (1996), any updates or revisions, and applicable regulations, before 
completing any study related procedures.
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(s)/LAR must be available at approximately 7:00AM (±2 hours) to dispense the dose 
of investigational product for the duration of the study.
4. Subject must meet DSM-IV-TR criteria for a primary diagnosis of ADHD (any sub-type) 
based on a detailed psychiatric evaluation.
5. Subject has an ADHD-RS-IV Preschool Version Total Score at the baseline visit (Visit 0) of 
≥28 for boys and ≥24 for girls.
6. Subject has a Clinical Global Impressions – Severity of Illness (CGI-S) score ≥4 at the 
baseline visit (Visit 0).
7. Subject has a Peabody Picture Vocabulary Test standard score of ≥70 at the screening visit 
(Visit -1).
8. 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.
9. 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.
10. 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 is required to or anticipates the need to take any prohibited medications or 
medications that have CNS effects or have an effect on performance, such as sedating 
antihistamines and decongestant sympathomimetics, or other monoamine oxidase inhibitors. 
Stable use of bronchodilator inhalers is not exclusionary.
2. Subject has taken another investigational product or has taken part in a clinical study within 
30 days prior to the screening visit (Visit -1).
3. Subject is well-controlled on his/her current ADHD medication with acceptable tolerability.
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 
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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 conditions 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 glaucoma.
6. Subject has failed to fully respond, based on investigator judgment, to an adequate course of 
amphetamine therapy.
7. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any 
excipients in the investigational product.
8. Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
9. 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.
10. 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

other serious cardiac problems placing them at increased vulnerability to the 
sympathomimetic effects of a stimulant drug.
11. Subject has any clinically significant clinical laboratory abnormalities at the screening visit 
(Visit -1) or ECG at screening visit (Visit -1) or baseline visit (Visit 0) based on investigator 
judgment.
12. 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). Treatment with a stable dose of thyroid medication for at least 3 months is 
permitted.
13. 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:
i.
post-traumatic stress disorder or adjustment disorder


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ii.
bipolar illness, psychosis, or a family history of these disorders 
iii.
pervasive developmental disorder
iv.
obsessive-compulsive disorder (OCD) 
v.
psychosis/schizophrenia
vi.
a serious tic disorder, or a family history of Tourette’s disorder
vii.
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. 
viii.
a history of physical, sexual, or emotional abuse
ix.
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.
14. Subject has initiated behavioral therapy within 1 month of the baseline visit (Visit 0). Subject 
may not initiate behavioral therapy during the study.
15. Subject has a height 5th percentile for age and sex at the screening visit (Visit -1).
16. Subject has a weight 5th percentile for age and sex at the screening visit (Visit -1).
17. Subject lives with anyone who currently abuses stimulants or cocaine.
18. Subject has a history of seizures (other than infantile febrile seizures).
19. Subject is taking any medication that is excluded per the protocol.
4.3
Reproductive Potential
4.3.1
Female Contraception
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 (parent[s]/LAR) 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 for any reason (eg, in the interest of subject 
safety). The investigator is encouraged to discuss withdrawal of a subject from the clinical study 
with the medical monitor. 
Upon discontinuation of the investigational product, regardless of the reason, the evaluations 
listed for Visit 6 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 and date of stopping investigational product must be 
recorded in the case report form (CRF) and source documents.


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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 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 of Health Fourth Report on the Diagnosis, Evaluation, and 
Treatment of High Blood Pressure in Children and Adolescents (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 >15 mmHg from the baseline visit 
(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 potential discontinuation 
based upon the clinical judgment of the investigator and in conjunction with the medical 
monitor. 

Elevations in the average (of 3 readings) sitting systolic blood pressure defined as an increase 
of >15 mmHg from the baseline visit (Visit 0) OR a value >95th percentile for age, sex, and 
height 

Elevations in average (of 3 readings) sitting diastolic blood pressure defined as an increase of 
>15 mmHg from the baseline visit (Visit 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). 
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 continued participation in the study. 
If a visit cannot be scheduled the next day, the subject may be discontinued from the study.


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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(s)/LAR

Lost to follow-up

Lack of efficacy

Blood pressure and/or pulse criteria met

Other. If “Other” is selected, the investigator must specify on the CRF
4.4.3
Subjects “Lost to Follow-up” Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject or parent/LAR in the 
event that any subject is 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 within 30 days prior 
to the screening visit (Visit -1) (or pharmacokinetic equivalent of 5 half-lives, whichever is 
longer) and through the final study contact (including protocol-defined follow-up period) must 
be recorded on the appropriate 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 
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The investigator will document that the subject has undergone an adequate course of 
non-pharmacological treatment or document that the subject has a severe enough condition to 
consider enrollment without undergoing prior non-pharmacological treatment.
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 (ie, for at least  3 months prior to the screening visit [Visit -1]) dose of thyroid 
medication is permitted

Stable (ie, for at least 1 month prior to the screening visit [Visit -1]) 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 the baseline visit (Visit 0), for treatments that are 
excluded during this study. Subjects can only be instructed to discontinue a medication for this 
study after informed consent has been obtained. 
Table 2
Common Excluded Treatments and Associated Washout Period – Relative to 
Baseline Visit (Visit 0)
Minimum Number of Days Before Baseline Visit
Treatment
7
14
30
Psychostimulants, amphetamines and amphetamine-like 
agents
X
Antihypertensives a
X


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Table 2
Common Excluded Treatments and Associated Washout Period – Relative to 
Baseline Visit (Visit 0)
Minimum Number of Days Before Baseline Visit
Treatment
7
14
30
Antihistamines (centrally and peripherally-active)
X
Herbal preparations (including melatonin)
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
CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine, 
ritonavir)
X
Alkalinizing agents (eg, sodium bicarbonate, 
acetazolamide, some thiazides)
X
Acidifying agents (eg, guanethidine, reserpine, glutamic 
acid HCl, ascorbic acid, ammonium chloride, sodium acid 
phosphate, methenamine salts)
X
a These medications may signal that an exclusionary diagnosis is present. The medical monitor should be consulted 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, 20, and 30 mg capsule form. 
Additional information is provided in the current SPD489 IB.
The reference/comparator product is placebo which will be provided in matching capsule form.  
6.1.1
Blinding the Treatment Assignment
This is a double-blind, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule. The associated treatment assignments giving 
details of individual subject treatment are automatically assigned by the Interactive Web 
Response System (IWRS).  
All investigational and reference product will appear identical to protect the study blind.


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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
This is a randomized, double-blind, fixed-dose, placebo-controlled study. The actual treatment 
given to individual subjects is determined by a randomization schedule. Subjects will be 
randomized in a 5:5:5:5:6 ratio to SPD489 5, 10, 20, 30 mg or placebo.  
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), the subject number is assigned to subjects according 
to the sequence of presentation for study participation.
The randomization number represents a unique number corresponding to investigational product 
allocated to the subject, once eligibility has been determined.
Individual subject treatment is automatically assigned by the interactive web response system
(IWRS).
If a randomization number/unique identifier is allocated incorrectly, the clinical research 
associate (CRA)/study monitor must be notified as soon as the error is discovered.
Investigational product packaging identification numbers, separate from randomization numbers, 
may also be assigned to subjects for specific treatment assignment as dictated by the study. In 
these cases, the same investigational product packing identification number may not be assigned 
to more than 1 subject.
6.2.3
Dosing
Dosing should begin at approximately 7:00AM (±2 hours) on the morning after the baseline visit 
(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 may be administered in one of the following ways:

Swallow SPD489 capsule whole, or

Open capsule, empty and mix the entire contents 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 into a trash receptacle by the parent/LAR.
Subjects will begin dosing with the lowest strength of SPD489 (5 mg) and will be titrated until 
the randomly assigned fixed-dose is reached.
Once subjects reach the fixed-dose level, this dose will be maintained until the end of the study. 
No dose reductions are permitted during the study. Subjects who are unable to tolerate 
investigational product will be discontinued.
6.2.4
Unblinding the Treatment Assignment
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product is required for further treatment of the 
subject. The investigator should contact the medical monitor as soon as possible after the 
investigator has been unblinded.  
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code, and the reason for breaking the code, are recorded in IWRS and the source 
documents. Upon breaking the blind, the subject is withdrawn from the study, but should be 
followed up for safety purposes. Any code-breaks that occur must be reported to the contract 
research organization (CRO) and sponsor. Code-break information is held by the 
pharmacist/designated person at the site and by the CRO medical monitor for the study or 
designee.
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 United States [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 (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label

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 10-count high density polyethylene bottles with child-resistant 
closures. Each bottle contains a desiccant.
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 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.


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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 provided that the blind of the study is not compromised.
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 (ie, 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.


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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 (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-I, and C-SSRS must be completed by the same rater whenever possible.
Throughout the Fixed-dose titration and Dose-maintenance Periods of the study, visits should be 
scheduled as outlined (3 days) with reference to the Baseline visit (Visit 0). The Safety 
Follow-up Call should be scheduled 7 days post-last dose with a +3 day visit window.
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). 


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There must also be documentation of assent (if required by Institutional Review Board [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 (Table 2). A subject 
cannot be instructed to washout any medication for this study until after informed consent is 
obtained.
Screening procedures may take place across multiple days to allow enough time to complete all 
procedures and confirm initial subject eligibility. Screening procedures and dates should be well 
documented in the source documents and CRF. The date of the screening visit (Visit -1) 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 randomized or 
administered investigational product(s).
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. 
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:

Eligibility will be established per inclusion and exclusion criteria, including documentation 
of any prior non-pharmacological treatment and specified ADHD and CGI-S severity criteria. 
Areas of impairment will be recorded for all subjects for assessing the severity of the 
subject’s condition.

All AEs occurring after signature of informed consent must be recorded in the source 
documents and CRF.

Twelve-lead ECG will be performed after 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 after 5 minutes of rest 3 times (with at least 
2 minutes in between each collection) using a manual cuff during the visit. 


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The average of each set of 3 measurements will be used to determine continued participation 
in the study (see Section 4.4.1).

BMI should be calculated using one of the following formulae:
BMI =  Weight in pounds * 703
(Height in inches)2
BMI =    Weight in kilograms 
(Height in meters)2

The “Lifetime Recent” 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
7.1.1.2
Other Medications Used During the 30 Days Prior to the Screening Visit 
(Visit -1) Washout Telephone 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. 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 the baseline visit (Visit 0)

Review the inclusion/exclusion criteria

Ask about any concomitant medications that the subject is taking. If new concomitant 
medications that require washout are noted, instructions for appropriate washout should be 
provided.

Provide instructions on discontinuing any medication requiring washout.

Determine if any AEs have occurred since the screening visit (Visit -1).
If a medication washout is not necessary, the Washout Telephone Call will include all the above 
procedures except providing instructions on discontinuing any current medications.
7.1.1.3
Baseline Visit (Visit 0)
Once the screening central clinical laboratory tests and 12-lead ECG results have been obtained, 
in addition to repeat assessments (if required), and the subject has completed the required 
washout period (if applicable), the subject will return to the site for the baseline visit (Visit 0). 


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Inclusion/exclusion criteria must also be reviewed during this visit to ensure subjects continue to 
meet all eligibility criteria.
Table 1 outlines all procedures to be conducted during the baseline visit (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, clinical laboratory tests, and 
12-lead ECG must be repeated, and the results reviewed by the investigator prior to the 
subject being enrolled.

After 5 minutes rest, blood pressure, and pulse will be collected 3 times (with at least 
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).

Three ECGs will be taken, with approximately 5 minutes in between each one, to ensure 
appropriate baseline intervals are established. The investigator will perform the initial 
interpretation of the ECG immediately after collection to ensure the safety of each subject to 
continue with the study. The ECG tracing will be sent to the central reader for analysis. Upon 
review of the report from the central reader, the investigator will re-evaluate the clinical 
significance of the ECG in light of other safety data for the subject. If abnormal and 
significant results are observed following assessment by the central reader, the investigator, 
in consultation with the appointed CRO medical monitor, will confirm the subject’s 
continued participation in this study.  

The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired Version 
should be completed.

For eligible subjects, the investigator or assigned site staff designee will access the IWRS to 
enroll the subject and obtain an investigational product bottle number to dispense to the 
subject. 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 the baseline visit (Visit 0).
7.1.2
Double-blind Evaluation Periods
7.1.2.1
Fixed-dose Titration Period (Visits 1 to 3)
During the first 3 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 randomly 
assigned fixed-dose strength.  
Subjects who are unable to tolerate investigational product should be discontinued from the 
study.
Throughout the Fixed-dose titration 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 3. Further clarification for these 
visits is outlined below:

At each visit during the Fixed-dose titration 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.

Blood pressure and pulse will be collected 3 times (with at least 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 with input from the same parent/LAR 
whenever possible.

The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired Version 
should be completed during the Fixed-dose titration Period.
7.1.2.2
Dose-maintenance Period (Visits 4 to 6)
Following titration to the randomly assigned fixed-dose strength of SPD489/Placebo, subjects 
will continue daily morning treatment for an additional 3 weeks.
Throughout the Dose-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 Dose-maintenance 
Period. Additional clarification on the procedures to be performed during the Dose-maintenance 
Period is provided below:

Scales are to be completed by the same rater with input from the same parent/LAR whenever 
possible

At each visit during the Dose-maintenance 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.

The C-SSRS “Since Last Visit” Version of the Pediatric/Cognitively Impaired Version 
should be completed during the Dose Maintenance Period.

After 5 minutes rest, blood pressure and pulse will be collected 3 times (with at least 
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).


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7.1.2.3
End-of-Study Visit (Visit 6/Early Termination)
All randomized subjects who complete the study or discontinue early will complete Visit 6/early 
termination (ET).
Table 1 lists the procedures to be completed at Visit 6/ET and should serve as the primary point 
of reference regarding visit-specific study procedures.
Further clarification on the procedures performed during Visit 6/ET is provided below:

Unused investigational product and empty containers will be collected to calculate 
medication compliance.

After 5 minutes rest, blood pressure and pulse will be collected 3 times (with at least 
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). 
7.1.3
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 staff to query for 
serious adverse events (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
Subjects who have completed the study at Visit 6 end of study (EOS)/ET may be evaluated for 
eligibility to enter a long-term safety study of SPD489. 
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 6/ET and the 
Safety Follow-up Call should be completed. Whenever possible, raters (including parent(s)/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.


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7.2.2
Screening Assessments
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 Kiddie–Schedule for 
Affective Disorders and Schizophrenia for School-age Children–Present and Lifetime 
Version-Diagnostic Interview (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[s]/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
The Peabody Picture Vocabulary Test, Third Edition, 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 will be used as a proxy for general cognitive ability. 
The Peabody Picture Vocabulary Test, Third Edition, should be administered by someone with 
general knowledge of psychological testing. All individuals performing this assessment must be 
pre-approved by the Sponsor or designee.


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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 primary efficacy measure, is 
completed by the clinician and will be administered at Baseline (Visit 0) and each subsequent 
visit up to and including Visit 6/ET 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 should 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 designee.
The title, version, and date of the ADHD-RS-IV Preschool Version used in this study are 
included in Appendix 3.
7.2.3.2
Clinical Global Impressions
The Clinical Global Impressions (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 the 
baseline visit (Visit 0). Additionally, at the baseline visit (Visit 0), the investigator should 
establish 3 target areas of improvement with the subject 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 6/ET, the investigator will assess the 
subject’s overall improvement relative to the 3 target areas of improvement recorded at the 
baseline visit (Visit 0), on the CGI-I, a 7-point scale ranging from 1 (very much improved) to 
7 (very much worse).


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The CGI-S and 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 designee.
The title, version, and date of the CGI-S and the CGI-I used in this study are included in 
Appendix 3. 
7.2.4
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
The investigator will perform a complete medical history at the screening visit (Visit -1), 
including a medication history, and record all information gathered. The investigator must record 
all clinically or medically relevant information regardless of how much time has elapsed since 
the date of diagnosis.
With the subject’s parent(s)/LAR’s consent, medical records from other treatment providers 
should be requested.
7.2.4.2
Physical Examination 
A full physical examination will be performed at the screening visit (Visit -1) and Visit 6/ET. 
Additionally, an abbreviated physical examination is required at the baseline visit (Visit 0) if 
>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 (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.


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If an abbreviated physical examination is required at the baseline visit (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 (ie, “Have you had any health problems since your last 
visit, eg, decreased appetite?”). This information should be collected prior to the 
completion of assessments at all study visits. In addition, any symptoms/conditions reported 
during assessments and deemed to be clinically significant by the investigator will be assessed as 
AEs. 
AEs are collected from the time the informed consent is signed. Please refer to Section 8.
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) and Visit 6/ET only.  
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 at rest 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. After 5 minutes 
of rest, three measurements should be obtained using the manual cuff 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.


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7.2.4.5
Height and Weight
Height will be captured at the screening visit (Visit -1) and Visit 6/ET. 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) and Visit 6/ET. 
Additionally, clinical laboratory tests are required to be repeated prior to the baseline visit 
(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 of having laboratory assessments 
collected by a qualified home health care professional at their home. 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
Aspartate Transaminase (AST)
Uric Acid
Phosphorus
Blood Urea Nitrogen
Alanine Transaminase (ALT)
Total Bilirubin
Sodium
Creatinine
Alkaline Phosphatase (ALP)
Glucose
Potassium
Albumin
Gamma Glutamyl Transferase (GGT)
Total Protein


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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
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
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
Nitrate
Bilirubin
If urinalysis detects protein and/or blood, a microscopic examination will be conducted. The 
microscopic examination will consist of red blood cell, white blood cell, casts, and bacteria.
7.2.4.7
Electrocardiogram
A 12-lead ECG will be performed at the screening visit (Visit -1) and every post-baseline visit 
(Visit 1 to Visit 6/ET). Additionally, three ECGs taken approximately 5 minutes apart will be 
collected at the baseline visit (Visit 0). 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 
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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 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.
7.2.4.8
Children’s Sleep Habits Questionnaire and Sleep Diary
The Children’s Sleep Habits Questionnaire (CSHQ) is a parent report questionnaire 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 
conducted at each visit to the site starting with the baseline visit (Visit 0) and will be completed 
by the subject’s parent(s)/LAR. 
The subject’s parent(s)/LAR will complete a sleep diary to log daytime napping, bedtime, and 
wake time. 
7.2.4.9
Columbia-Suicide Severity Rating Scale
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 but self-injurious behavior. In 
situations where there is a positive response to the screening questions, there are 8 additional 
suicidal ideation items and 4 additional suicidal behavior items which are completed. Thus, there 
is a maximum of 19 items to be completed.
The C-SSRS must be performed by an individual who is trained and certified and is preapproved 
by the sponsor or delegated vendor and the site investigator. 


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The Pediatric/Cognitively Impaired Version of the scale will be used in the study. Two time 
point versions of the C-SSRS are used in this study:

The “Lifetime Recent” version will be administered at the screening visit (Visit -1). 

The “Since Last Visit” version will be completed at 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 Appendix 3.
7.2.4.10
Suitability of the Subject to Remain in the Study
At each visit (except for Visit 6/ET) starting with the baseline visit (Visit 0), 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 for 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 
to others, as well as psychiatric disorders. The investigator should make this assessment by 
conducting a clinical interview with the subject and by reviewing of all other relevant sources 
available, including results of the C-SSRS. Any subject who has 1 or more positive responses 
must undergo further evaluation to ensure that they are not in any way at risk. As part of this 
assessment, if appropriate, the investigator should discuss risk factors for suicide with the 
subject. Where a subject has suffered an accidental injury, the investigator should ensure that this 
was a true accidental injury, rather than an episode of self-harming or a suicide attempt. 
The 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.
7.2.4.11
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)
Safety
Biochemistry 
5
2
10
Hematology
4
2
8
Total mL
18


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During this study, it is expected that approximately 18 mL of blood will be drawn from all 
subjects, regardless of sex.
Note: The amount of blood to be drawn for each assessment is an estimate. The amount of blood 
to be drawn may vary according to the instructions provided by the manufacturer or laboratory 
for an individual assessment; however, the total volume drawn over the course of the study 
should be approximately 18 mL. When more than 1 blood assessment is to be done at the 
timepoint/period, if they require the same type of tube, the assessments may be combined. If a 
catheter is used, the first 1 mL of blood from each sampling will be discarded. Biochemistry and 
hematology clinical laboratory tests will be repeated at the baseline visit (Visit 0) if >30 days 
have elapsed since the screening visit (Visit -1).  
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

Recovered/Resolved

Recovered/Resolved With Sequelae 

Recovering/Resolving

Unknown.


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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 6/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 pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant, and therefore represents an AE.
8.1.6
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.


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
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 dispensing, 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(s)/LAR/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. 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. 


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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 Timeframe
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 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.
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).


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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. 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
Data that may potentially unblind the treatment assignment (ie, treatment and bottle allocation) 
will be handled with special care during the data cleaning and review process. These data will be 
handled in such a way that, prior to unblinding, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available. If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 


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9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the efficacy and safety data, as well as describe the approaches to be taken for 
summarizing other study information such as subject disposition, demographics and baseline 
characteristics, investigational product exposure, and prior and concomitant medications. The 
SAP will also include a description of how missing, unused, and spurious data will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock. 
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513) and R 
MCP-Mod package.
9.5
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
9.5.1
Interim Analysis
The study implements a group sequential design with one interim analysis. The interim analysis 
is proposed when approximately 60% of planned subjects who either complete or discontinue the 
study.
The interim analysis will be conducted on the interim analysis dataset, which is defined as all 
data from 60% of initially planned subjects who have either completed or discontinued the study, 
together with data for subjects who are in the study up to the interim analysis data cut time point. 
The efficacy, safety, and sensitivity on missing data mechanisms analyses at the interim analysis 
will primarily be conducted using this dataset.
The Lan-DeMets alpha spending function with O’Brien-Fleming boundary will be used for alpha 
spending between the interim and EOS analysis for the primary efficacy endpoint. Following 
evaluations in the stage-wise hierarchical setting (Glimm et al. 2010), the Lan-DeMets alpha 
spending function with Pocock boundary will be applied to analyze the key secondary efficacy 
endpoint. This approach will strongly control the study-wide type I error at the overall 0.05 
significance level, and in general increase power for the test on the key secondary endpoint.
If the hypothesis for the primary efficacy endpoint is rejected at the interim analysis, then the 
study will be stopped for efficacy and all ongoing subjects from the study (SPD489-347) will be 
immediately rolled over to the open-label extension study (Study SPD489-348). In this case, 
using the same data cut point that contains the same information fractions as the primary efficacy 
interim analysis, the key secondary efficacy endpoint will be tested. In addition, the incremental 
data collected during the interim analysis process, i.e., the overrun, together with the interim 
analysis dataset will be utilized in sensitivity analyses for major efficacy and safety end points. 
Otherwise, if the primary efficacy criterion is not met at the interim analysis, then the hypothesis 
for the key secondary endpoint will not be tested at this time, and the study will continue to its 
completion, then the primary efficacy endpoint will be tested. 


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If the primary efficacy test is rejected, then the key secondary efficacy endpoint will be tested. 
This testing procedure strongly protects the overall alpha level. In addition, all other efficacy and 
safety analyses will be conducted at this time.  
At the interim or final efficacy analysis, only the primary efficacy result will be used to 
determine if the study meets the efficacy criterion. The nominal significance level for the interim 
or final primary and key secondary efficacy endpoints for a 2-sided at a 0.05 significant level are 
specified below, calculated using East® 6.4. The calculations are based on 60% of planned 
sample size, and will be updated based on the actual information fraction at the interim analysis.
Efficacy Boundary p-value Scale
Interim 
Analysis
Final Analysis
Primary 
Endpoint
0.0074
0.0477
Key Secondary 
Endpoint
0.0354
0.0257
If the primary efficacy criterion is not met at the interim analysis, and the blinded sample size 
re-estimation causes a sample size increase, the nominal significance levels at the end of the 
study will be recalculated such that the overall alpha level is not greater than 0.05 for the primary 
and key secondary analyses together. The calculations will be based on the new increased sample 
size, the actual information ratio, and the alpha already spent.
It is estimated that the interim analysis will take up to 8 weeks from data cutoff to its completion. 
If the recruitment rate is high and the remaining 40% planned subjects are projected to be all or 
nearly all enrolled within those 8 weeks, the interim analysis will be waived with reasons 
documented. In this case, the EOS analysis will be conducted at the 2-sided significance level of 
0.05 with primary and key secondary endpoints tested sequentially. 
Separately, if the primary efficacy criterion is met at the interim analysis, the interim analysis 
dataset together with overrun data will be used to evaluate the dose-response relationship with 
the Dose Response Analysis Set (DRAS). If the primary efficacy criterion is not met at the 
interim analysis and study continues to its completion, dose-response evaluation will be 
conducted using the EOS data.
9.5.2
Sample Size Re-estimation
In order to maintain sufficient study power to detect a clinically meaningful treatment effect 
for the primary efficacy endpoint, a blinded sample size re-estimation is planned. If the 
study continues beyond the proposed interim analysis, or if the interim analysis is waived, then 
the sample size re-estimation will be performed when approximately 75% of the 195 subjects 
have either completed or discontinued from the study. In this case, cumulative primary 
efficacy data will be used to estimate a pooled common standard deviation (SD) to ensure the 
variability hypothesized at the design stage is not underestimated. 


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Together with the assumed treatment difference of 8.4, the final total number of subjects to be 
enrolled will be calculated using the re-estimated pooled SD (Friede and Kieser 2006). 
The final total sample size could potentially be as high as 218 completers, which corresponds to 
the 97.5% percentile of the distribution of the estimator on the assumed true common SD of 
14 postulated at the design stage. If the re-estimated pooled common SD is larger than 14, the 
sample size will be increased. Otherwise, the sample size will remain the same. Note that the 
total of 218 completers is not considered a cap. As the final sample size is data driven, a higher 
number, though unlikely, is possible.
The Type-I error level for the sample size re-estimation will be adjusted based on the 
O'Brien-Fleming boundary when applicable.
9.5.3
Data Monitoring Committee
An external independent 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 this 
Pediatric Written Request program, which includes studies SPD489-211, SPD489-347, and 
SPD489-348. The same DMC will evaluate the efficacy analysis results and supportive safety 
summaries to determine if the interim efficacy criteria are met for this study. Confidentiality of 
the unblinded DMC analyses is a critical concern and to address this, an unblinded independent 
reporting team will be identified within a CRO. The independent reporting team will have no 
involvement in the conduct of the study. Further details regarding the DMC can be found in the 
DMC charter.
The DMC will not be involved in the blinded sample size re-estimation and dose-response 
relationship evaluations.
9.6
Sample Size Calculation and Power Considerations
Approximately 195  subjects will be randomized in a 5:5:5:5:6 ratio to SPD489 5, 10, 20, 30 mg 
or placebo to achieve 156  completers for the study (30 in each active treatment group and 36 in 
the placebo group) and 85% power for the primary efficacy analysis at a 2-sided 0.05 
significance level. The sample size planned at study initiation is estimated based on the primary 
comparison between pooled SPD489 10, 20, and 30 mg dose levels (excluding the 5 mg) and 
placebo on the primary efficacy endpoint, in a group sequential design with 1 interim analysis 
using the Lan-DeMets alpha spending function with O'Brien-Fleming boundary for the primary 
efficacy endpoint. Assumptions for the calculation include the true mean difference of 8.4 with 
the common standard deviation (SD) of 14 for the primary efficacy endpoint, for an effect size of 
0.6, and a dropout rate of 20%. 
The dose-response relationship that measured as the ADHD-RS-IV Preschool Version Total 
Score change from baseline will be evaluated separately. Assuming the maximum difference in 
change from baseline in ADHD-RS-IV Preschool Version Total Score between 0 mg (placebo) 
and SPD489 (5, 10, 20 or 30 mg) is 13.0 points, and has a standard deviation of 14 for the 
change, then in order to detect a plausible dose-response curve at 85% power and a significance 
level of 0.05 (2-sided) using MCP-Mod with equal allocation to the treatment groups, it is 
necessary to have 18 completers for each arm. 


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Assuming a 20% dropout rate, a total of 24 subjects for each treatment group are required to be 
randomized. Therefore, the overall sample size of the study will be sufficient for dose-response 
analysis.
9.7
Study Population
The Screened Set will consist of all subjects who have signed an informed consent.
The Randomized Set will consist of all subjects in the Screened Set for whom a randomization 
number has been assigned.
The Safety Analysis Set will consist of all subjects in the Randomized Set 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 baseline ADHD-RS-IV Preschool Version Total Score assessment, where baseline is 
defined as the last valid assessment prior to taking the first dose of investigational product.
The Dose Response Analysis Set (DRAS) will consist of all subjects in the Safety Analysis Set 
who have at least 1 valid primary efficacy measurement (ADHD-RS- IV Preschool Version 
Total Score) on the randomized target dose level of the investigational product.
The above analysis sets are similarly defined for both the interim and the complete study 
analyses.
9.8
Efficacy Analyses
The primary and key secondary analyses, including sensitivity analyses, will be based on the 
FAS and will be conducted on either the interim analysis dataset or all cumulative data up to 
study completion, whenever it is appropriate. Specifically, these analyses will compare between 
placebo and pooled SPD489 10, 20, 30 mg dose strengths together, excluding the 5 mg arm. For 
primary and key secondary endpoints, statistical tests are planned to control the study-wide type 
I error at the 2-sided 5% level, as described in Section 9.5. All other statistical tests will be 
2-sided hypothesis tests performed at the 5% level of significance, with no adjustment for 
multiplicity. All confidence intervals will be 2-sided 95% confidence intervals, unless stated 
otherwise.  In addition, the dose response relationship evaluations will be performed over the 
DRAS and using appropriate datasets. For this case, all randomized investigational product 
groups, which include 0 (placebo), 5, 10, 20, 30 mg (SPD489) doses will be used.
Rules for missing data handling will be described in the SAP.
9.8.1
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as the change from baseline in clinician-administered 
ADHD-RS-IV Preschool Version Total Score at Visit 6 (Week 6).


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The statistical hypotheses of the primary efficacy analysis are:

The null hypothesis is: there is no treatment difference between pooled SPD489 (10, 20, and 
30 mg) dose group and placebo at Visit 6 (Week 6)

The alternate hypothesis is: there is a difference between pooled SPD489 (10, 20, and 30 mg) 
dose group and placebo at Visit 6 (Week 6). 
The estimand of primary interest is:
Estimate of the average effect attributable to the experimental treatment as compared to placebo 
at Visit 6 (Week 6), for all subjects in the FAS of the study.
The primary efficacy endpoint will be analyzed using the linear mixed-effects model for repeated 
measures (MMRM). The analysis includes the fixed categorical effects of treatment, visit, and 
treatment-by-visit interaction, the covariate of baseline ADHD-RS-IV Preschool Version Total 
Score, and with the baseline ADHD-RS-IV Preschool Version Total Score-by-visit interaction 
adjusted in the model. The primary contrast of interest will be pooled 10, 20, and 30 mg 
treatment effect at Visit 6 (Week 6) for SPD489 compared with placebo. Missing data will not be 
imputed.
Sensitivity analysis on missing data for the primary efficacy endpoint will be described in the 
SAP.
9.8.2
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoint CGI-I provides an overall assessment of global symptom 
improvement. It will be analyzed using the same analysis method (MMRM) as for the primary 
efficacy endpoint. The baseline CGI-S score will be used as the covariate. The contrast of 
interest will be at Visit 6 (Week 6) for SPD489 compared with placebo. 
9.8.3
Secondary Efficacy Endpoints
The primary and key secondary efficacy analyses, and dose-response analysis will be conducted 
separately, and therefore no multiplicity adjustment will be considered for these objectives 
together.
Using a pre-specified set of candidate dose-response curves that are selected based on prior 
knowledge of SPD489 dose-response and assumptions on fixed-doses effects (placebo, SPD489 
5, 10, 20, and 30 mg), the dose-response relationship of SPD489 as measured by the change from 
baseline for ADHD-RS-IV Preschool Version Total Score will be evaluated using the DRAS. 
The MCP-Mod methodology will be used to identify the optimized dose-response curve and the
minimum effective dose (MED). 
The assumed family of plausible dose-response curves consists of linear, Emax, and logistic 
relationships, with appropriate parameters, covering the dose ranges of 0 mg (placebo) to 30 mg 
of investigational product. When the study completes, regardless at the interim analysis or at end 
of the study, using all cumulative available data, the dose-response relationship of SPD489 as 
measured by the change from baseline for ADHD-RS-IV Preschool Version Total Score fitting 
with a candidate curve will be evaluated.


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9.9
Safety Analyses
The Safety Analysis Set based on either the interim analysis dataset or all cumulative data up to 
study completion, whenever it is appropriate, will be used to report the safety data.  
Clinical laboratory tests, vital signs, and ECG findings will be summarized by treatment group 
and visit using appropriate descriptive statistics. Potentially clinically important findings will 
also be summarized by treatment group and listed.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities. TEAEs 
are defined as AEs that start or deteriorate on or after the date of the first dose of investigational 
product and no later than 3 days following the last dose of investigational product in the 
double-blind phase. 
Treatment-emergent AEs will be summarized. The number and percent of subjects with TEAEs 
will be calculated for each system organ class, by preferred term, and by treatment. The severity 
of the TEAEs, the relationship to the investigational product, TEAEs causing study 
discontinuation, serious AEs and death will also be presented. 
The CSHQ will be summarized by treatment group using appropriate descriptive statistics at 
each visit. 
Sleep diary data will be descriptively summarized by treatment group.
A summary and listing of the C-SSRS data will be provided for subjects with a positive response 
only.
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
10.1
Sponsor’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.
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996) and any updates or revisions, 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.


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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) and any updates or revisions, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time, resources, and appropriately 
trained personnel 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 subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.


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A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any 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.
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 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 diary cards and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.


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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, eg, 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).
10.2.4
Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation
When using controlled substances, 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. Subject’s 
parent(s) or LAR must provide signature of informed consent, and there must be documentation 
of assent (if applicable) by the subject in accordance with the International Council on 


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Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 (1996), any updates or 
revisions, and applicable regulations, before completing any study related procedures. All 
consent and assent documentation must be in accordance with applicable regulations and GCP. 
Each subject, parent or the subject’s LAR, as applicable, is requested to sign and date the subject 
informed consent form or a certified translation if applicable, after the subject, parent, 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 (ie, a complete set of subject information sheets and fully 
executed signature pages) must be given to the subject or the subject’s LAR, as applicable. This 
document may require translation into the local language. Signed consent forms must remain in 
each subject’s study file and must be available for verification at any time.
Within the source documents, site personnel should document instruction of and understanding 
by the parent(s)/LAR/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 (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.
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.


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10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.
After subjects have consented to take part in the study, the sponsor, and/or its representative’s
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 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 – 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 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. 


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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 International Committee of Medical Journal Editors 
(ICMJE) current standards. Participation as an investigator does not confer any rights to 
authorship of publications.


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11
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treatments in preschool children with attention-deficit/hyperactivity disorder: current 
evidence and practice. J Child Adolesc Psychopharmacol, 18, 413-47.
Glimm, E., Maurer, W. & Bretz, F. 2010. Hierarchical testing of multiple endpoints in group-
sequential trials. Stat Med, 29, 219-28.
Greenhill, L., Kollins, S., Abikoff, H., McCracken, J., Riddle, M., Swanson, J., McGough, J., 
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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 
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Hardman, J. G., Limbird, L. E. & Gilman, A. G. 2001. Goodman & Gillman’s The 
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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 
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Hartung, C. M., Chronis, A. & Massetti, G. 2004. Three-year predictive validity of DSM-
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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, 
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Kelsey, D., Stevens, L. & Allen, A. J. 2005. A randomized, placebo-controlled study of 
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Kapelinski, A., Martinez, J., Modi, N. B., Stehli, A. & Swanson, J. 2007. 
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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 
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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
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 2.2 BOYS’ STATURE-FOR-AGE AND WEIGHT-FOR-AGE 
PERCENTILES




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APPENDIX 2.4 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 
Lifetime Recent 
Since Last Visit
Lifetime Recent  6/23/10 
Since Last Visit 6/23/10
Peabody Picture Vocabulary Test
3rd Edition
1997
Kiddie–Schedule for Affective Disorders 
and Schizophrenia for School-age Children–
Present and Lifetime Version–Diagnostic 
Interview
1.0
1996
ADHD Rating Scale – IV Preschool Version 
(Teacher)
N/A
2007
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.

SAP_001.pdf: 
 
 
STATISTICAL ANALYSIS PLAN 
Protocol No.: 
SPD489-347 
Protocol Title: 
A Phase 3, Randomized, Double-blind, Multicenter, Parallel-group, 
Placebo-controlled, Fixed-dose Safety and Efficacy Study of SPD489 
Compared with Placebo in Preschool Children Aged 4-5 Years with 
Attention-deficit/Hyperactivity Disorder 
Drug: 
SPD489, Lisdexamfetamine dimesylate 
Sponsor:  
 Shire Development LLC and International Affiliates  
300 Shire Way, Lexington, MA 02421 
Version No. and Date 
Version 1.1; Date: 07 June 2017 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
INTRODUCTION ...............................................................................................................6 
2. 
STUDY DESIGN ................................................................................................................7 
2.1 
General Study Design ........................................................................................................7 
2.2 
Randomization ...................................................................................................................8 
2.3 
Blinding .............................................................................................................................8 
2.4 
Schedule of Assessments .................................................................................................10 
2.5 
Determination of Sample Size .........................................................................................13 
2.6 
Interim Analysis and Multiplicity Adjustments for Type I Error Control ......................14 
2.6.1 
Waiving of Interim Analysis .......................................................................................14 
2.6.2 
Interim Analysis ..........................................................................................................14 
2.7 
Decision Tree of Efficacy Analyses ................................................................................16 
3. 
OBJECTIVES ....................................................................................................................17 
3.1 
Primary Objective ............................................................................................................17 
3.2 
Secondary Objectives ......................................................................................................17 
4. 
SUBJECT POPULATION SETS ......................................................................................18 
4.1 
Screened Set ....................................................................................................................18 
4.2 
Randomized Set ...............................................................................................................18 
4.3 
Safety Analysis Set ..........................................................................................................18 
4.4 
Full Analysis Set ..............................................................................................................18 
4.5 
Dose-response Analysis Set ............................................................................................18 
5. 
SUBJECT DISPOSITION .................................................................................................20 
6. 
PROTOCOL DEVIATIONS .............................................................................................21 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................22 
7.1 
Demographic and Other Baseline Characteristics ...........................................................22 
7.2 
Medical History ...............................................................................................................22 
8. 
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ..................................23 
8.1 
Exposure to Investigational Product ................................................................................23 
8.2 
Measurement of Treatment Compliance .........................................................................23 
9. 
PRIOR AND CONCOMITANT MEDICATION .............................................................25 


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10. 
EFFICACY ANALYSES ..................................................................................................26 
10.1 
Primary Efficacy Endpoint and Analysis ........................................................................26 
10.2 
Sensitivity Analyses for the Primary Efficacy – Missing Not at Random ......................27 
10.3 
Key Secondary Efficacy Endpoint and Analysis .............................................................29 
10.4 
Dose-response Analyses ..................................................................................................29 
10.4.1  Dose-response Candidate Curves................................................................................29 
10.4.2  Dose-response Relationship Evaluations ....................................................................30 
10.4.3  Minimum Effective Dose ............................................................................................31 
10.4.4  Additional Analyses ....................................................................................................31 
10.5 
Supportive Analyses ........................................................................................................32 
10.5.1  Subgroup Analysis ......................................................................................................32 
10.5.2  Other Analyses ............................................................................................................32 
11. 
SAFETY ANALYSES ......................................................................................................33 
11.1 
Adverse Events ................................................................................................................33 
11.2 
Clinical Laboratory Variables .........................................................................................34 
11.3 
Vital Signs .......................................................................................................................36 
11.4 
Electrocardiogram (ECG) ................................................................................................38 
11.5 
Other Safety Variables ....................................................................................................39 
11.6 
Children’s Sleep Habits Questionnaire and Sleep Diary .................................................39 
11.7 
Columbia-Suicide Severity Rating Scale ........................................................................40 
11.8 
Follow-up Phone Call ......................................................................................................41 
12. 
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES .......42 
13. 
OTHER ANALYSES ........................................................................................................43 
14. 
INTERIM ANALYSIS ......................................................................................................44 
15. 
DATA MONITORING/REVIEW COMMITTEE ............................................................45 
16. 
COMPUTER METHODS .................................................................................................46 
17. 
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ............................................47 
18. 
DATA HANDLING CONVENTIONS .............................................................................48 
18.1 
General Data Reporting Conventions ..............................................................................48 
18.2 
Derived Efficacy Endpoints ............................................................................................48 
18.3 
Repeated or Unscheduled Assessments of Safety Parameters ........................................49 
18.4 
Missing Date of Investigational Product .........................................................................49 
18.5 
Missing Date Information for Prior or Concomitant Medications ..................................49 


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18.6 
Incomplete Start Date ......................................................................................................49 
18.7 
Incomplete Stop Date ......................................................................................................50 
18.8 
Missing Date Information for Adverse Events ................................................................51 
18.9 
Missing Severity Assessment for Adverse Events ..........................................................51 
18.10 
Missing Relationship to Investigation Product for Adverse Events ................................51 
18.11 
Character Values of Clinical Laboratory Variables ........................................................51 
19. 
REFERENCES ..................................................................................................................52 
20. 
APPENDIX .......................................................................................................................53 
20.1 
Appendix 1 Algorithms for Deviation of the Pooled Common Variance .......................53 
20.2 
Appendix 2 Sample SAS Codes ......................................................................................54 
LIST OF TABLES AND FIGURES 
Figure 1: 
Study Design Flow Chart ..............................................................................................7 
Table 1:  Schedule of Assessments ...................................................................................................9 
Table 2:  Criteria for Potentially Clinically Important Laboratory Tests .......................................35 
Table 3:  Criteria for Potentially Clinically Significant Vital Signs ...............................................37 
Table 4:  Criteria for Potentially Clinically Important ECG Values ..............................................38 
Table 5:  Examples for Coding of Special Character Values for Clinical Laboratory  
Variables ..........................................................................................................................51 
 


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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 Rating Scale 
DINFC 
date of informed consent 
DMC 
data monitoring committee 
DOB 
date of birth 
ECG 
electrocardiogram 
ET 
early termination 
FAS 
Full Analysis Set 
K-SADS-PL 
Kiddie-Schedule for Affective Disorders and Schizophrenia for 
School-age Children-Present and Lifetime Version-Diagnostic Interview 
LS 
least squares 
MAR 
missing at random 
MED 
minimum effect dose  
MMRM 
mixed-effects model for repeated measures 
MNAR 
missing not at random 
PCI 
potentially clinically important 
PT 
preferred term 
SD 
standard deviation 
SE 
standard error 
SOC 
system organ class 
TEAE   
treatment-emergent adverse event 


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1. INTRODUCTION 
This statistical analysis plan provides a technical and detailed elaboration of the statistical 
analyses of efficacy and safety data as described in the final study protocol. Specifications for 
tables, figures, and listings will be provided in a separate document.  


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2. STUDY DESIGN  
2.1 
General Study Design 
This is a Phase 3, randomized, double-blind, multicenter, parallel-group, placebo-controlled, 
fixed-dose study to evaluate the safety and efficacy of SPD489 compared to placebo, 
administered as a daily morning dose in the treatment of preschool children 4-5 years of age, 
diagnosed with attention deficit/hyperactivity disorder (ADHD).  
A randomized design is used to avoid baseline characteristics selection bias for different 
treatment groups on the part of the participants and investigators. Blinded treatment is used to 
reduce potential bias during data collection and evaluation of clinical results. The placebo arm is 
used to control the subject’s expectation that a treatment would have an effect, to optimize 
sensitivity, to maintain the scientific rigor of the study, and to validate the study internally. 
The study has 4 periods: 1) Screening and Washout; 2) Fixed-dose titration; 3) Dose 
Maintenance; and 4) Safety Follow-up. The duration of the double-blind evaluation period 
(Fixed-dose titration and Dose-maintenance Periods) will be 6 weeks.  
The study will be conducted in up to 60 sites in the North America. The subject’s maximum 
duration of participation is expected to be approximately 11 weeks. The study will be completed 
in approximately 24 months. Subjects will be randomized at baseline (Visit 0) in a 5:5:5:5:6 ratio 
to SPD489 5, 10, 20, 30mg or placebo group. Approximately 25% of the subjects enrolled will 
be female. Subjects are titrated to the randomly assigned dose strength of the investigational 
product (refer to SPD489-347 Protocol, Section 6.2.3).  
SPD489 will be provided in dose strengths of 5, 10, 20 and 30 mg, and matching placebo will 
also be provided. Visits and phases are presented graphically in Figure 1. 
Figure 1: 
Study Design Flow Chart 


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ET = early termination, V = visit, W = week, WO = washout. 
 
2.2 
Randomization 
Subject numbers are assigned to all subjects as they consent to take part in the study. Within each 
site (numbered uniquely within a protocol), this number is assigned to subjects according to the 
sequence of presentation for study participation. 
Individual subject treatment is automatically assigned by the interactive voice/web response 
system. Investigational product packaging identification numbers, separate from randomization 
numbers/unique identifiers, may also be assigned to subjects for specific treatment assignment as 
dictated by the study. In these cases, the same investigational product packing identification 
number may not be assigned to more than 1 subject. 
Approximately 245 subjects will be screened to randomize approximately 195 subjects. Subjects 
who meet all the inclusion criteria and none of the exclusion criteria will be randomized in a 
5:5:5:5:6 ratio to SPD489 5, 10, 20, 30 mg or placebo, using the interactive voice/web response 
system.  
2.3 
Blinding 
This is a double-blind study. All investigational product (SPD489 5, 10, 20, 30 mg or placebo) is 
over-encapsulated and appears identical, in order to protect the blinding of the study. 
Data that may potentially unblind the treatment assignment (ie, investigational product serum 
concentrations, antibodies to investigational product, treatment allocation, and investigational 
product preparation/accountability data) will be handled with special care during the data 
cleaning and review process. These data will be handled in such a way that, prior to unblinding, 


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any data that may unblind study team personnel will be presented as blinded information or 
otherwise will not be made available. If applicable, unblinded data may be made available to 
quality assurance representatives for the purposes of conducting independent drug audits. 
The treatment assignment must not be broken during the study except in emergency situations 
where the identification of the investigational product for an individual subject is required for 
further treatment of the subject. Prior to unblinding, and if the situation allows, the Investigator 
should first contact the Medical Monitor. 
In the event that the treatment assignment is broken, the date, the signature of the person who 
broke the code and the reason for breaking the code will be recorded in the interactive voice/web 
response system and the source documents. Upon breaking the blind, the subject will be 
withdrawn from the study, but should be followed up for safety purposes.  
 


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2.4 
Schedule of Assessments 
Table 1: Schedule of Assessments 
Period 
Screening and  Washout 
Dose-titration  
Dose-maintenance  
Safety 
Follow-up 
Visita 
-1 
(Screening) 
Washout 
Telephone 
Call 
0 
(Baseline) 
1 
2 
3 
4 
5 
6/ ET 
Telephone Call 
Assessment Week 
-4 to -1 
-1  
0 
1 
2 
3 
4 
5 
6 
7 
Assessment Day  
-28 to -1 
0 
7 
14 
21 
28 
35 
42 
49 
Informed consent/assent 
 
 
 
 
 
 
 
 
 
 
Psychiatric evaluation (utilizing 
the K-SADS-PL) 
 
 
 
 
 
 
 
 
 
 
Peabody Picture Vocabulary Test 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
 
b 
b 
 
 
 
 
 
 
 
Demographics 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
 
 
 
Medical and medication historyc 
 
 
 
 
 
 
 
 
 
 
Physical examination 
 
 
d 
 
 
 
 
 
 
 
Vital signse 
 
 
 
 
 
 
 
 
 
 
Heightf 
 
 
 
 
 
 
 
 
 
 
Body weight f 
 
 
 
 
 
 
 
 
 
 
Calculate BMI g 
 
 
 
 
 
 
 
 
 
 
Clinical laboratory testsh, i 
 
 
d 
 
 
 
 
 
 
 
12-lead ECG j 
 
 
d 
 
 
 
 
 
 
 
ADHD-RS-IV Preschool Versionk 
 
 
 
 
 
 
 
 
 
 
CGI-S l 
 
 
 
 
 
 
 
 
 
 
CGI-I k 
 
 
 
 
 
 
 
 
 
 
CSHQ k 
 
 
 
 
 
 
 
 
 
 


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Table 1: Schedule of Assessments 
Period 
Screening and  Washout 
Dose-titration  
Dose-maintenance  
Safety 
Follow-up 
Visita 
-1 
(Screening) 
Washout 
Telephone 
Call 
0 
(Baseline) 
1 
2 
3 
4 
5 
6/ ET 
Telephone Call 
Assessment Week 
-4 to -1 
-1  
0 
1 
2 
3 
4 
5 
6 
7 
Assessment Day  
-28 to -1 
0 
7 
14 
21 
28 
35 
42 
49 
Sleep diary l 
 
 
 
 
 
 
 
 
 
 
C-SSRS k 
 
 
 
 
 
 
 
 
 
 
Suitability of subject to remain in 
study m 
 
 
 
 
 
 
 
 
 
 
Investigator dose assessment 
 
 
 
 
 
 
 
 
 
 
Access IWRS 
 
 
 
 
 
 
 
 
 
 
Investigational product distributed  
 
 
 
 
 
 
 
 
 
 
Investigational product returned  
 
 
 
 
 
 
 
 
 
 
Investigational product 
compliance  
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
 
 
 
 
 
 
 
 
 
 
Adverse events  
 
 
 
 
 
 
 
 
 
 
ADHD-RS-IV=ADHD Rating Scale-IV; BMI=body mass index; 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; ECG=Electrocardiogram; ET=early termination; IWRS= Interactive Web 
Response System; K-SADS-PL=Kiddie-Schedule for Affective Disorders and Schizophrenia for School-age Children-Present and Lifetime Version-Diagnostic Interview 
a Visit windows are 3 days [in reference to the baseline visit (Visit 0) date] during the Fixed-dose titration and Dose-maintenance Periods. Safety Follow-up Telephone Call 
window is +3 days. 
b Inclusion/exclusion criteria must be reviewed at the Washout Telephone Call and at the baseline visit (Visit 0). 
c Medication history will include a lifetime history of pharmacologic and non-pharmacologic therapies for ADHD. 
d An abbreviated physical examination, 12-lead ECG, and all clinical laboratory tests must be repeated and results reviewed by the investigator prior to the baseline visit (Visit 0) if 
more than 30 days have elapsed since the safety measurements at the screening visit (Visit -1) were collected. Results must be obtained and reviewed prior to determining 
eligibility.  
e Includes oral or tympanic temperature, sitting blood pressure, pulse, and respiratory rate. Measurements of blood pressure and pulse will be performed at each visit to the site. 
Measurements of temperature and respiratory rate will be performed at the screening visit (Visit -1) and Visit 6/ET only. Blood pressure, pulse, and respiratory rate will be 


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Table 1: Schedule of Assessments 
Period 
Screening and  Washout 
Dose-titration  
Dose-maintenance  
Safety 
Follow-up 
Visita 
-1 
(Screening) 
Washout 
Telephone 
Call 
0 
(Baseline) 
1 
2 
3 
4 
5 
6/ ET 
Telephone Call 
Assessment Week 
-4 to -1 
-1  
0 
1 
2 
3 
4 
5 
6 
7 
Assessment Day  
-28 to -1 
0 
7 
14 
21 
28 
35 
42 
49 
determined after subjects have remained seated for a minimum of 5 minutes. Measurement of blood pressure and pulse will be collected 3 times (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 
measurements should be taken prior to the collection of blood draws. 
f Height and weight to be measured without shoes. 
g BMI will be recorded at Screening for eligibility. BMI will be derived from height and weight during the course of the study for analysis.  
h Clinical laboratory tests will include hematology, chemistry, endocrinology, and urinalysis. 
i 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 the study visit date, with 
the exception of the 6/ET home draw which has a -1 day window.  
j Three ECGs, taken approximately 5 minutes apart, are to be collected so that appropriate baseline intervals are established. Results must be reviewed prior to determining 
eligibility. 
k Scales to be completed by same rater with input from the same parent/LAR whenever possible. 
l Sleep diary to be completed by parent(s)/LAR. Sleep diaries will be dispensed at Visits 0-5 and collected at Visits 1-6.  
m C-SSRS “Lifetime Recent” version completed at the screening visit (Visit -1). C-SSRS “Since Last Visit” version completed for all subsequent visits. 
 
 
 
 
 
 


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2.5 
Determination of Sample Size 
Approximately 245 subjects will be screened to randomize approximately 195 subjects in a 
5:5:5:5:6 ratio to SPD489 5, 10, 20, 30 mg  or placebo to achieve 156 completers for the study 
(30 in each active treatment group and 36 in the placebo group) and 85% power for the primary 
efficacy analysis at a 2-sided 0.05 significance level.  
The sample size planned at study initiation is estimated based on the primary comparison between 
SPD489 10, 20, 30 mg pooled together (excluding the 5mg) compare with placebo on the primary 
efficacy endpoint, in a group sequential design with 1 interim analysis using the Lan-DeMets alpha 
spending function with O’Brien-Fleming boundary for the primary efficacy endpoint. Assumptions 
for the calculation include the true mean difference of 8.4 with the common standard deviation 
(SD) of 14 for the primary efficacy endpoint, for an effect size of 0.6, and a dropout rate of 20%. 
In order to maintain sufficient study power to detect a clinically meaningful treatment effect for the 
primary efficacy endpoint, a blinded sample size re-estimation is planned. If the study continues 
beyond the proposed interim analysis, or if the interim analysis is waived, then the sample size re-
estimation will be performed when approximately 75% of the 195 subjects have either completed or 
discontinued from the study. In this case, cumulative primary efficacy data will be used to estimate a 
pooled common SD to ensure the variability hypothesized at the design stage is not underestimated. 
Together with the assumed treatment difference of 8.4, the final total number of subjects to be 
enrolled will be calculated using the re-estimated pooled SD (Friede and Kieser 2006).  Step by step 
details for estimating the pooled SD are included in the Appendix 1. Using the pooled common 
variance estimated to do a blinded sample size re-estimation does not inflate the Type I error. 
 
The final total sample size could potentially be as high as 218 completers, which corresponds to 
the 97.5% percentile of the distribution of the estimator on the assumed true common SD of 14 
postulated at the design stage. If the re-estimated pooled common SD is larger than 14, the 
sample size will be increased. Otherwise, the sample size will remain the same. Note that the 
total of 218 completers is not considered a cap. As the final sample size is data driven, a higher 
number, though unlikely, is possible. 
The Type-I error level for the sample size re-estimation will be adjusted based on the Lan-
DeMets alpha spending function with O’Brien-Fleming boundary when applicable. 
The dose-response relationship that is measured by the ADHD-RS-IV Preschool Version Total 
Score change from baseline will be evaluated separately.  Assuming the maximum difference in 
change from baseline in ADHD-RS-IV Preschool Version Total Score between 0 mg (placebo) 
and SPD489 (5, 10, 20 or 30 mg) is 13.0 points, and has a standard deviation of 14 for the 
change, then in order to detect a plausible dose-response curve at 85% power and a significance 
level of 0.05 (2-sided) using MCP-Mod with equal allocation to the treatment groups, it is 
necessary to have 18 completers for each arm. Assuming a 20% dropout rate, a total of 24 
subjects for each treatment group are required to be randomized. Therefore, the overall sample 
size of the study will be sufficient for dose-response analysis 


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2.6 
Interim Analysis and Multiplicity Adjustments for Type I Error Control 
The study implements a group sequential design with 1 interim analysis. The interim analysis is 
proposed at approximately 60% of planned subjects, who either complete or discontinue the 
study. 
The interim analysis will be conducted on the interim analysis dataset, which is defined as all 
data from 60% of initially planned subjects who have either completed or discontinued the study, 
together with data for subjects who are in the study up to the interim analysis data cut time point. 
The efficacy, safety, and sensitivity on missing data mechanisms analyses at the interim analysis 
will primarily be conducted using this dataset.  
2.6.1 
Waiving of Interim Analysis  
It is estimated that the interim analysis will take up to 8 weeks from data cutoff to its completion. 
If the recruitment rate is high and the remaining 40% planned subjects are projected to be all or 
nearly all enrolled within those 8 weeks, the interim analysis will be waived with reasons 
documented. In this case, the end of study analysis will be conducted at the 2-sided significance 
level of 0.05 with primary and key secondary endpoints tested sequentially. Furthermore, the 
dose-response relationship will be evaluated as well.  
2.6.2 
Interim Analysis  
The Lan-DeMets alpha spending function with O’Brien-Fleming boundary will be used for alpha 
spending between the interim and end of study analysis for the primary efficacy endpoint. 
Following evaluations in the stage-wise hierarchical setting (Glimm et al. 2010), the Lan-DeMets 
alpha spending function with Pocock boundary will be applied to analyze the key secondary 
efficacy endpoint. 
If the hypothesis for the primary efficacy endpoint is rejected at the interim analysis, then the 
study will be stopped for efficacy and all ongoing subjects from the study (SPD489-347) will be 
immediately rolled over to the open-label extension study (Study SPD489-348). In this case, 
using the same data cut point that contains the same information fractions as the primary efficacy 
interim analysis, the key secondary efficacy endpoint will be tested, and all safety summaries 
that the DMC to be needed for their decision will be generated, which will include disposition, 
demographic and baseline characteristics, main AE and vital signs information. Additionally, the 
incremental data collected during the interim analysis process, i.e., the overrun, together with the 
interim analysis dataset will be utilized in sensitivity analyses for efficacy and safety. Otherwise, 
if the primary efficacy criterion is not met at the interim analysis, then the hypothesis for the key 
secondary endpoint will not be tested at this time, and the study will continues to its completion, 
at which time the primary efficacy endpoint will be tested. If the primary efficacy test is rejected, 
then the key secondary efficacy endpoint will be tested. This testing procedure strongly protects 
the overall alpha level for the primary and key secondary efficacy analyses. All other efficacy 
and safety analyses will be conducted at this time as well.   
At the interim or final efficacy analysis, only the primary efficacy result will be used to 
determine if the study meets the efficacy criterion.  The nominal significance level for the 
interim or final primary and key secondary efficacy endpoints for a 2-sided at a 0.05 significant 
level are specified below, calculated using East® 6.4. The calculations are based on 60% of 


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planned sample size at the interim analysis, and the significance values may be updated (in a 
blinded fashion), based on the actual information fraction at the interim analysis. 
 
 
Efficacy Boundary p-value Scale 
Interim Analysis 
Final Analysis 
Primary Endpoint 
0.0074 
0.0477 
Key Secondary Endpoint 
0.0354 
0.0257 
 
In general, the nominal significance level used for the interim analysis will no longer apply for 
the sensitivity analysis, it should be recalculated. However, if the information fraction increase is 
limited, for example, if the increase is less than 1%, then the nominal significance levels for the 
interim analysis can be used as a good approximation (Proschan et al. 2006) for the sensitivity 
analyses. 
If the primary efficacy criterion is not met at the interim analysis, and the blinded sample size 
re-estimation causes a sample size increase, then the nominal significance levels at end of the study 
will be recalculated, such that the overall alpha level is not greater than 0.05 for the primary and 
key secondary analyses together. The calculations will be based on the new increased sample size, 
the actual information ratio, and the alpha already spent. The new increased sample size extends 
the information time scale from interval [0, 1] to a wider one. In order to find the critical value for 
the completion study analysis, the extended time interval will be converted to the original time 
scale. The information fractions of the interim analysis can be identified within the new time scale. 
Applying it along with the increased new sample size, the critical values for the completion study 
analysis can be calculated. This process will be documented prior to database lock and unblinding. 
Separately, if the primary efficacy criterion is met at the interim analysis, the interim analysis 
dataset together with data for the subjects in the study up to the interim analysis data cut time 
point will be used to evaluate the dose-response relationship over the DRAS. Otherwise, all 
cumulative data up to completion of the study will be used. 
 
 


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2.7 
Decision Tree of Efficacy Analyses  
 


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3. OBJECTIVES 
3.1 
Primary Objective 
The primary objective is to evaluate the efficacy of SPD489 compared to placebo in preschool 
children (4-5 years of age inclusive at the time of consent) with ADHD. The primary measure of 
efficacy will be the clinician-administered ADHD Rating Scale Preschool Version 
(ADHD-RS-IV Preschool Version) Total Score. 
3.2 
Secondary Objectives 
 Key Secondary: To evaluate the efficacy of SPD489 compared to placebo, using the global 
clinical measure of improvement, the Clinical Global Impression – Global Improvement 
(CGI-I) scale.  
 Secondary:  
o To evaluate dose-response relationship in preschool children with ADHD, using the 
ADHD-RS Preschool Version Total Score. 
o To evaluate the safety and tolerability of SHP489 based on the occurrence of TEAEs, 
specific evaluation of vital signs (systolic and diastolic blood pressure and pulse), 
height, weight, and body mass index (BMI), clinical laboratory evaluations and 
electrocardiogram (ECG) results, sleep assessment, and the Columbia Suicide Rating 
Scale (C-SSRS). 
 


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4. SUBJECT POPULATION SETS 
The following subject sets are applicable to this study.  
4.1 
Screened Set  
The Screened Set will consist of all subjects who have signed informed consent. 
4.2 
Randomized Set  
The Randomized Set will consist of all subjects in the Screened Set for whom a randomization 
number has been assigned. 
4.3 
Safety Analysis Set  
The Safety Analysis Set will consist of all Randomized Set who have taken at least 1 dose of 
investigational product. 
4.4 
Full Analysis Set  
The Full Analysis Set (FAS) will consist of all subjects in the Safety Analysis Set who have at 
least 1 post-dose ADHD-RS-IV-Preschool Version Total Score assessment. 
4.5 
Dose-response Analysis Set  
The Dose Response Analysis Set (DRAS) will consist of all subjects in the Safety Analysis Set 
who have at least 1 valid primary efficacy measurement (ADHD-RS- IV Preschool Version 
Total Score) on the randomized target dose level of the investigational product. 
The above analysis sets will be utilized for both the interim and the end of study analyses.  
Subjects are randomized at baseline (Visit 0) in a 5:5:5:5:6 ratio to SPD489 5, 10, 20, 30 mg or 
placebo group. If not stated otherwise, each dose strength and pooled doses (10, 20, 30 mg 
pooled together) will be used for reporting the study variables, as below.  
 
 
 
SPD489 
Parameter 
Placebo 
5mg 
10mg 
20mg 
30mg 
Pooled 
10, 20, 
30 mg 
Baseline Characteristics 
  
  
  
  
  
  
Primary Efficacy 
  
 
 
 
 
  
Key Secondary Efficacy 
  
 
 
 
 
  
All Other Efficacy  
  
 
 
 
 
  


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SPD489 
Parameter 
Placebo 
5mg 
10mg 
20mg 
30mg 
Pooled 
10, 20, 
30 mg 
Dose-response Relationship 
  
  
  
  
  
  
Safety Reporting 
  
  
  
  
  
  
 


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5. SUBJECT DISPOSITION 
A listing of all Screen Failures (ie, subjects who were screened but not randomized) will be 
presented along with reasons for screen fail and details of any adverse events (AEs).  
The number of subjects included in each analysis set (ie, Screened, Randomized, Safety, FAS 
and DRAS) will be summarized by treatment group, pooled doses and overall, except for the 
Screened Set, which will be summarized only overall. 
The number and percentage of subjects who completed and prematurely discontinued during the 
Double-blind Evaluation Period will be presented for each treatment group, pooled doses and 
overall for the Safety Set. Reasons for premature discontinuation from the Double-blind 
Evaluation Period, as recorded on the end of study discontinuation page of the electronic case 
report form, will be summarized (number and percentage) by treatment group, pooled doses and 
overall for the Safety Set. The subjects who completed the study are those that completed the 
final scheduled visit at the end of the Double-blind Evaluation Period. When the interim analysis 
is conducted, for reporting purpose, an ongoing category will be added, and it will be reported by 
treatment, pooled doses and overall. 
All subjects who prematurely discontinued during the Double-blind Evaluation Period will be 
listed by discontinuation reason for the Randomized Set. 
The number of subjects randomized 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). 
Follow-up phone call information will be listed for the Safety Analysis Set. 
 


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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 treatment unblinding and database lock.  
Decisions of the review will include accuracy of protocol deviation categorization. 
For any criteria for protocol deviations that can be completely implemented by a computer 
program, the detailed algorithm will be agreed upon. Details of such algorithms will be included 
in the derived dataset specifications and finalized before treatment unblinding. 
Confirmed protocol deviations will be documented in the Protocol Deviation tracker for the 
study. Protocol deviations will be summarized using the Randomized Set by category and site for 
each treatment group, pooled doses and overall. Protocol deviations will be listed for the 
Randomized Set. 
 


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7. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
7.1 
Demographic and Other Baseline Characteristics 
Demographics and baseline characteristics will be examined to assess the comparability of the 
treatment groups at baseline, where baseline is defined as the last assessment prior to the first 
administration of the investigational product. The demographics and baseline data will be 
summarized by treatment group, pooled doses and overall for the Safety Analysis Set, FAS and 
DRAS. Listings will be provided as well. 
Age will be calculated as the difference between date of birth (DOB) and date of informed 
consent (DINFC), truncated to months, using the following SAS function:  
Age = floor((intck('month', DOB, DINFC) - (day(DINFC) <day(DOB))) / 12) 
 
The Screening height and body weight will be used to calculate BMI using the following 
formula: 
 
Weight [kg] 
BMI = (Height [m])2 
The 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: 
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. 
The following demographic characteristics will be summarized: age, sex, ethnicity, race, weight, 
height, BMI, and BMI category. In addition, other baseline characteristics to be summarized 
include the Peabody Picture Vocabulary Test standard score, Children’s Global Assessment 
Scale scores, Clinical Global Impression – Severity of Illness (CGI-S), and ADHD subtypes. 
Continuous variables will be summarized by descriptive statistics including number of subjects, 
mean, 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.  
All demographic and baseline characteristics will be listed for the Safety Analysis Set.  
7.2 
Medical History 
Medical history is collected at the Screening Visit (Visit -1). Prior and ongoing psychiatric 
evaluation will be established with the Screening Visit (Visit -1) interview using the 
Kiddie-Schedule for Affective Disorders and Schizophrenia for School-age Children-Present and 
Lifetime Version-Diagnostic Interview (K-SADS-PL). Both of the assessment results will be 
listed for the Safety Analysis Set. 


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8. EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE 
8.1 
Exposure to Investigational Product  
Exposure to double-blind investigational product for the Safety Analysis Set will be summarized 
by treatment, pooled doses. The following statistics will be calculated for the Fixed-dose 
Titration Period, the Dose Maintenance Period, and the whole Double-blind Evaluation Period 
for the investigational product: 
 Total days of dosing: sum of the days of dosing for each period. Within each period, it is 
defined as (date of last dose - date of first dose + 1) 
 Average daily dose (mg/day) for SPD489: the total dose/total days of dosing 
 Maximum dose for SHP489: the highest dose level received 
 
An appropriate statistical summary will be applied to present for each of the above statistical 
quantity for each of the study period respectively. In addition, person-time (overall total 
exposure in days) 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.  
Dosing information will be listed.  
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 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. Subjects that do not return the investigational product but return to the site for a 
following visit will have zero capsule returned entered into the database. In this case, it will be 
assumed for analysis purposes that all capsules were ingested.  
8.2 
Measurement of Treatment Compliance 
Investigational product dosing compliance, during the Dose Optimization Period, the Dose 
Maintenance Period, and the whole Double-blind Evaluation Period, respectively, is defined as 
the total number of capsules taken by a subject during that period divided by the number of 
capsules expected to be taken during the same period multiplied by 100, that is (number of 
capsules actually taken × 100 / number of capsules expected to be taken). The number of 
capsules taken is calculated by the 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 
the subject is in the particular period multiplied by the number of capsules to be taken per day 
during that period. If the number of capsules taken or returned is missing, then the compliance 
will be missing.  
For each study period, the compliance data will be reported using number of subjects, mean, SD, 
median, minimum, and maximum for the Safety Analysis Set by treatment group and pooled 


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doses. Furthermore, the compliance data will be categorized as <80%, 80-120%, or >120%, and 
it will be presented using subject counts and percentages for the Safety Analysis Set by treatment 
group and pooled doses. 
Treatment compliance data will also be listed for all subjects in the Safety Analysis Set. 


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9. PRIOR AND CONCOMITANT MEDICATION  
The most updated available version of the World Health Organization drug dictionary will be 
used to classify prior and concomitant medications by therapeutic class. 
Prior medication is defined as any medication with a start date prior to the date of the first dose 
of investigational product.  
Concomitant medication is defined as any medication with a start date prior to the date of the 
first dose of investigational product and continuing after the first dose of investigational product 
or with a start date between the dates of the first and last doses of investigational product, 
inclusive. Any medication with a start date after the date of the last dose of investigational 
product will not be considered a concomitant medication. 
Both prior and concomitant medication usage (including ADHD medication) will be summarized 
by the number and proportion of subjects within each preferred term for the Safety Analysis Set 
by treatment group and pooled doses. 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 within 
each preferred term for the Safety Analysis Set by treatment group and pooled doses.  
All prior and concomitant medication will be listed for the Safety Analysis Set. Separate listings 
will also be provided for prior and concomitant ADHD medication and prior and concomitant 
ADHD behavioral therapy. 


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10. EFFICACY ANALYSES 
The primary and key secondary analyses, including their sensitivity analyses, will be based on 
the FAS and will be conducted on either the interim analysis dataset, which is defined in Section 
2.6, or all cumulative data up to study completion, whenever it is appropriate. Specifically, these 
analyses will compare placebo and pooled SPD489 10, 20, 30 mg dose strengths together, 
excluding the 5 mg arm.  For primary and key secondary endpoints, statistical tests are planned 
to control the study-wise type I error at the 2-sided 5% level, as described in Section 2.6. All 
other statistical tests will be 2-sided hypothesis tests performed at the 5% level of significance, 
with no adjustment for multiplicity. All confidence intervals (CIs) will be 2-sided 95% CIs), 
unless stated otherwise. Additionally, the dose response relationship evaluations will be 
performed over the DRAS and using appropriate datasets. For this analysis, all randomized 
investigational product groups, which include 0 (placebo), 5, 10, 20, 30 mg (SPD489) dose 
strengths will be used.    
Baseline for all efficacy analyses is defined as the last valid value for the efficacy assessment 
prior to the first dose of investigational product. An efficacy measurement that is assessed more 
than 3 days after the date of the last dose of investigational product will not be included for 
analysis.  
10.1 
Primary Efficacy Endpoint and Analysis  
The primary efficacy endpoint is defined as the change from baseline in clinician-administered 
ADHD-RS-IV Preschool Version Total Score at Visit 6 (Week 6). 
The statistical hypotheses of the primary efficacy analysis are: 
 The null hypothesis is: there is no treatment difference between pooled SPD489 (10, 20 and 
30mg) dose group  and placebo at Visit 6 (Week 6)  
 The alternate hypothesis is: there is a treatment difference between pooled SPD489 (10, 20 
and 30mg) dose group and placebo at Visit 6 (Week 6).  
 
The estimate of primary interest is estimate of the average effect attributable to the experimental 
treatment (pooled SPD489 10, 20 and 30 mg) as compared to placebo at Visit 6 (Week 6), for all 
subjects in FAS of the study. 
The primary efficacy endpoint will be analyzed using the linear mixed-effects model for repeated 
measures (MMRM). The analysis includes the fixed categorical effects of treatment, visit, and 
treatment-by-visit interaction, the covariate of baseline ADHD-RS-IV Preschool Version Total 
Score, and with the baseline ADHD-RS-IV Preschool Version Total Score-by-visit interaction 
adjusted in the model. The restricted maximum likelihood method will be used, with an 
unstructured covariance structure (UN) shared across treatment groups used to model the 
within-patient errors. The Kenward-Roger method is used to estimate denominator degrees of 
freedom and adjust standard errors (SEs). The primary contrast of interest will be at Visit 6 
(Week 6) for pooled SPD489 (10, 20 and 30mg) dose group compared with placebo. 


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For the above MMRM analysis, contrast coefficients that are based on the actual sample size of 
placebo or each dose in the pooled SPD489 group will be used to obtain a weighted average for 
performing the comparison.   
If the UN covariance structure fails to converge, as an alternative, the Toeplitz (TOEP) or 
Autoregressive (1) [AR(1)] covariance matrix will be applied in that order, that is, test the TOEP 
structure first, if it does not converge then test the AR(1).  Both of these covariance matrices can 
model data with correlations that decline over time. Comparing AR(1) with TOEP, the AR(1) 
has less constraining conditions, so when the TOEP structure fails to converge, the AR(1) may 
still converge. Regardless which covariance structure is chosen, missing data will not be 
imputed. 
Descriptive statistics will be displayed for pooled SPD489 (10, 20 and 30mg), and placebo 
group. To compare pooled SPD489 dose group and placebo, the difference of LS means, the 
corresponding 95% CI and p-value, and the effect size (Cohen 1988) (defined as difference of 
the least squares means divided by the estimated SD from the corresponding covariance matrix) 
will be displayed. The p-value and effect size will only be presented for Visit 6 (Week 6). 
Additionally, a corresponding line graph of the LS means of change from baseline and associated 
95% CI in ADHD-RS-IV Preschool Version Total Score by pooled SPD489 (10, 20 and 30mg) 
dose group and placebo, and visit will be presented.  
10.2 
Sensitivity Analyses for the Primary Efficacy – Missing Not at Random  
The primary efficacy analysis (MMRM) relies on the assumption that the missing data 
mechanism follows the missing at random (MAR) scenario. In this case, it is assumed that the 
reason for data being missing may depend on observed data, but not on the unobserved missing 
data. The likelihood-based MMRM analysis is an appropriate method for the statistical analysis 
under MAR assumption. 
The following 2 sensitivity analysis models, which are within the pattern-mixture model 
framework, will be used to examine the robustness of the primary efficacy analysis results for the 
missing not at random (MNAR) mechanisms. Under MNAR, it is assumed that the reason for 
data being missing is related to the unobserved missing data.  
Model 1: Placebo Multiple Imputation 
Rationale: The imputations are based on the distribution of placebo group responses over time. 
The underlying assumption is that the missing data for a subject on the active treatment follow 
the distribution of the placebo responses, i.e., the mean values and intra-subject correlations 
based on the placebo responses will be applied.  
The model is implemented in 3 steps: 1) imputations, 2) analysis of complete data sets, and 3) 
inference. Sample SAS codes are provided in Appendix 2. 
Step 1: Imputations  


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A total of 200 sets of posterior mean and co-variance estimates are extracted from the SAS MI 
procedure using the available non-missing placebo data. One hundred of the posterior sets will 
be applied to the pooled active treatment group, while the other 100 will be applied to the 
placebo group. One set of imputations for all missing values will be generated based on each 
variation of posterior estimates. All 100 datasets for imputations within a treatment group will be 
ordered from 1 to 100 and combined between pooled active treatment group and placebo, for a 
total of 100 completely imputed datasets.  
Step 2: Analysis of Complete Datasets  
The primary efficacy endpoint will be analyzed for each of the 100 complete datasets with 
imputed data using an analysis of covariance with treatment group as factors and the baseline 
value as a covariate.  
Step 3: Inference  
The LS mean difference estimates will be averaged, and the associated SEs will be summarized 
based on within-imputation and between-imputation variance using the SAS MIANALYZE 
procedure to yield a final estimate with associated 95% CI and p-value. 
If the primary efficacy criterion is met at the interim analysis, then the above process will be 
adjusted. For subjects who are ongoing at the time of study stop, the posteriors from the 
corresponding treatment group will be applied. For dropouts at the time of the interim analysis, 
the placebo posteriors will be applied. 
Model 2: Multiple Imputations with Penalties Applied to Dropouts 
Rationale: The underlying assumption is that subjects who dropout performing worse than MAR 
by a penalty.  
The model is implemented in 3 steps: 1) imputations and application of penalty, 2) analysis of 
complete data sets, and 3) inference. Sample SAS codes for steps 1a and 1b are provided in  
Step 1a: Imputations  
Missing data will be multiply imputed for 100 times on a treatment specific, multivariate normal 
distribution of the response overtime, using the SAS MI procedure with treatment in the BY 
statement. This step is based on the MAR assumption. 
Step 1b: Application of Penalty 
A penalty will then be applied to the multiply imputed values at the last scheduled visit (Visit 6). 
The penalty will be a fraction of the estimated SD for the primary efficacy endpoint (the square 
root of the estimated element for the last scheduled visit of the co-variance matrix R from the 
primary MMRM model): (0*SD), (0.25*SD), (0.5*SD), etc.  
Step 2 (analysis of complete data sets) and Step 3 (inference) are the same as Step 2 and Step 3, 
respectively, for Model 1. 


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If the primary efficacy criterion is met at the interim analysis, then the penalties will only apply 
to dropouts. Multiply imputed values for ongoing subjects at the time of study stop will be used 
in the analysis without penalties. 
10.3 
Key Secondary Efficacy Endpoint and Analysis  
The key secondary efficacy endpoint CGI-I provide an overall assessment of global symptom 
improvement. It will be analyzed using the same analysis method (MMRM) as for the primary 
efficacy endpoint. The baseline CGI-S score will be used as the covariate. The contrast of 
interest will be at Visit 6 (Week 6) for the pooled SPD489 group compared with placebo. 
The CGI-I will be analyzed using the 2 sensitivity analysis models described in Section 10.2 to 
examine the robustness of the key secondary efficacy analysis (MMRM) results.   
10.4 
Dose-response Analyses  
The primary and key secondary efficacy analyses, and dose-response analysis will be conducted 
separately, and therefore no multiplicity adjustment will be considered for these objectives 
together.  
In this section all analyses will be performed on DRAS using R MCPMod package, and 
treatment arms 0 mg (placebo), 5, 10, 20, 30 mg (SPD489) will not be pooled. 
10.4.1 
Dose-response Candidate Curves 
The MCP-Mod approach was created for dealing with model-uncertainty at the study design 
stage, by pre-specified set of candidate dose-response curves, combining principles of multiple 
comparisons with modeling techniques (Bretz et al., 2005). For this study, the candidate dose-
response curves were selected based on prior knowledge of SPD489 dose-response, and 
assumptions on fixed-doses effects (placebo, SPD489 5, 10, 20, and 30 mg). The assumed family 
of plausible dose-response curves consists of linear, Emax, and logistic relationships, with 
appropriate parameters, covering the dose ranges of 0mg (placebo) to 30mg of investigational 
product. The candidate models and their figures are presented below. 
 
Family of the Curves 
Candidate Dose-response Curves 
Linear 
– 0.4×d 
Emax 
– 19.5×d/(15.0 + d) 
Logistic 
0.5 – 13.5/{1 + Exp[(10 – d)/3]} 
0.3 – 13.6/{1 + Exp[(15 – d)/4]} 
 
Where d stands for dose levels, d = 0, 5, 10, 20, 30 mg. 
 
 


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10.4.2 
Dose-response Relationship Evaluations 
When the study completes, regardless at the interim analysis or at end of the study, using the 
MCP-Mod methodology (Pinheiro et al, 2006) and all cumulative available data, the dose-
response relationship of SPD489 as measured by the change from baseline for ADHD-RS-IV 
Preschool Version Total Score will be evaluated on the DRAS, fitting with an optimized 
candidate curve to identify the minimum effect dose (MED). 
 
The dose response modelling in MCP-Mod uses a nonlinear least squares routine to fit the data to 
each of the candidate curve. Each of the dose response shapes in the candidate set will be tested 
using an appropriate contrast T-statistic. Using of the multivariate t-distribution to determine a 
critical value for all of the contrast T-statistics controls the overall Type-I error rate. The 
maximum contract test statistic will be used to select a dose response curve out of the set of 
significant curves, if there are any significant curves. If at least 1 of the specified candidate curve 
is selected, using a 2-sided significance level of 0.05, then for this selection process, dose 
response for SPD489 is established. 
 
The dose response model will include sex (female vs. male), baseline ADHD subtypes and 
baseline ADHD-RS total scores as explanatory variables in the dose response analysis. The 
baseline ADHD-RS score will be a continuous covariate, whereas sex and ADHD subtypes will 
be factors. 
 
The modeling results of the candidate curves will be tabulated that include T-statistic and 
corresponding adjusted p-values for each curve. Also parameters estimated for the final dose 
response relationship curve, and figures showing the dose response relationship will be 
presented. Fitted significant curves with ADHD-RS total score change from baseline data will be 
displayed as well.  


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10.4.3 
Minimum Effective Dose  
If a significant dose-response relationship can be established using the maximum contrast test 
statistic, then a clinically relevant threshold,– 5.6 reduction from baseline in ADHD-RS-IV 
Preschool Version Total Score, which derived from assumed minimum clinical meaningful effect 
size of 0.40 and common standard deviation of 14,  will be used for the MED derivations. The 
95% CI of the MED will be bootstrapped, that is, subjects will be sampled with replacement 
within the randomized treatment group for resampling, and the full MCP-Mod procedure will be 
applied to the resampled data, producing a bootstrap sample of MED values. The 95% CI for the 
MED correspond to the 2.5% and 97.5% quantiles of the bootstrap samples.  
 
By default, MCP-Mod reports the MED as missing if any of the significant curves fails to 
converge or if an estimate cannot be determined from a particular converged model. 
If an MED estimate cannot be determined from the selected significant curve, then available 
MED estimates from other converged models will be used to calculate an MED using the 
average AIC method. 
10.4.4 
Additional Analyses  
A line-plot of mean change from baseline with 95% CI for each randomized treatment group will 
be generated.  
 
Each SPD489 arm will be compared with placebo in ADHD-RS-IV Preschool Version Total 
Score change from baseline using MMRM. The comparisons will be conducted in a sequential 
order for adjusting for the multiplicity, which will test the highest dose level, 30 mg, first.  The 
model structure will be similar to the primary efficacy analysis. However, this analysis is not 
powered for the comparisons. 
 
A sigmoid nonlinear ܧ௠௔௫ model (MacDougall, J. 2006) below will be fitted, and the sigmoid 
ܧ௠௔௫ model curve will be plotted.  
 
ܴ௜ൌܧ଴൅ ܦ௜
௠ൈܧ௠௔௫
ܦ௜
௠൅ܧܦହ଴
௠ ൅ߝ௜ 
  
Where i = the subject indicator; ܴ௜ = dose response for subject i that measured as ADHD-RS-IV 
Preschool Version Total Score change from baseline; ܧ଴ = the dose response when dose strength 
is 0 mg (placebo);  ܦ௜ = the dose level for subject i; m = the slope factor determining the 
steepness of the dose response curve (m > 0); ܧ௠௔௫ = the maximum possible effect for the 
investigational product; ܧܦହ଴ = The dose level, which produces half of  ܧ௠௔௫;  ߝ௜ = the random 
error term for subject i.  
 
For the ܧ௠௔௫ model evaluations, initial parameters will be set to ܧ଴ = 0; ܧ௠௔௫ = - 19.5; ܧܦହ଴ = 
15.0 and m = 3.17. Where the m was calculated using the formula  
 
ܧܦ௣ൌ ܧܦହ଴ ሺ
݌
1 െ݌ሻଵ/௠ 


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 let p = 0.9,  ܧܦଽ଴ =30.0.  
 
The MCP-Mod methodology provides a flexibility of modeling for dose response relationship, 
while preserving the robustness to model misspecification associated with multiple comparison 
procedures (Bretz et al. 2005). However, if the MCP-Mod fails to converge to any pre-specified 
candidate curves, the sigmoid nonlinear ܧ௠௔௫ model, as a backup, will provide a dose response 
relationship. Using the relationship and clinically relevant threshold– 5.6 reduction from baseline 
in ADHD-RS-IV Preschool Version Total Score together, an approximately estimate of MED 
will be obtained. 
 
10.5 
Supportive Analyses  
10.5.1 
Subgroup Analysis  
The subgroups considered for analyses will be sex (male, female), race (white, non-white), and 
ethnicity. There is no formal hypothesis testing is planned for the pooled SPD489 (10, 20 and 30 
mg) dose group and placebo for the subgroup analysis. 
ADHD-RS-IV total score and CGI-I data will be summarized descriptively for each subgroup 
that is defined above at each visit by pooled SPD489 (10, 20, 30 mg) and placebo group. 
10.5.2 
Other Analyses  
The items in the ADHD-RS-IV Preschool Version will also be grouped into 2 subscales: 
hyperactivity/impulsivity (even-numbered items 2-18) and inattentiveness (odd-numbered items 
1-17). Each subscale will be analyzed using a similar model as the primary efficacy endpoint and 
summarized descriptively at each visit by pooled SPD489 treatment group and placebo. A 
corresponding line graph of the LS means of change from baseline and associated 95% CI in 
ADHD-RS-IV Preschool Version subscale scores by pooled SPD489 treatment, placebo and visit 
will be presented. 
The ADHD-RS-IV total score will be summarized descriptively at each visit by pooled SPD489 
treatment and placebo. 
The key secondary efficacy measurement, CGI-I, will also be analyzed using the proportion of 
subjects with an “improved” CGI-I measurement at endpoint. The CGI-I categories will be 
dichotomized into 2 categories: “very much improved” and “much improved” classified as 
“improved,” and all other assessed categories grouped together as “not improved.” The key 
secondary efficacy analysis will be conducted to compare pooled SHP489 treatment and placebo 
on the FAS for the “improved” rate using a Cochran-Mantel-Haenszel test stratified by CGI-S 
value at baseline.  
Dichotomized CGI-I values will be summarized by visit and pooled SHP489 treatment and 
placebo. A corresponding bar chart showing the percentage of subjects improved by visit, pooled 
SHP489 treatment, and placebo group will be presented. CGI-I values and CGI-S values will be 
listed. 
The CGI-I will be summarized descriptively at each visit by pooled SHP489 treatment and 
placebo. 


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11. SAFETY ANALYSES 
The Safety Analysis Set based on either the interim analysis dataset that for the safety summary 
at interim analysis, or the interim analysis dataset together with the overrun if the efficacy 
criterion meets, or all cumulative data up to study completion, whenever it is appropriate, will be 
used to report the safety data.  
Safety data will be summarized by SPD489 dose strengths, pooled doses and placebo. Safety 
variables include AEs, clinical laboratory variables, vital signs, physical examinations, 
Children’s Sleep Habits Questionnaire (CSHQ), sleep diary, ECG, and C-SSRS variables. For 
each safety variable, the last value collected before the first dose of investigational product will 
be used as baseline for all analyses of that safety variable.  
11.1 
Adverse Events  
Adverse events will be coded using Version 18.0 or newer of the Medical Dictionary for 
Regulatory Activities. 
An AE (classified by preferred term [PT]) that occurs during the Evaluation Period will be 
considered a TEAE if it has a start date on or after the first dose of investigational product or if it 
has a start date before the date of the first dose of investigational product, but increases in 
severity on or after the date of the first dose of investigational product. If more than 1 AE with 
the same PT is reported before the date of the first dose of investigational product, then the AE 
with the greatest severity will be used as the benchmark for comparison to the AEs occurring 
during the Evaluation Period under the preferred term. An AE that occurs more than 3 days after 
the date of the last dose of investigational product will not be counted as a TEAE. 
An overall summary of number of subjects with TEAEs in each treatment group will be 
presented by treatment group, 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.  
Number and percentage of subjects reporting TEAEs in each treatment group will be tabulated 
by system organ class (SOC) and PT. TEAEs will be further summarized by maximum severity 
and relationship to investigational product. If more than 1 AE occurs with the same PT for the 
same subject, then the subject will be counted only once for that PT using the most severe and 
most related occurrence for the summarization by severity and by relationship to investigational 
product.  
The incidence of TEAEs, serious TEAEs, and TEAEs leading to withdrawal will be summarized 
by SOC, PT, and treatment group, sorted in decreasing frequency for subjects on SPD489 then 
for placebo. The incidence of common (2% of subjects in any treatment group) will be 
summarized by PT and treatment group, sorted in decreasing frequency for subjects on SPD489 
and then for placebo. 
The number and percentage of subjects reporting TEAEs over the Safety Analysis Set will also 
be presented by week of AE onset, preferred term and treatment group, where week of AE onset 
is calculated as (AE occurred date – first dose date + 1) / 7,  then rounded up to an integer. 


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All information about AEs collected on the electronic case report form will be listed alongside 
the dose, PT, 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. 
11.2 
Clinical Laboratory Variables 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for clinical laboratory 
values (in SI units) and changes from Baseline to Visit 6/early termination (ET), as well as shift 
tables from Baseline to Visit 6/ET for quantitative variables, will be presented by treatment 
group for the following clinical laboratory variables:   
Biochemistry and Endocrinology 
 
Total cholesterol 
Calcium 
Aspartate transaminase  
Uric acid 
Phosphorus 
Blood urea nitrogen 
Alanine transaminase  
Total bilirubin 
Sodium 
Creatinine 
Alkaline phosphatase  
Glucose 
Potassium 
Albumin 
Gamma glutamyl transferase  
Total protein 
Thyroid stimulating hormone 
Lactate dehydrogenase 
Free thyroxine 
 
 
Hematology 
 
Hemoglobin 
Neutrophils 
Hematocrit 
Lymphocytes 
Red blood cells  
Monocytes 
Platelet count 
Eosinophils 
White blood cell count – total and differential  
Basophils 
Mean corpuscular hemoglobin  
Bands 
Mean corpuscular hemoglobin concentration  
Mean corpuscular volume  
 


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Urinalysis 
 
Glucose 
pH 
Specific gravity 
Urobilinogen 
Blood 
Color 
Ketones 
Leukocyte esterase 
Protein 
Nitrate 
Bilirubin 
 
 
If urinalysis detects protein and/or blood, then a microscopic examination will be conducted. The 
microscopic examination will consist of red blood cell, white blood cell, 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 
both baseline and 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 2. The number and percentage of subjects with 
post-baseline PCI values will be tabulated. The percentages will be calculated relative to the 
number of subjects with 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 2:  
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 
- 
>30 mg/dl or >2.5 x 
ULN 
Calcium 
mg/dL 
<8mg/dL 
>11.5mg/dL 
Total cholesterol 
mg/dL 
- 
>300mg/dl 
Creatinine 
mg/dl 
- 
>2 mg/dl or >1.5 x ULN 
Gamma glutamyl transferase 
- 
- 
≥2.5 x ULN 
Glucose 
mg/dL 
<55mg/dL 
>160mg/dL 
Lactate dehydrogenase 
- 
- 
>3 x ULN 
Phosphorus 
mg/dL 
<2.5mg/dL 
>7mg/dL 


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Table 2:  
Criteria for Potentially Clinically Important Laboratory Tests  
Parameter 
SI Unit 
Lower Limit 
Higher Limit 
Potassium 
mmol/l 
<3mmol/l 
>5.5mmol/l 
Thyroid stimulating hormone 
- 
<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% 
Basophils 
- 
- 
>10% 
Hemoglobin 
g/dL 
<9g/dl 
>16g/dl 
Hematocrit 
% 
<30% 
>50% 
Platelet count 
103/μL 
<75x103/μL 
>600x103/μL 
Red blood cells 
106/μL 
<2.5x106/μL 
- 
White blood cell 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 
 
11.3 
Vital Signs 
Descriptive statistics (n, mean, SD, minimum, median, and maximum) for vital sign variables 
(systolic and diastolic blood pressure, pulse rate, body weight, temperature, and respiration rate), 
and their changes from baseline at each assessment time point will be presented by treatment 
group.  
Body weight is collected at every visit, while height is collected only at Screening and the last 
scheduled visit/ET. At each visit excluding the last scheduled visit/ET, the Screening height will 


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be used to derive BMI values. For the last scheduled visit/ET, corresponding height and body 
weight will be used to calculate the BMI values. The resulting BMI values will be rounded to 1 
decimal place for reporting. Descriptive statistics for BMI will be tabulated by visit and 
treatment group for actual values and change from baseline.  
Percentiles of body weight and BMI can be normalized by sex and age using the CDC growth 
charts (Kuczmarski et al. 2002). Descriptive statistics of percentiles, for both, body weight, and 
BMI will be generated by visit and treatment group, for actual values and change from baseline.  
Furthermore, the body weight percentiles can be categorized as <5th, 5th to <95th, and 95th 
percentiles, and the BMI percentiles can be categorized as: 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; and Obese – BMI greater than or equal to 
the 95th percentile. Post-baseline shifts in body weight and BMI percentile category from 
baseline at each visit will be presented by treatment group. The data also will be presented 
categorically using number of subject and percentages at each visit by treatment group.   
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 treatment group 
and visit. 
All vital sign values will be listed for the Safety Analysis Set. 
All vital sign values, include an unscheduled visit, will be considered PCI if they meet either the 
observed value criteria or the change from baseline criteria listed in Table 3. The number and 
percentage of subjects with PCI post-baseline values will be tabulated by treatment group. The 
percentages for the observed value criteria will be calculated relative to the number of subjects 
with at least 1 post-baseline assessment available per parameter and visit. The percentages for 
the change from baseline criteria will be calculated relative to the number of subjects with 
available baseline and at least 1 post-baseline assessment per parameter and visit. The numerator 
is the total number of subjects with at least 1 PCI post-baseline 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 3:  
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% 


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Table 3:  
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign Parameter 
Flag 
Criteriaa 
Observed Value 
Change from Baseline 
Temperature (deg. C) 
High 
>39 
- 
Low 
<35 
- 
BMI (kg/m2) 
High 
>95th percentile for age and 
sex 
- 
Low 
<5th percentile for age and 
sex 
- 
BMI=body mass index 
a A post-baseline value is considered as a PCI value if its meets either the criteria for observed value or the criteria for change 
from baseline. 
 
11.4 
Electrocardiogram (ECG) 
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. QTc interval 
will be calculated using both Bazett (QTcB = QT/(RR)1/2) and Fridericia (QTcF = QT/(RR)1/3) 
corrections; if RR is not available, it will be replaced with 60/hr in the correction formula. ECG 
interpretation will be summarized by visit (and Visit 6/ET) and treatment group. A shift table 
from baseline to each visit (and Visit 6/ET) for qualitative ECG results will also be presented.  
All ECG values will be listed for the Safety Analysis Set. 
Electrocardiogram variable values, include unscheduled visit, will be considered PCI if they 
meet either the observed value criteria or the change from baseline criteria listed in Table 4. The 
number and percentage of subjects with post-baseline PCI values will be tabulated by treatment 
group. The percentages for the observed value criteria will be calculated relative to the number 
of subjects with at least 1 post-baseline assessment available per parameter and visit. The 
percentages for the change from baseline criteria will be calculated relative to the number of 
subjects with available baseline and at least 1 post-baseline assessment per parameter and visit. 
The numerator is the total number of subjects with at least 1 PCI post-baseline ECG value. A 
listing of all subjects with post-baseline PCI value will be provided including the subject 
number, site, baseline, and post-baseline PCI values. 
Table 4:  
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 


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Table 4:  
Criteria for Potentially Clinically Important ECG Values 
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 
- 
- 
 
11.5 
Other Safety Variables 
11.6 
Children’s Sleep Habits Questionnaire and Sleep Diary 
The CHSQ 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:  


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1. Bedtime resistance (sum of the responses for Goes to bed at same time, Falls asleep in own 
bed, Falls asleep in other’s bed, Needs parent in room to sleep, Struggles at bedtime and 
Afraid of sleeping alone) 
2. Sleep-onset delay (Falls asleep in 20 minutes item)  
3. Sleep duration (sum of the responses for Sleeps too little, Sleeps the right amount and Sleeps 
same amount each day)  
4. Sleep anxiety (sum of the responses for Needs parent in room to sleep, Afraid of sleeping in 
the dark, Afraid of sleeping alone and Trouble sleeping away) 
5. Night wakings (sum of the responses for Moves to other’s bed in night, Awakes once during 
night and Awakes more than once)  
6. Parasomnias (sum of the responses for Wets the bed at night, Talks during sleep, Restless 
and moves a lot, Sleepwalks, Grinds teeth during sleep, Awakens screaming, sweating and 
Alarmed by scary dream) 
7. Sleep-disordered breathing (sum of the responses for Snores loudly, Stops breathing and 
Snorts and gasps)  
8. Daytime sleepiness (sum of the responses for Wakes by himself, Wakes up in negative mood, 
Others wake child, Hard time getting out of bed, Takes long time to be alert, Seems tired, 
Watching TV and Riding in car) 
  
Each subscale and each individual item will be summarized using descriptive statistics (n, mean, 
SD, minimum, median, and maximum) at each visit (and Visit 8/ET) by treatment group. All 
CSHQ data will be listed for the Safety Analysis Set. 
Sleep diary data will be summarized at each visit (and Visit 8/ET) for total daytime napping 
time, nighttime sleep time and time to fall asleep using descriptive statistics (n, mean, SD, 
minimum, median, and maximum) by treatment group. Sleep diary data are collected daily. The 
average daily value per visit and their change from baseline will be summarized by treatment 
group. Sleep diary data will also be listed for the Safety Analysis Set. 
11.7 
Columbia-Suicide Severity Rating Scale 
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   


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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. 
11.8 
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 
See Section 10.5.2. 
 


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14. INTERIM ANALYSIS 
See Sections 2.6 and 15. 


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15. DATA MONITORING/REVIEW COMMITTEE 
An external independent 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 this 
Pediatric Written Request program, which includes studies SPD489-211, SPD489-347, and 
SPD489-348. The same DMC will evaluate the efficacy analysis results and supportive safety 
summaries to determine if the interim efficacy criteria are met for this study. 
Confidentiality of the unblinded DMC analyses is a critical concern, and to address this, an 
unblinded independent reporting team will be identified within an external contract research 
organization. The independent reporting team will have no involvement in the conduct of the 
study. Further details regarding the DMC and the independent reporting team can be found in the 
DMC charter. 
The DMC and the independent reporting team will not be involved in the blinded sample size 
re-estimation and dose-response relationship evaluations. 
 
 


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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 
Not applicable. 


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18. DATA HANDLING CONVENTIONS 
18.1 
General Data Reporting Conventions 
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, SD, minimum, and maximum. 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 2 more decimal places 
than the raw data, whenever it is appropriate. 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. 
18.2 
Derived Efficacy Endpoints  
18.2.1 
Primary Efficacy Endpoint 
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 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 to 
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 (hyperactivity/impulsivity and inattentiveness) must be non-missing in order 
to calculate the total score. 
 
18.2.2 
Key Secondary Endpoint 
The key secondary efficacy endpoint, CGI-I, provides an overall assessment of global symptom 
improvement. For a supportive analysis, the CGI-I categories will be dichotomized into 2 
categories: “very much improved” and “much improved” classified as “improved,” and all other 
assessed categories grouped together as “not improved.” 
   


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18.3 
Repeated or Unscheduled Assessments of Safety Parameters  
If a subject has repeated assessments before the start of investigational product, then the results 
from the final assessment made prior to the start of investigational product will be used as 
baseline. If end-of-study assessments are repeated or unscheduled, the last post-baseline 
assessment while on investigational product will be used for generating descriptive statistics. 
However, all post-baseline assessments will be used for PCI value determination and all 
assessments will be presented in the data listings.  
18.4 
Missing Date of Investigational Product  
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. 
18.5 
Missing Date Information for Prior or Concomitant Medications  
For prior or concomitant medications, including rescue medications, incomplete (ie, partially 
missing) start date and/or stop date will be imputed. When the start date and the stop date are 
both incomplete for a subject, impute the start date first.    
18.6 
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. 
18.6.1 
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. 
 
18.6.2 
Missing Month Only 
 The day will be treated as missing, and both month and day will be replaced according to the 
above procedure. 
 
18.6.3 
Missing Day Only 
 If the month and year of the incomplete start date are the same as the month and year of the 


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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.  
 
18.7 
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. 
18.7.1 
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. 
 
18.7.2 
Missing Month Only 
 The day will be treated as missing, and both month and day will be replaced according to the 
above procedure. 
 
18.7.3 
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. 


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18.8 
Missing Date Information for Adverse Events  
For AEs, the default is to only impute incomplete (ie, 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. 
18.9 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE starting prior to the date of the first dose of investigational 
product, then a severity of “mild” will be assigned. If the severity is missing for an AE starting 
on or after the date of the first dose of investigational product, then a severity of “severe” will be 
assigned. The imputed values for severity assessment will be used for incidence summaries, 
while the actual values will be used in data listings. 
18.10 
Missing Relationship to Investigation Product for Adverse Events 
If the relationship to investigational product is missing for an AE starting on or after the date of 
the first dose of investigational product, a causality of “related” will be assigned. The imputed 
values for relationship to double-blind investigational product will be used for incidence 
summaries, while the actual values will be presented in data listings. 
18.11 
Character Values of Clinical Laboratory Variables  
If the reported value of a clinical laboratory variable cannot be used in a statistical analysis 
because, for example, a character string is reported for a numerical variable, then 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 5:  
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 
ALT=alanine transaminase; AST=aspartate transaminase 
 


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19. REFERENCES 
Bretz, F., Pinheiro, J., and Branson, M. (2005). Combining multiple comparisons and modeling 
techniques in dose response studies. Biometrics 61, 738-748. 
Cohen, J. 1988. Statistical power analysis for the behavioral sciences, Hillsdale, NJ, Lawrence 
Earlbaum Associates. 
Friede, T. & Kieser, M. 2006. Sample size recalculation in internal pilot study designs: a review. 
Biom J, 48, 537-55. 
Glimm, E., Maurer, W. & Bretz, F. 2010. Hierarchical testing of multiple endpoints in group-
sequential trials. Stat Med, 29, 219-28. 
Kuczmarski, R. J., Ogden, C. L., Grummer-Strawn, L. M., Flegal, K. M., Guo, S. S., Wei, R. & 
Et Al 2002. 2000 CDC growth charts for the United States: Methods and development. 
Vital Health Stat, 11. 
MacDougall, J. (2006). Analysis of dose-response studies - Emax model, in N. Ting 
(ed.), Dose Finding in Drug Development, Springer, New York, pp. 127–145 
Pinheiro J, Bornkamp B, Bretz F 2006. Design and analysis of dose-finding studies combining 
multiple comparisons and modeling procedures. Biopharml Sta; 16:(5): 639-56. 
Proschan, M., Lan, K. & Wittes, J. 2006. Statistical Monitoring of Clinical Trials: A Unified 
Approach, Springer Science + Business Media, LLC. 
 
 


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20. APPENDIX  
20.1 
Appendix 1 Algorithms for Deviation of the Pooled Common Variance 
Based on the rationale that the total variance is similar to the within group variance as long as the 
treatment effect is not too large, a pooled common variance can be estimated by using blinded 
cumulative primary efficacy data that are collected during the study, up to the time of sample 
size re-estimation.  The pooled common variance can be used along with the pre-specified 
treatment difference to re-estimate the sample size.  Below are steps in detail:  
• 
Ignoring treatment difference and applying the formula below to estimate the pooled 
sample variance, which is an unbiased estimate of the variance. 
ܵ௣௢௢௟௘ௗ
ଶ
 = 
ଵ
 ௡భିଵ ∑ሺܺ௜௝െ 
௜,௝
 ܺത ሻଶ, 
where ݊ଵ is total number of subjects who either completed or discontinued from the study at 
the time point of the sample size re-estimation. ݅ൌ1, 2;   ݆ൌ1, ⋯, ݊ଵ௜ and ݊ଵൌ ݊ଵଵ൅ ݊ଵଶ. 
• 
Let ∆∗ be the alternative hypothesis of treatment mean difference that is pre-specified as 
8.4, for which the study is powered.  Hence, a common variance that can be used for the 
sample size re-estimation is:  
 
2
*
1
1
2
2
)1
(
4




n
n
S
S
pooled
final
. 
• 
Applying 
2
final
S
 and the assumed true mean treatment effect difference together, an 
updated effect size can be calculated.  Using the effect size, the sample size can be re-
estimated (Friede and Kieser, 2006).  
Furthermore, the blinded sample size re-estimation only allow upwards adjustments of the 
initially (at the study design stage) planned sample size, and using the pooled common variance 
estimated above to do a blinded sample size-estimation does not inflate the Type I error rate 
(Friede and Kieser, 2006).  
 
 


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20.2 
Appendix 2 Sample SAS Codes 
Mixed Model Repeated Measures (MMRM) 
 
proc mixed /* select derived dataset */; 
    class trt subjid visit; 
    model chg = trt visit trt*visit base base*visit / ddfm=kr; 
    repeated visit / subject=subjid type=UN; 
   /* LSmean, Estimate and/or LSMestimate statement(s) */ 
   /* Data output or object delivery statement(s) */ 
Run; 
 
Missing Not at Random (MNAR) Sensitivity Analysis 
 
Model 1 - Placebo Multiple Imputation 
 
*Step 1; 
proc mi data=unimputed out=discard nimpute=200 seed=347 noprint; 
  where treatment=1; *where 1 is placebo; 
  var baseline chy1-chy7 
  mcmc outset=posteriors; *picks up the placebo posteriors;  
run; 
 
*100 posteriors for the placebo, rest for active; 
data posteriors(type=est); 
  set posteriors; 
  if 1<=_imputation_<=100 then do; *assign placebo posteriors; 
    treatment=1; 
  end; 
  if 100<=_imputation_<=200 then do; *assign posteriors to active; 
    treatment=2; 
    imputation_=_imputation_-100; 
  end; 
run; 
 
proc sort data=unimputed; 
  by treatment; 
run; 
 
proc mi data=unimputed out=imputed; 
  by treatment; 
  var baseline chy1-chy7; 
  mcmc inest=posteriors; *use the placebo posteriors; 
run; 
 
*Step 2; 
data endpoint; 
  set imputed; 
  endpoint=chy7; 
run; 
 


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proc sort data=endpoint; 
  by _imputation_; 
run; 
 
proc glm data=endpoint; 
  by _imputation_; 
  class treatment; 
  model endpoint = baseline treatment / solution; 
  estimate ‘Active vs Placebo’ treatment -1 1; 
ods output estimates=est; 
run; 
 
*Step 3; 
proc sort data=est; 
  by label _imputation_; 
run; 
 
proc mianalyze data=est; 
  by label; 
  modeleffects estimate; 
  stderr stderr; 
run; 
 
Model 2 - Multiple Imputations with Penalties Applied to Dropouts 
 
*Note: dataset “unimputed” has one row per subject, repeated measures are structured in 
columns;  
 
*Step 1; 
data unimputed; 
  set unimputed; 
  missing=(chg4=.); 
run; 
 
proc sort data=unimputed; 
  by treatment; 
run; 
 
proc mi data=unimputed out=imputed nimpute=200 seed=347 noprint; 
  by treatment; 
  var baseline chy1-chy7; 
run; 
 
%let SD=10; 
* This will be replaced by the estimated SD[chg7] from the MMRM co-variance matrix R 
(use R or RCORR option in REPEATED statement under PROC MIXED); 
%let penalty=0.25*&SD; 
* Repeat this step for various values (0.25, 0.5, etc) as per SAP; 
data imputed;  


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  set imputed; 
  if missing then chg7=chg7 + &penalty; * + or -, depending on the measure; 
run; 
 
*Step 2 (analysis of completed datasets) and Step 3 (inference) are the same as Step 2 
and Step 3, respectively, for Model 1;