Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Keywords: ADHD Hyperactivity SHP465
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 89
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the efficacy and safety of SHP465 at 6.25 mg in the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) in children aged 6-12 years.

Detailed description:

Arms:
arm 1: Participants will be randomized to receive SHP465 capsule 6.25 milligram (mg) orally once daily for 4 weeks. arm 2: Participant will receive placebo matching to SHP465 capsule orally once daily for 4 weeks.

Interventions: intervention 1: SHP465 intervention 2: Placebo
Intervention descriptions: intervention 1: SHP465 capsule 6.25 mg orally once daily for 4 weeks intervention 2: Placebo matching to SHP465 capsule orally once daily for 4 weeks

Protocol document:
Prot_000.pdf: 
CLINICAL STUDY PROTOCOL 
 
NCT Number:   
NCT03325881 
 
Study Title:  
A Phase 3, Randomized, Double-blind, Multicenter, Placebo-
controlled, Fixed-Dose, Efficacy, and Safety Study of SHP465 in 
Children Aged 6-12 Years with Attention-Deficit/Hyperactivity 
Disorder (ADHD) 
 
Study Number:  
SHP465-309 
 
Protocol Version:  
Protocol  
 
Protocol Version Date: 07 September 2017 


PROTOCOL:  SHP465-309
TITLE:
A Phase 3, Randomized, Double-blind, Multicenter, Placebo-controlled, 
Fixed-Dose, Efficacy, and Safety Study of SHP465 in Children Aged 6-
12 Years with Attention-Deficit/Hyperactivity Disorder (ADHD)
DRUG:
SHP465, mixed salts of a single-entity amphetamine 
IND:
66,329
EUDRACT NO.:
Non-EUDRACT 
SPONSOR:
Shire Development LLC
300 Shire Way, Lexington, MA 02421 USA
PRINCIPAL/
COORDINATING
INVESTIGATOR: TBD
PROTOCOL 
HISTORY:
Original, 07 September 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to confidentiality 
and non-disclosure obligations. This information should be used solely for the purposes for which it was provided 
and should not be copied, shared with, or disclosed to any third party without the express written consent of Shire.




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CONFIDENTIAL
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Study Protocol 
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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................4
LIST OF TABLES.........................................................................................................................10
LIST OF FIGURES .......................................................................................................................10
ABBREVIATIONS .......................................................................................................................11
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULE(S) ...............................................................................................................19
1
BACKGROUND INFORMATION.......................................................................................22
1.1
Indication and Current Treatment Options...............................................................22
1.2
Product Background and Clinical Information ........................................................23
1.2.1
Clinical Information...............................................................................................23
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................25
2.1
Rationale for the Study.............................................................................................25
2.2
Study Objectives ......................................................................................................25
2.2.1
Primary Objectives.................................................................................................25
2.2.2
Secondary Objectives.............................................................................................25
3
STUDY DESIGN ...................................................................................................................26
3.1
Study Design and Flow Chart ..................................................................................26
3.2
Duration and Study Completion Definition .............................................................27
3.3
Sites and Regions .....................................................................................................27
4
STUDY POPULATION.........................................................................................................28
4.1
Inclusion Criteria......................................................................................................28
4.2
Exclusion Criteria.....................................................................................................29
4.3
Reproductive Potential .............................................................................................30
4.3.1
Female Contraception............................................................................................30
4.3.2
Male Contraception................................................................................................31
4.4
Discontinuation of Subjects .....................................................................................31
4.4.1
Management of Blood Pressure and Pulse During the Study................................31
4.4.1.1
Systolic and Diastolic Blood Pressure ...................................................32
4.4.1.2
Pulse .......................................................................................................32
4.4.2
Reasons for Discontinuation..................................................................................33
4.4.3
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit..................................33
5
PRIOR AND CONCOMITANT TREATMENT ...................................................................34


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5.1
Prior Treatment ........................................................................................................34
5.2
Concomitant Treatment............................................................................................34
5.2.1
Permitted Treatment...............................................................................................34
5.2.2
Prohibited Treatment .............................................................................................35
6
INVESTIGATIONAL PRODUCT ........................................................................................36
6.1
Identity of Investigational Product...........................................................................36
6.1.1
Blinding the Treatment Assignment......................................................................36
6.2
Administration of Investigational Product(s)...........................................................36
6.2.1
Interactive Response Technology for Investigational Product Management ........36
6.2.2
Allocation of Subjects to Treatment ......................................................................36
6.2.3
Dosing....................................................................................................................37
6.2.4
Unblinding the Treatment Assignment..................................................................37
6.3
Labeling, Packaging, Storage, and Handling ...........................................................37
6.3.1
Labeling .................................................................................................................37
6.3.2
Packaging...............................................................................................................38
6.3.3
Storage ...................................................................................................................38
6.4
Drug Accountability.................................................................................................39
6.5
Subject Compliance..................................................................................................40
7
STUDY PROCEDURES........................................................................................................41
7.1
Study Schedule.........................................................................................................41
7.1.1
Screening and Washout Period..............................................................................41
7.1.1.1
Screening Visit (Visit 1).........................................................................42
7.1.1.2
Washout Telephone Call ........................................................................42
7.1.1.3
Baseline Visit (Visit 2)...........................................................................43
7.1.2
Treatment Period....................................................................................................44
7.1.2.1
Treatment Period (Visits 3-5).................................................................44
7.1.2.2
End of Study/Early Termination Visit (Visit 6/ET)...............................44
7.1.3
Safety Follow-up Period ........................................................................................45
7.1.4
Additional Care of Subjects After the Study .........................................................45
7.2
Study Evaluations and Procedures ...........................................................................45
7.2.1
Demographic and Other Baseline Characteristics .................................................45
7.2.2
Screening Assessments..........................................................................................45
7.2.2.1
Mini International Neuropsychiatric Interview for Children and 
Adolescents ............................................................................................45
7.2.3
Efficacy..................................................................................................................46
7.2.3.1
Attention-deficit/Hyperactivity Rating Scale.........................................46
7.2.3.2
Clinical Global Impression.....................................................................46


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7.2.4
Safety .....................................................................................................................47
7.2.4.1
Medical and Medication History............................................................47
7.2.4.2
Physical Examination.............................................................................47
7.2.4.3
Adverse Event Collection.......................................................................48
7.2.4.4
Vital Signs (Including Height and Weight)............................................48
7.2.4.5
Clinical Laboratory Evaluations.............................................................49
7.2.4.6
Urine Drug Screen..................................................................................51
7.2.4.7
Pregnancy Test .......................................................................................51
7.2.4.8
Electrocardiogram ..................................................................................51
7.2.4.9
Children’s Sleep Habits Questionnaire ..................................................52
7.2.4.10
Post Sleep Questionnaire........................................................................52
7.2.4.11
Columbia-Suicide Severity Rating Scale ...............................................52
7.2.4.12
Suitability of the Subject to Remain in the Study..................................53
7.2.5
Others.....................................................................................................................54
7.2.6
Volume of Blood to be Drawn From Each Subject...............................................54
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................55
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse 
Events.......................................................................................................................55
8.1.1
Severity Categorization..........................................................................................55
8.1.2
Relationship Categorization...................................................................................56
8.1.3
Outcome Categorization ........................................................................................56
8.1.4
Symptoms of the Disease Under Study .................................................................56
8.1.5
Clinical Laboratory and Other Safety Evaluations................................................57
8.1.6
Pregnancy...............................................................................................................57
8.1.7
Abuse, Misuse, Overdose, and Medication Error..................................................58
8.2
Serious Adverse Event Procedures ..........................................................................58
8.2.1
Reference Safety Information................................................................................58
8.2.2
Reporting Procedures.............................................................................................58
8.2.3
Serious Adverse Event Definition .........................................................................59
8.2.4
Serious Adverse Event Collection Time Frame.....................................................59
8.2.5
Serious Adverse Event Onset and Resolution Dates .............................................60
8.2.6
Fatal Outcome........................................................................................................60
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting................................................................................................................60
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................61
9.1
Data Collection.........................................................................................................61
9.2
Clinical Data Management.......................................................................................61


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9.3
Data Handling Considerations..................................................................................61
9.4
Statistical Analysis Process......................................................................................61
9.5
Data Monitoring Committee ....................................................................................62
9.6
Planned Interim Analysis .........................................................................................62
9.7
Sample Size Calculation and Power Considerations................................................62
9.8
Study Population ......................................................................................................63
9.9
Efficacy Analyses.....................................................................................................63
9.9.1
Primary Efficacy Endpoint ....................................................................................63
9.9.2
Key Secondary Efficacy Endpoints .......................................................................64
9.9.3
Exploratory Efficacy Endpoints.............................................................................65
9.10
Safety Analyses........................................................................................................65
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................67
10.1
Sponsor’s Responsibilities .......................................................................................67
10.1.1 Good Clinical Practice Compliance.......................................................................67
10.1.2 Public Posting of Study Information......................................................................67
10.1.3 Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees...........................................67
10.1.4 Study Suspension, Termination, and Completion..................................................67
10.2
Investigator’s Responsibilities .................................................................................68
10.2.1 Good Clinical Practice Compliance.......................................................................68
10.2.2 Protocol Adherence and Investigator Agreement..................................................68
10.2.3 Documentation and Retention of Records.............................................................69
10.2.3.1
Case Report Forms.................................................................................69
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................69
10.2.3.3
Audit/Inspection.....................................................................................70
10.2.3.4
Financial Disclosure...............................................................................70
10.2.4 Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation............................70
10.3
Ethical Considerations..............................................................................................70
10.3.1 Informed Consent...................................................................................................70
10.3.2 Institutional Review Board or Ethics Committee..................................................71
10.4
Privacy and Confidentiality......................................................................................71
10.5
Study Results/Publication Policy .............................................................................72
11 REFERENCES .......................................................................................................................74
12 APPENDICES ........................................................................................................................77
APPENDIX 1
PROTOCOL HISTORY ........................................................................78


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APPENDIX 2
DIAGNOSTIC CRITERIA/DISEASE CLASSIFICATION.................79
Appendix 2.1
DSM-5 criteria for Attention Deficit/Hyperactivity Disorder................79
Appendix 2.2
Boys’ Stature-For-Age And Weight-For-Age Percentiles.....................81
Appendix 2.3
Blood Pressure For Boys By Age and Height Percentile.......................82
Appendix 2.4
Girls’ Stature-For-Age And Weight-For-Age Percentiles .....................84
Appendix 2.5
Blood Pressure Levels for Girls By Age and Height Percentile ............85
APPENDIX 3
SCALES AND ASSESSMENTS...........................................................87


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Study Protocol 
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LIST OF TABLES
Table 1: 
Schedule of Assessments...............................................................................19
Table 2:
Common Excluded Treatments and Associated Washout Period 
Relative to Baseline Visit (Visit 2)................................................................35
Table 3:
Volume of Blood to be Drawn From Each Subject.......................................54
LIST OF FIGURES
Figure 1:
Study Design Flow Chart ..............................................................................26


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ABBREVIATIONS
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS-5
Attention-deficit/Hyperactivity Disorder Rating Scale-5
AE
adverse event
BMI
body mass index
CGI-I
Clinical Global Impressions – Global Improvement
CGI-S
Clinical Global Impressions – Severity of Illness 
CRA
clinical research associate
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CSHQ
Children's Sleep Habits Questionnaire
DSM-IV-TR®
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition –
Text Revision®
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
EC
ethics committee
ECG
electrocardiogram
ET
EU
early termination
European Union
FAS
full analysis set
FDA 
Food and Drug Administration 
GCP
Good Clinical Practice
-HCG
human chorionic gonadotropin beta
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator’s brochure
ICH
International Conference on Harmonisation
IR
immediate release
IRB
Institutional Review Board
IWRS
interactive web response system 
LAR
legally authorized representative
MedDRA
Medical Dictionary for Regulatory Activities
MINI-KID
Mini International Neuropsychiatric Interview for Children and 
Adolescents
MPH
methylphenidate


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PSQ  
SAE
Post Sleep Questionnaire
serious adverse event
SAP
statistical analysis plan
TEAE
treatment-emergent adverse event
US
United States


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STUDY SYNOPSIS
Protocol number:  SHP465-309
Drug: SHP465, mixed salts of a single-entity amphetamine 
Title of the study: A Phase 3, Randomized, Double-blind, Multicenter,  Placebo-controlled, Fixed-Dose, 
Efficacy, and Safety Study of SHP465 in Children Aged 6-12 Years with Attention-Deficit/Hyperactivity 
Disorder (ADHD) 
Number of subjects (total and for each treatment arm):
Approximately 60 subjects will be enrolled into the study. Approximately 52 subjects are expected to complete 
the safety and efficacy evaluation: approximately 50% of subjects will be aged 6-8 years and approximately 
50% of subjects will be aged 9-12 years.  Approximately 25% of all subjects will be female.
Investigator(s): Multicenter 
Site(s) and Region(s): 
Approximately 45 sites in the United States (US).
Study period (planned):
2017 to 2018
Clinical phase:
3
Objectives:
Primary: To evaluate the efficacy of SHP465 at 6.25 mg compared to placebo as a daily morning dose in 
children 6-12 years of age (inclusive at the time of consent) diagnosed with ADHD. The primary measure of 
efficacy will be the clinician-administered ADHD-Rating Scale 5 Child, Home version (ADHD-RS-5) Total 
score.
Key Secondary: To assess the efficacy of SHP465 at 6.25 mg compared to placebo using a global clinical 
measure of improvement, the Clinical Global Impression of Improvement (CGI-I) scale.
Secondary:  
To evaluate safety and tolerability of SHP465 at 6.25 mg based on the occurrence of treatment-emergent 
adverse events (TEAEs), evaluation of vital signs (systolic and diastolic blood pressure and pulse), weight, 
height, body mass index (BMI); clinical laboratory and electrocardiogram (ECG) results; sleep assessment (Post 
Sleep Questionnaire [PSQ] and Children’s Sleep Habits Questionnaire [CSHQ]); and responses to the 
Columbia-Suicide Severity Rating Scale (C-SSRS).
Rationale:
The purpose of this study is to evaluate the efficacy and safety of SHP465 at 6.25 mg in the treatment of ADHD 
in children aged 6-12 years. Results from the completed SHP465-305 study in this age group have demonstrated 
SHP465 to be well tolerated and efficacious in reducing ADHD symptom severity. This study will provide 
additional data to inform clinicians about the efficacy and safety of SHP465 at lower dose levels in the pediatric 
ADHD population.
Investigational product, dose, and mode of administration:

SHP465 will be provided in 6.25 mg capsules.

Placebo will be provided as capsules identical to SHP465.
The parent/legally authorized representative (LAR) will be instructed to dispense 1 capsule to the subject daily 
throughout the study at 7:00 AM (±2 hours). SHP465 6.25 mg will be administered in 1 of the following ways:

Swallow SHP465 capsules whole, or

Open capsule and sprinkle the entire contents on applesauce


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Study Protocol 
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The sprinkled applesauce should be consumed immediately; it should not be stored. Subjects should take the 
applesauce with sprinkled beads in its entirety without chewing.
Methodology:
This study is a Phase 3 randomized, multicenter, double-blind, placebo-controlled, fixed-dose efficacy and 
safety study in children aged 6-12 years (inclusive at the time of consent,) diagnosed with ADHD. Children with 
ADHD will be randomized in a 1:1 ratio between SHP465 6.25 mg and placebo arms for a 4-week treatment.  
SHP465 dose of 6.25 mg or placebo will be administered to subjects for the entire treatment period.
The study will have 3 periods: (1) screening and washout: (2) treatment period; and (3) safety follow-up.   The 
duration of the evaluation period will be 4 weeks. 
Subjects will be required to visit the site up to 6 times over a 10-week period. 
The investigator or designee must obtain written informed consent from the subject's parent/LAR and 
documentation of assent (if applicable) by the subject before any protocol-related procedure is performed. 
Procedures performed at each visit for all subjects are defined in the Study Schedule, Table 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):
Subject is male or female and must be 6-12 years, inclusive, at the time of consent.
1.
Subject’s parent or legally authorized representative (LAR) must provide signature of informed 
consent, and there must be documentation of assent (as applicable) by the subject in accordance with 
the International Council on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 (1996) 
and any updates and applicable regulations, before completing any study-related procedures.
2.
Subject and parent/LAR are willing and able to comply with all of the testing and requirements defined 
in the protocol, including oversight of morning dosing. Specifically, the parent/LAR must be available 
at approximately 7:00 AM (±2 hours) to dispense the dose of investigational product for the duration of 
the study.
3.
Subject must meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 
criteria for a primary diagnosis of ADHD (any subtype) based on a detailed psychiatric evaluation 
using the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID).
4.
Subject who is a female and of child-bearing potential must not have a positive serum beta human 
chorionic gonadotropin pregnancy test at the screening visit (Visit 1) and must have a negative urine 
pregnancy test at the baseline visit (Visit 2) and agree to comply with any applicable contraceptive 
requirements of the protocol.
5.
Subject has an ADHD-RS-5 Child, Home Version Total Score of ≥28 at baseline (Visit 2).
6.
Subject has a Clinical Global Impression – Severity of Illness (CGI-S) score ≥4 at baseline (Visit 2).
7.
Subject functions as an age-appropriate level intellectually, as determined by the investigator.
8.
Subject is currently not on ADHD therapy, or is not completely satisfied with any aspect of their
current ADHD therapy.
9.
Subject has lived with the same parent or LAR for at least 6 months.


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Study Protocol 
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Exclusion Criteria:
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Subject is required or anticipated to take medications that have central nervous system effects or affect 
performance, such as sedating antihistamines, decongestant sympathomimetics, or monoamine oxidase 
inhibitors. Stable use of bronchodilator inhalers is not exclusionary.
2.
Subject has a concurrent chronic or acute illness (such as severe allergic rhinitis or an infectious 
process requiring antibiotics), disability, or other condition that might confound the results of safety 
assessments conducted in the study or that might increase risk to the subject. Similarly, the subject will 
be excluded if he or she has any additional condition(s) that, in the investigator’s opinion, would 
prohibit the subject from completing the study or would not be in the best interest of the subject. The 
additional condition(s) would include any significant illness or unstable medical condition that could 
lead to difficulty complying with the protocol. Mild, stable asthma is not exclusionary.
3.
Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients 
in the investigational product.
4.
Subject has failed to fully respond, based on investigator judgment, to an adequate course of 
amphetamine therapy.
5.
Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
6.
Subject has a blood pressure measurement 95th percentile for age, sex, and height at screening 
(Visit 1) and/or baseline (Visit 2).
7.
Subject has a height ≤5th percentile for age and sex at screening (Visit 1) or baseline (Visit 2).
8.
Subject has a weight ≤5th percentile for age and sex at screening (Visit 1) or baseline (Visit 2).
9.
Subject has a known history of symptomatic cardiovascular disease, structural cardiac abnormality, 
cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac conditions placing them 
at increased vulnerability to the sympathomimetic effects of a stimulant drug.
10. Subject has a history of seizures (other than infantile febrile seizures).
11. Subject is taking any medication that is excluded per the protocol.
12. Subject had any clinically significant ECG or clinical laboratory abnormalities at the screening 
(Visit 1) or baseline visit (Visit 2).
13. Subject has current abnormal thyroid function, defined as abnormal thyroid-stimulating hormone and 
thyroxine at the screening or baseline visit. Treatment with a stable dose of thyroid medication for at 
least 3 months is permitted.
14. Subject has a current, controlled (requiring medication or therapy) or uncontrolled, comorbid 
psychiatric disorder including but not limited to any of the following comorbid Axis I disorders and 
Axis II disorders:

Post-traumatic stress disorder or adjustment disorder

Bipolar disorder, psychosis, schizophrenia or family history of these disorder

Pervasive developmental disorder

Obsessive-compulsive disorder

Serious tic disorder, or a family history of Tourette disorder

Any other disorder that in the opinion of the investigator contraindicates SHP465 or 
amphetamine treatment or confounds efficacy or safety assessments
15. Subject has a primary sleep disorder (eg, sleep apnea, narcolepsy).
16. Subject has a history or is currently diagnosed with an eating disorder.


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17. Subject is currently considered a suicide risk in the opinion of the investigator, has previously made a 
suicide attempt, or has a prior history of or currently demonstrating suicidal ideation.
18. Subject has a history of physical, sexual, or emotional abuse.
19. Subject has initiated behavioral therapy within 1 month of baseline (Visit 2). Subject may not initiate 
behavioral therapy during the study.
20. Subject has a clinically important abnormality on the urine drug and alcohol screen (excluding the 
subject’s current ADHD stimulant, if applicable) at screening (Visit 1) or baseline (Visit 2).
21. Subject is female and is pregnant or lactating.
22. Subject cannot swallow a pill and/or applesauce or has an allergy to applesauce.
Maximum duration of subject involvement in the study:
The estimated duration of the study is up to 10 weeks
Planned duration of screening/washout period: up to 32 days
Planned duration of treatment period: 4 weeks

Planned duration of safety follow-up period: 1 week 
Endpoints and statistical analysis:
Analysis Sets

Screened Set: all subjects who have provided an informed consent.

Randomized Set:  all subjects in the screened set for whom a randomization number has been assigned.

Safety Set: all subjects in the randomized set who have taken at least 1 dose of investigational product.

Full Analysis Set (FAS):  all subjects in the safety set who have at least 1 post-dose ADHD-RS-5 Total 
Score.
Efficacy Analyses
The FAS will be used to report the efficacy data.
The primary efficacy endpoint is defined as the change from baseline for the ADHD-RS-5 Total Score at Visit 6 
(Week 4), where baseline is defined as the last ADHD-RS-5 Total Score assessment prior to the first dose of 
double blind investigational product, usually at Visit 2. The primary and key secondary analyses will be 
conducted based on the entire age group in the FAS. 
The primary efficacy analysis will be conducted for the change from baseline in the ADHD-RS-5 Total Scores, 
including all assessments from Visit 3 (Week 1) up to Visit 6 (Week 4), using the linear mixed-effects model 
for repeated measures (MMRM) with treatment group, visit, age group and the interaction of treatment group 
with visit as factors, baseline ADHD-RS-5 Total Score as a covariate, and the interaction of the baseline 
ADHD-RS-5 Total Score with visit adjusted in the model. The primary contrast of interest will be at Visit 6 
(Week 4) for SHP465 6.25 mg compared with placebo at the 2-tailed significance level of 0.05. 
The null and alternative hypotheses of the primary efficacy analysis will be the following:

Null hypothesis: There is no difference in primary endpoint mean change from baseline at Visit 6 
(week 4) in ADHD-RS-5 total scores between SHP465 6.25 mg and placebo.

Alternative hypothesis: There is a difference in primary endpoint mean change from baseline at Visit 6 
(week 4) in ADHD-RS-5 total scores between SHP465 6.25 mg and placebo.
As the primary efficacy analysis (MMRM) relies on the assumption that the missing data mechanism follows 
the MAR (missing-at-random) scenario, appropriate sensitivity analyses to examine the effect of data that are 
missing not at random and robustness on the results of the primary analysis will be conducted. 


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One sensitivity analysis model assumes that a subject on SHP465 6.25 mg treatment with missing data follows 
the distribution of the placebo responses, i.e., the means and the intra-subject correlations based on the placebo 
responses will apply. Another sensitivity analysis model will be performed under the assumption that subjects 
who drop out perform worse than MAR by a penalty. The details of the sensitivity analysis methods will be 
specified in the Statistical Analysis Plan (SAP).
The key secondary efficacy endpoint, CGI-I 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 primary contrast of 
interest will be at Visit 6 (Week 4) for SHP465 6.25 mg compared with placebo at the 2-tailed significant level 
of 0.05. Appropriate sensitivity analyses to explore the effect of data that are missing not at random on the 
results of the key secondary efficacy analysis will be specified in the SAP.
In order to protect the study-wide Type I error at the 2-sided 0.05 level for testing across the primary and the 
key secondary hypotheses, the Fixed-Sequence Test procedure will be applied. The hypotheses will be tested in 
order of the primary (ADHD-RS-5 Total Score) and then the key secondary (CGI-I), if significant for the 
primary, each at the 2-sided 0.05 significance level. Both tests in the sequence are based on the MMRM. 
The key secondary efficacy measurement will also be analyzed using the proportion of subjects with an 
“improved” CGI-I measurement at Visit 6/ET (Week 4/ET). In this approach, 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”. If missing data exist at the Visit 6 (Week 4) visit, 
the visit will be imputed by carrying forward the last post baseline observation value. The secondary efficacy 
analysis for the dichotomized CGI-I will be conducted to compare SHP465 6.25 mg and placebo on the FAS for 
the “improved” rate using a Cochran-Mantel-Haenszel test stratified by age group and CGI-S value at baseline.
Treatment effect of SHP465 6.25 mg on primary and key secondary efficacy measures will be estimated using a 
similar model as the primary efficacy endpoint for each age group (6-8 years vs. 9-12 years),  sex, race (white 
and nonwhite), and ethnicity subgroup.
Safety Analyses
Safety data will be analyzed for the safety set. Safety endpoints include the occurrence of TEAEs, systolic and 
diastolic blood pressure, pulse, and weight, height, BMI, ECG results, clinical laboratory test results, PSQ, 
CSHQ, and C-SSRS Exposure to investigational product will be summarized.
Adverse events will be coded using the agreed upon version of the Medical Dictionary for Regulatory Activities 
(MedDRA). 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, and serious AEs will also 
be presented. 
Vital signs (systolic and diastolic blood pressure, and pulse), weight, height, BMI, and ECG results including 
potentially clinically important results will be summarized by treatment and visit.
Clinical laboratory test results will be descriptively presented by treatment group for each visit. Shifts of clinical 
laboratory abnormality from baseline to Visit 6/ET will be presented. Number and percent of subjects with 
potentially clinically important laboratory values will be presented by treatment group.
The PSQ and CSHQ results will be summarized by treatment and visit. 
The C-SSRS results will be summarized and listings of the C-SSRS data will be provided for subjects with a 
positive response.
The safety data on TEAEs will also be descriptively summarized by treatment within each age group (6-8 years 
vs. 9-12 years), sex, race, and ethnicity subgroups.
Sample Size Calculation and Power Considerations
Approximately 60 subjects will be randomized in a 1:1 ratio to SHP465 6.25 mg and placebo to achieve 
52 completers for the study (26 in each treatment group) and 85% power for the primary efficacy analysis at the 
2-sided 0.05 significance level. 


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The sample size planned is estimated based on the primary comparison between SHP465 6.25 mg and placebo 
on the primary efficacy endpoint change from baseline in ADHD-RS-5 total score at Visit 6 (Week 4). 
Assumptions for the calculation include the true mean difference of 11.9 with the common standard deviation 
(SD) of 14 for an effect size of 0.85, and a dropout rate of 15%.
The effect size of 0.85 is low compared with that observed in recently completed study (SHP465-305) of 
children and adolescents aged 6-17 years with ADHD treated with SHP465. The SHP465-305 study yielded an 
effect size of 0.93 in children aged 6-12 years (N=101 subjects).
Planned Interim Analysis
A blinded interim analysis at the late stage of the trial (when approximately 75% of all randomized subjects 
have either completed or discontinued from the study) will be performed to reassess the sample size in case of 
an underestimated variability postulated at the design stage.
Using the cumulative real data, a blinded, pooled analysis of both treatment groups for estimating variability 
will be conducted on the change from baseline in ADHD-RS-5 total score at Visit 6 (Week 4). If the 
re-estimated pooled standard deviation is larger than the 14 postulated at the design stage, the final total number 
of subjects to be enrolled will be calculated using the re-estimated pooled standard deviation together with the 
assumed treatment difference of 11.9 (Friede et al, 2006). If the re-estimated pooled standard deviation is 
smaller than 14, the sample size will not be adjusted.








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1
BACKGROUND INFORMATION
SHP465 extended-release capsules contain mixed salts of a single-entity amphetamine, a 
CNS stimulant. The product was previously referred to as SPD465 however it is now 
being studied under the code of SHP465. SHP465 contains equal amounts (by weight) of 
4 salts: dextroamphetamine sulfate and amphetamine sulfate, dextroamphetamine saccharate 
and amphetamine aspartate monohydrate. This results in a 3:1 mixture of dextro- to 
levo- amphetamine base equivalent.
SHP465 capsules are for oral administration. They contain 3 types of drug-releasing 
beads, an immediate release and 2 different types of delayed release (DR) beads. The first 
DR bead releases amphetamine at pH 5.5 and the other DR bead releases amphetamine at 
pH 7.0. 
Amphetamines are noncatecholamine sympathomimetic amines with central nervous system 
stimulant activity. Amphetamine increases the availability of biogenic amines (primarily 
dopamine and norepinephrine) in central nerve terminals through multiple actions, including 
stimulating neurotransmitter release into the nerve terminal and inhibiting reuptake from the 
synapse. These actions may be the basis of its therapeutic actions in ADHD; however, the mode 
of therapeutic action in ADHD is not known.
Additional information can be found in the current Investigator's Brochure (IB) for SHP465.
1.1
Indication and Current Treatment Options 
Attention-deficit/hyperactivity disorder is a psychiatric disorder characterized by 
developmentally inappropriate degrees of inattentiveness, impulsivity, and hyperactivity. 
Although ADHD is the most common neurodevelopmental disorder of childhood (Rowland et al. 
2002) and it has been extensively studied in young children, ADHD occurs in all age groups 
(Brown 2000).
Prevalence estimates of ADHD in school-age children have ranged from 2-18% in community 
samples (Rowland et al. 2002; Centers for Disease Control and Prevention 2005). The 
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition – Text Revision®
estimates that the disorder is prevalent in 3-7% of school-age children (American Psychiatric 
Association 2000). An analysis of data from the National Survey of Children’s Health performed 
by the Centers for Disease Control and Prevention (2005) estimates that 7.8% of children aged 
4-17 years have been diagnosed with the disorder in the US as of 2003.
Although ADHD was initially believed to be predominantly a childhood disorder, the advent 
of consensus diagnostic criteria for ADHD along with more rigorous prospective research 
has documented the persistence of this disorder into adolescence in up to 70% and into 
adulthood in up to 66% of childhood cases (Mannuzza et al. 1998; Barkley 1998; Zametkin and 
Ernst 1999). Despite the prevalence of ADHD in all age groups, the majority of studies 
have been done in children and adults. 


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A review of available literature indicates that psychostimulants are efficacious in treating 
adolescents as well as the treatment for younger children with ADHD (Biederman et al. 1996; 
Findling et al. 2001).
The 3 main symptoms of ADHD are inattention, hyperactivity, and impulsivity. Symptoms of 
inattention include difficulty paying attention, making careless mistakes, difficulty organizing 
tasks, not finishing tasks, not listening, and being forgetful and easily distracted. Symptoms of 
hyperactivity and impulsivity include fidgeting, running, or moving about when expected to be 
still, difficulty playing quietly, talking excessively, and interrupting others. Many people have 
symptoms like these occasionally, but patients with ADHD have these symptoms more often and 
to a greater extent than others their age. These symptoms must appear before age 7 years, be 
present for more than 6 months, and must be adversely affecting social, occupational, or school 
functioning for the diagnosis of ADHD to be made.
The presumed pathophysiology of ADHD is an abnormality in central dopaminergic and 
noradrenergic tone (Biederman and Spencer 1999). This presumption is based on the 
discovery that effective pharmacotherapies in children and adults have an impact on these 
2 neurotransmitters (Wilens and Spencer 2000; Faraone and Biederman 1998).
Stimulants, including amphetamine and methylphenidate products are currently the most 
prescribed medications for the treatment of ADHD. Other nonstimulant classes of medications 
are also approved for the treatment of ADHD including a norepinephrine reuptake inhibitor, 
STRATTERA® (atomoxetine hydrochloride) and alpha-2-agonists, INTUNIV® (guanfacine 
hydrochloride) and KAPVAY® (clonidine hydrochloride). However, comprehensive reviews of 
clinical studies investigating the pharmacotherapy of ADHD clearly demonstrate that stimulant 
medications (ie, methylphenidate and amphetamine) produce the most robust improvements in 
symptom expression across age ranges as compared with nonstimulant therapies (Faraone et al. 
2006).
1.2
Product Background and Clinical Information
1.2.1
Clinical Information
SHP465 and its prototypes have been evaluated in 1641 subjects in 16 clinical studies, of which 
13 clinical studies were in adult subjects aged 18 to 55 years and 3 clinical studies were in 
pediatric subjects aged 6 to 17 years. The SHP465 clinical development program has shown that 
doses of 12.5 to 50 mg in adult subjects and 6.25 to 25 mg in pediatric subjects demonstrate a 
safety and efficacy comparable to the profile reflected in class labeling for stimulant products 
approved in the United States (US).
The pharmacokinetic (PK) profile of SHP465 is not affected if the capsule is consumed intact or 
if capsule contents are sprinkled onto a small amount of food (ie, 1 tablespoon of applesauce) 
and then ingested. The PK properties of SHP465 are not affected by sex or race. The PK 
properties between d- and l-amphetamine are similar.


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Acceptable safety and tolerability profiles observed were consistent with the types of side effect 
specified in stimulant class labeling in the US. Specifically, administration of SHP465 was 
associated with increases in blood pressure (mean increase approximately 2-4 mmHg) and heart 
rate (mean increase approximately 3-6 bpm), and treatment-emergent adverse events (TEAEs) of 
insomnia, decreased appetite, decreased weight, heart rate increased, and anxiety, as well as 
psychiatric events (eg, mania, suicidality).
Always refer to the latest version of the SHP465 IB for the overall risk/benefit assessment and 
the most accurate and current information regarding the drug metabolism, PK, efficacy, and 
safety of SHP465. 


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2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The purpose of this study is to evaluate the efficacy and safety of SHP465 at 6.25 mg in the 
treatment of ADHD in children aged 6-12 years. Results from the completed SHP465-305 study 
in this age group have demonstrated SHP465 to be well tolerated and efficacious in reducing 
ADHD symptom severity. This study will provide additional data to inform clinicians about the 
efficacy and safety of SHP465 at lower dose levels in the pediatric ADHD population.
2.2
Study Objectives
2.2.1
Primary Objectives
To evaluate the efficacy of SHP465 at 6.25 mg compared to placebo as a daily morning dose in 
children 6-12 years of age (inclusive at the time of consent) diagnosed with ADHD. The primary 
measure of efficacy will be the clinician-administered ADHD-Rating Scale 5 Child, Home 
version (ADHD-RS-5) Total score.
2.2.2
Secondary Objectives
Key Secondary: 

To assess the efficacy of SHP465 at 6.25 mg compared to placebo using a global clinical 
measure of improvement, the Clinical Global Impression of Improvement (CGI-I) scale.
Secondary: 

To evaluate safety and tolerability based on the occurrence of treatment-emergent adverse 
events (TEAEs), evaluation of vital signs (systolic and diastolic blood pressure and pulse), 
weight, height, body mass index (BMI); clinical laboratory and electrocardiogram (ECG) 
results; sleep assessments (Post Sleep Questionnaire [PSQ] and Children’s Sleep Habits 
Questionnaire [CSHQ]); and responses to the Columbia-Suicide Severity Rating Scale 
(C-SSRS).




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3.2
Duration and Study Completion Definition
The subject’s duration of participation is expected to be approximately 6-10 weeks. The study 
will be completed in approximately 7 months.

Planned duration of screening/washout period: up to 32 days

Planned duration of treatment period: 4 weeks

Planned duration of safety follow-up: 1 week
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
The study will be conducted in approximately 45 sites in the US. 


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4
STUDY POPULATION
Each subject and parent/LAR must participate in the informed consent process and provide 
written informed consent and/or assent (as applicable) before any procedures specified in the 
protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the criteria below 
(including test results).
1. Subject is male or female aged 6-12 years inclusive at the time of consent.
2. Subject’s parent or LAR must provide signature of informed consent, and there must be 
documentation of assent (as applicable) by the subject in accordance with the International 
Council on Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 (1996) and any 
updates and applicable regulations, before completing any study-related procedures.
3. Subject and parent/LAR are willing and able to comply with all of the testing and 
requirements defined in the protocol, including oversight of morning dosing. Specifically, the 
parent/LAR must be available at approximately 7:00 AM (±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, Fifth Edition 
(DSM-5) criteria for a primary diagnosis of ADHD (any subtype) based on a detailed 
psychiatric evaluation using the Mini International Neuropsychiatric Interview version for 
Children and Adolescents (MINI-KID).
5. Subject who is a female and of child-bearing potential must not have a positive serum beta 
human chorionic gonadotropin pregnancy test at the screening visit (Visit 1) and must have a 
negative urine pregnancy test at the baseline visit (Visit 2) and agree to comply with any 
applicable contraceptive requirements of the protocol.
6. Subject has an ADHD-RS-5 Child, Home Version Total Score of ≥28 at baseline (Visit 2). 
7. Subject has a Clinical Global Impression – Severity of Illness (CGI-S) score ≥4 at baseline 
(Visit 2).
8. Subject functions as an age-appropriate level intellectually, as determined by the investigator.
9. Subject is currently not on ADHD therapy, or is not completely satisfied with their current 
ADHD therapy.
10. Subject has lived with the same parent/LAR for at least 6 months.


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4.2
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met. 
1. Subject is required or anticipated to take medications that have central nervous system effects 
or affect performance, such as sedating antihistamines, decongestant sympathomimetics, or 
monoamine oxidase inhibitors. Stable use of bronchodilator inhalers is not exclusionary.
2.
Subject has a concurrent chronic or acute illness (such as severe allergic rhinitis or an 
infectious process requiring antibiotics), disability, or other condition that might confound 
the results of safety assessments conducted in the study or that might increase risk to the 
subject. Similarly, the subject will be excluded if he or she has any additional condition(s) 
that, in the investigator’s opinion, would prohibit the subject from completing the study or 
would not be in the best interest of the subject. The additional condition(s) would include any 
significant illness or unstable medical condition that could lead to difficulty complying with 
the protocol. Mild, stable asthma is not exclusionary.
3. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any 
excipients in the investigational product.
4. Subject has failed to fully respond, based on investigator judgment, to an adequate course of 
amphetamine therapy.
5. Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
6. Subject has a blood pressure measurement ≥95th percentile for age, sex, and height at 
screening (Visit 1) and/or baseline (Visit 2).
7. Subject has a height ≤5th percentile for age and sex at screening (Visit 1) or baseline 
(Visit 2).
8. Subject has a weight ≤5th percentile for age and sex at screening (Visit 1) or baseline 
(Visit 2).
9. Subject has a known history of symptomatic cardiovascular disease, structural cardiac 
abnormality, cardiomyopathy, serious heart rhythm abnormalities, or other serious cardiac 
conditions placing them at increased vulnerability to the sympathomimetic effects of a 
stimulant drug.
10. Subject has a history of seizures (other than infantile febrile seizures).
11. Subject is taking any medication that is excluded per the protocol.
12. Subject had any clinically significant ECG or clinical laboratory abnormalities at the 
screening Visit 1) or baseline visit (Visit 2).
13. Subject has current abnormal thyroid function, defined as abnormal thyroid-stimulating 
hormone and thyroxine at the screening or baseline visit. Treatment with a stable dose of 
thyroid medication for at least 3 months is permitted.


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14. Subject has a current, controlled (requiring medication or therapy) or uncontrolled, comorbid 
psychiatric disorder including but not limited to any of the following comorbid Axis I 
disorders and Axis II disorders:

Post-traumatic stress disorder or adjustment disorder

Bipolar disorder, psychosis, schizophrenia or family history of these disorder

Pervasive developmental disorder

Obsessive-compulsive disorder

Serious tic disorder, or a family history of Tourette disorder

Any other disorder that in the opinion of the investigator contraindicates SHP465 or 
amphetamine treatment or confounds efficacy or safety assessments
15. Subject has a primary sleep disorder (eg, sleep apnea, narcolepsy).
16. Subject has a history or is currently diagnosed with an eating disorder.
17. Subject is currently considered a suicide risk in the opinion of the investigator, has 
previously made a suicide attempt, or has a prior history of or currently demonstrating 
suicidal ideation.
18. Subject has a history of physical, sexual, or emotional abuse.
19. Subject has initiated behavioral therapy within 1 month of baseline (Visit 2). Subject may not 
initiate behavioral therapy during the study.
20. Subject has a clinically important abnormality on the urine drug and alcohol screen 
(excluding the subject’s current ADHD stimulant, if applicable) at screening (Visit 1) or 
baseline (Visit 2).
21. Subject is female and is pregnant or lactating.
22. Subject cannot swallow a pill and/or applesauce or has an allergy to applesauce.
4.3
Reproductive Potential
4.3.1
Female Contraception
Sexually active females of child-bearing potential must be advised to use acceptable 
contraceptives throughout the study period and for 30 days following the last dose of 
investigational product. If hormonal contraceptives are used they should be administered 
according to the package insert. Females of child-bearing potential who are not currently 
sexually active must agree to use acceptable contraception, as defined below, if they become 
sexually active during the period of the study and 30 days following the last dose of 
investigational product. 


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Female children and adolescent subjects should be either:

Premenarchal and either Tanner Stage 1 or less than age 9 years, or

Females of child-bearing potential with a negative serum -HCG pregnancy test at the 
screening visit (Visit 1) and a negative urine pregnancy test at the baseline visit (Visit 2) 
prior to randomization. Females of child-bearing potential must agree to abstain from 
sexual activity that could result in pregnancy or agree to use acceptable methods of 
contraception.
Acceptable methods of contraception are:

Intrauterine devices plus condoms

Double-barrier methods (eg, condoms and diaphragms with spermicidal gel or foam)

Hormonal contraceptives (oral, depot, patch, injectable, or vaginal ring), stabilized for at 
least 30 days prior to the screening visit (Visit 1), plus condoms. Note:  if subject becomes 
sexually active during the study, they should use 1 of the other acceptable methods noted 
above in addition to the hormonal contraceptive until it has been stabilized for 30 days.
4.3.2
Male Contraception
Male subjects must agree to either abstain from sexual activity or to use condoms.
4.4
Discontinuation of Subjects
A subject may withdraw from the study, or the parent/LAR may withdraw the subject from the 
study at any time for any reason without prejudice to their future medical care by the physician 
or at the institution. The investigator or sponsor may withdraw the subject at any time (eg, in the 
interest of subject safety). The investigator is encouraged to discuss withdrawal of a subject from 
investigational product with the medical monitor when possible.
If investigational product is discontinued, regardless of the reason, the evaluations listed for 
Visit 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, date of stopping investigational product, and the total amount of 
investigational product taken must be recorded in the source documents.
Subjects who discontinue will not be replaced. 
4.4.1
Management of Blood Pressure and Pulse During the Study 
To ensure that potential blood pressure and pulse increases associated with the use of SHP465 in 
this population are carefully monitored and appropriately managed, all subjects must be further 
evaluated if they meet any of the criteria defined below.


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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 (NIH, 2004).
Prior to obtaining vital signs (blood pressure and pulse) the subjects should be at rest for at least 
3 minutes.
If any subject’s blood pressure measurements meet either criterion below, the investigator will 
notify the medical monitor. If any subject’s blood pressure measurements meet either criterion 
below on 3 consecutive visits, the subject should be considered for potential discontinuation 
based upon the clinical judgment of the investigator and in conjunction with the medical 
monitor. 

Elevations in the average (of 3 readings) sitting systolic blood pressure defined as an increase 
of >15 mmHg from the baseline visit (Visit 2) OR a value >95th percentile for age, sex, and 
height.

Elevations in average (of 3 readings) sitting diastolic blood pressure defined as an increase of 
>15 mmHg from the baseline visit (Visit 2) OR an average (of 3 readings) sitting diastolic 
blood pressure value >95th percentile for age, sex, and height.
Any subject with a systolic or diastolic blood pressure measurement <95th percentile for age, sex, 
and height percentile may be discontinued from the study based upon the clinical judgment of 
the investigator regarding the subject’s safety.
4.4.1.2
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 >116 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 
>116 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. In careful consideration of the 
subject's pulse value, magnitude of increase from the baseline, and symptoms, a joint decision 
between the investigator and the medical monitor will be made regarding continued participation 
in the study. If a visit cannot be scheduled the next day, the subject may be discontinued from the 
study.
Any subject with a pulse rate equal or lower than the number for age defined above may be 
discontinued from the study based upon the clinical judgment of the investigator regarding the 
subject’s safety.


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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 source documents. If a subject is withdrawn for more than 1 reason, 
each reason should be documented in the source documents and the most clinically relevant 
reason should be entered on the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event

Protocol violation

Withdrawal by subject or parent/LAR

Lost to follow-up

Lack of efficacy

Blood pressure and/or pulse criteria met

Other (must be specified). 
4.4.3
Subjects ‘Lost to Follow-up’ Prior to Last Scheduled Visit
A minimum of 3 documented attempts must be made to contact any subject lost to follow-up at 
any time point prior to the last scheduled contact (office visit or telephone contact). At least 1 of 
these documented attempts must include a written communication sent to the subject’s last 
known address via courier or mail (with an acknowledgement of receipt request) asking that they 
return to the site for final safety evaluations and return any unused investigational product.


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5
PRIOR AND CONCOMITANT TREATMENT
All nonstudy treatment including but not limited to herbal treatments, vitamins, 
nonpharmacological treatment, such as psychotherapy, as appropriate 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.
In addition, the subject’s lifetime psychoactive medication history and the subject’s lifetime 
nonpharmacological interventions (behavioral therapy) for ADHD will be documented at the 
screening visit (Visit 1). The type of nonpharmacological intervention for ADHD and dates of 
occurrences should be recorded.
Psychoactive medications other than the investigational products are not allowed in the study.
Table 2 details the washout period for common prior treatments and highlights excluded 
medications.
5.1
Prior Treatment
Prior treatment includes all treatment including but not limited to herbal treatments, vitamins, 
nonpharmacological treatment such as psychotherapy as appropriate received within 30 days 
prior to the screening visit (Visit 1) or pharmacokinetics equivalent of 5 half-lives, whichever is 
longer of the date of first dose of investigational product. Prior treatment information must be 
recorded on the subject’s source documents.
Washout for all prior medications must be a minimum of 5 times the half-life of the medication.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the first dose of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded in the appropriate source document.
5.2.1
Permitted Treatment
Medications permitted during the study are listed below:

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, oral beta-agonists and chronic use of oral corticosteroids are prohibited)

Any medications that do not affect blood pressure, heart rate, or the central nervous system, 
and which are considered necessary for the subject’s welfare, may be administered at the 
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
Nonsedating antihistamines such as fexofenadine (ALLEGRA®, Sanofi), loratadine 
(CLARITIN®, Schering-Plough), and cetirizine hydrochloride (ZYRTEC®, McNeil-PPC)

Over-the-counter nonstimulant cold remedies

Hormonal contraceptives for female subjects used for at least 30 days prior to the baseline 
visit (Visit 2) and at least 30 days following the end of the subject’s participation in the study

Continued participation in behavioral therapy, provided the subject has been receiving the 
therapy for at least 1 month at the time of the baseline visit (Visit 2)
5.2.2
Prohibited Treatment
Shown in Table 2 are excluded medications for 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 2)
Minimum Number 
of Days Before 
Baseline Visit
Treatment
7
14
30
Psychostimulants, amphetamines, and amphetamine-like agents
X
Antihypertensivesa
X
Antihistamines (centrally and peripherally active)
X
Herbal preparations (including melatonin)
X
Sedatives, anxiolytics, antipsychoticsa
X
Monoamine oxidase inhibitora
X
Antidepressantsa
X
Clonidine and guanfacine
X
Selective noradrenaline reuptake inhibitors and noradrenaline reuptake inhibitorsa
X
CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine, ritonavir)
X
Alkalinizing agents (eg, sodium bicarbonate, acetazolamide, some thiazides)
X
Acidifying agents (eg, guanethidine, reserpine, glutamic acid HCl, ascorbic acid, 
ammonium chloride, sodium acid phosphate, methenamine salts)
X
a These medications may signal that an exclusionary diagnosis is present. The medical monitor should be consulted before 
instructing a subject to discontinue 1 of these medications for this study.


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6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is SHP465, which will be provided in 6.25 mg capsule form. Additional 
information is provided in the current SHP465 IB. The product was previously referred to as 
SPD465 and is registered with the Drug Enforcement Agency (DEA) as SPD465; however, it is 
now being studied under the code of SHP465. The drug will be labeled with SHP465 (SPD465).
The reference/comparator product is placebo which will also be provided in capsule form.  
6.1.1
Blinding the Treatment Assignment
The actual treatment given to individual subjects is determined by a randomization schedule. A 
randomization schedule will be prepared to assign eligible subjects to 1 of 2 treatment groups 
with an allocation ratio of 1:1 (SHP465 6.25 mg or placebo). The associated treatment 
assignments giving details of individual subject treatment are automatically defined by the 
IWRS. At each visit, subjects will be supplied bottles of investigational product that have been 
individually allocated by IWRS, and instructed to take 1 capsule every morning. All 
investigational product (SHP465 6.25 mg or placebo) will appear identical, in order to protect the 
study blind. 
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 shipment, 
supply, inventory, ordering, expiration, site-assignments, subject randomization, returns, and 
emergency unblinding of the investigational product. 
The IWRS provider will provide a user manual and training to each site, with detailed instruction 
on use of the IWRS.
6.2.2
Allocation of Subjects to Treatment 
This is a double-blind, placebo-controlled study. The actual treatment given to individual 
subjects is determined by a randomization schedule. Subjects will be randomly assigned in a 
1:1 ratio to SHP465 6.25 mg or placebo. Randomization will be stratified to ensure 
approximately 50% of subjects in each age group (6-8 years and 9-12 years), and to facilitate 
balance of treatment allocation within each age group.
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. 


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Individual subject treatment is automatically assigned by the interactive response technology.
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.
6.2.3
Dosing
Dosing should begin at approximately 7:00AM (±2 hours) on the morning after the baseline visit 
(Visit 2). 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.
The investigational product may be administered in 1 of the following ways:

Swallow the capsule whole, or

Open capsule and sprinkle the entire contents over a spoonful of applesauce. The sprinkled 
applesauce should be consumed immediately; it should not be stored. Subjects should take 
the sprinkled applesauce in its entirety without chewing. The dose of a single capsule should 
not be divided. The empty capsule shells should be discarded.
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 on the 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 CRO and 
sponsor. Code-break access will be provided to the investigator/designated person at the site and 
by the CRO medical monitor for the study.
For blinded studies, there will be a provision for unblinding to ensure adequate treatment of the 
subject in the case of an emergency.
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. 


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A computer-generated label is applied to the investigational product. All investigational 
product is labeled with a minimum of the protocol number, pack number (if applicable), dosage 
form (including product name and quantity in pack), directions for use, storage conditions, 
expiry date (if applicable), batch number and/or packaging reference, the statement ‘CAUTION: 
New Drug - Limited by Federal (or United States) Law to Investigational Use’, and ‘Keep out of 
reach of children’, and the sponsor's name and address. Any additional labeling requirements for 
participating countries and/or controlled substances will also be included on the label.
Space is allocated on the label so that the site representative can record a unique subject 
identifier and initials.
Additional labels (eg, those used when dispensing marketed product) may, on a case-by-case 
basis, be applied to the investigational product in order to satisfy local or institutional 
requirements, but must not:

Contradict the clinical study label

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:
9-count high density polyethylene bottles with child-resistant closures.
Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier initials on the investigational product 
bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. 


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Such a device (ie, certified min/max thermometer) would require manual resetting upon each 
recording. The sponsor must be notified immediately upon discovery of any excursion from the 
established range. Temperature excursions will require site investigation as to cause and 
remediation. The sponsor will determine the ultimate impact of excursions on the investigational 
product and will provide supportive documentation as necessary. Under no circumstances should 
the product be dispensed to subjects until the impact has been determined and the product is 
deemed appropriate for use by the sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
All controlled-substance investigational product for the sponsor’s studies must be stored in a 
securely locked, substantially constructed room or cabinet according to all applicable local, state, 
and/or national laws. Limited, controlled access to these investigational products must be 
maintained, as well as chain of custody, for all investigational product movement.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed number of subjects. The investigator or designee will acknowledge 
receipt of the investigational product, documenting shipment content and condition. Accurate 
records of all investigational product dispensed, used, returned, and/or destroyed must be 
maintained as detailed further in this section.
The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form. The 
investigator or designee will be required to have a valid DEA Form 223 certificate of registration 
for 2N Controlled Substances for the duration of the study, and be able to order and distribute 2N 
Controlled Substances via a valid DEA Form 222.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will dispense the investigational product only to the parent/LAR of 
subjects included in this study following the procedures set out in the study protocol. Each 
subject will be given only the investigational product carrying his/her treatment assignment. All 
dispensed 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 each subject's 
parent/LAR. 
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.


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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, interactive 
response technology) do not require a shipment form. Returned investigational products must be 
packed in a tamper-evident manner to ensure product integrity. Contact the sponsor for 
authorization to return any investigational product prior to shipment. Shipment of all returned 
investigational product must comply with local, state, and national laws.
Based on entries in the site drug accountability forms, it must be possible to reconcile 
investigational products delivered with those used and returned. All investigational products 
must be accounted for and all discrepancies investigated and documented to the sponsor’s 
satisfaction.
6.5
Subject Compliance
The parent/LAR of each subject must be instructed to bring their unused investigational product 
and empty/used investigational product packaging to every visit. Drug accountability must be 
assessed at the container/packaging level for unused investigational product that is contained 
within the original tamper-evident sealed container (eg, bottles, trays, vials) or at the individual 
count level for opened containers/packaging. The pharmacist/nominated person will record 
details on the drug accountability form.


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7
STUDY PROCEDURES
7.1
Study Schedule
The 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-5, 
CGI-S, CGI-I, and C-SSRS should be completed by the same rater with input from the same 
parent/LAR whenever possible. The parent/LAR completed CSHQ should be completed 
whenever possible. 
Throughout the treatment period of the study, visits should be scheduled as outlined (±2 days) 
with reference to the baseline visit (Visit 2). The safety follow-up call should be scheduled 
7 days post last dose with a +2 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). 
7.1.1
Screening and Washout Period 
The principal investigator or his/her designee must obtain written informed consent from the 
subject’s parent/LAR prior to any study-related procedures conducted during the screening visit 
(Visit 1). There must also be documentation of assent (if required by the 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. The date of the screening visit (Visit 1) is the date 
the parent/LAR has signed informed consent for this study. Subjects requiring washout must 
have an abbreviated physical examination, clinical laboratory tests, and 12-lead ECG repeated if 
>32 days have elapsed since the safety measurements at the screening visit (Visit 1) were 
collected.


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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 nonpharmacological treatment, specified Mini International Neuropsychiatric 
Interview for Children and Adolescents (MINI KID), and C-SSRS criteria. Areas of 
impairment will be recorded for all subjects for assessing the severity of the subject’s 
condition.

All adverse events (AEs) occurring after signature of informed consent must be recorded in 
the source documents and CRF.

Three ECGs will be taken, with approximately 3 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. 
The ECG tracing will be sent to the central reader for analysis. Upon review of the report 
from the central reader, the investigator will re-evaluate the clinical significance of the ECG 
in light of other safety data for the subject. If abnormal and significant results are observed 
following assessment by the central reader, the investigator, in consultation with the 
appointed CRO Medical Monitor, will confirm the subject’s eligibility to participate in this 
study.

Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in between 
each collection) using the age-appropriate cuff during the visit. 

The “baseline” version of the C-SSRS should be completed.

Record historical/concomitant medications as follows:
-
All lifetime psychoactive medications and lifetime nonpharmacological interventions 
(behavioral therapy) for ADHD
-
Other medications used during the 30 days prior to the screening visit (Visit 1)
A screen failure is a subject who has given informed consent and failed to meet the inclusion 
criteria and/or met at least 1 of the exclusion criteria and has not been randomized or 
administered investigational product. For screen failure subjects, the investigator or assigned site 
staff designee will access the IWRS to record the subject as a screen failure.
Subjects cannot be rescreened once they have been designated as a screen failure.
7.1.1.2
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. 


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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 2).

Review the inclusion/exclusion criteria.

Ask about any concomitant medications that the subject is taking. If new concomitant 
medications that require washout are noted, instructions for appropriate washout 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 and must 
occur prior to the baseline visit.
7.1.1.3
Baseline Visit (Visit 2)
Once the screening central clinical laboratory tests and 12-lead ECG results have been obtained, 
in addition to repeat assessments (if required), and the subject has completed the required 
washout period (if applicable), the subject will return to the site for the baseline visit (Visit 2).
Inclusion/exclusion criteria must also be reviewed during this visit to ensure subjects continue to 
meet all eligibility criteria.
Table 1 outlines all procedures to be conducted during the baseline visit (Visit 2) with further 
clarification provided below:

For subjects with >32 days since the safety measurements at the screening visit (Visit 1) were 
collected, an abbreviated physical examination, 12-lead ECG in triplicate, serum pregnancy 
test, urine drug screen, and all clinical laboratory tests must be repeated, and the results 
reviewed by the investigator prior to the subject being enrolled. 

Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in between 
each collection) using the age-appropriate cuff during the visit. 

If >32 days since the screening visit, 3 ECGs will be taken, with approximately 3 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 and to determine eligibility. 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.


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
The C-SSRS “since last visit” 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 9-count bottle of investigational product to cover them 
until their next regularly scheduled visit. Subjects will be instructed to take 1 capsule each 
day. Dosing will begin the morning following the baseline visit (Visit 2).
7.1.2
Treatment Period
7.1.2.1
Treatment Period (Visits 3-5)
During the 4 weeks of treatment, visits will be scheduled every 7 days (±2 days) to assess safety 
and efficacy based on TEAEs, efficacy, and the dosing guidelines in Section 6.2.3.
Throughout the treatment period, subjects may attend the clinic for unscheduled visits to address 
any medical needs that arise between scheduled visits.

Table 1 outlines all procedures to be conducted during Visits 3 to 5 and should serve as the 
primary point of reference regarding study procedures. Further clarification for these visits 
is outlined as follows: Subjects will be dispensed a 9-count bottle of investigational product 
to cover them until their next regularly scheduled visit. Subjects will be instructed to take 
1 capsule each day. Dosing will begin the morning after each visit.

Blood pressure and pulse will be collected 3 times (with at least 2 minutes in between each 
collection) 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 last treatment visit.
7.1.2.2
End of Study/Early Termination Visit (Visit 6/ET)
All enrolled subjects who complete the study or discontinue early will complete Visit 6/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. 

Blood pressure and pulse will be collected 3 times (with approximately 2 minutes in between 
each collection) using the age-appropriate cuff during the visit. The average of each set of 
3 measurements will be used to determine continued participation in the study (see 
Section 4.4.1).


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
Scales should be completed by the same rater with input from the same parent/LAR 
whenever possible.
7.1.3
Safety Follow-up Period
The follow-up period for this protocol is 7 days (+2 days) from the last dose of the 
investigational product. 
At the end of this period there will be a telephone call initiated by the site staff to query for 
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 may be evaluated for eligibility to enter a 
long-term safety study of SHP465.
The subject’s primary care physician will be responsible for determining the appropriate and 
available treatment options upon study completion for subjects who did not enroll into the 
long-term safety study of SHP465. However, to maintain the integrity of the study, subjects will 
not be unblinded to treatment assignment at the end of their participation in the study. 
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/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, and height will be collected throughout the 
study according to Table 1.
7.2.2
Screening Assessments
7.2.2.1
Mini International Neuropsychiatric Interview for Children and Adolescents
The MINI-KID is a structured clinical diagnostic interview designed to assess the presence of 
psychiatric disorders in children and adolescents in a way that is comprehensive and concise. It 
follows the structure and format of the adult version of the interview and is organized in 
diagnostic sections or modules. 
Using branching tree logic, the instrument asks 2 to 4 screening questions for each disorder. 


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Additional symptom questions within each disorder section are asked only if the screen questions 
are positively endorsed. The MINI is the structured psychiatric interview of choice for 
psychiatric evaluation and outcome tracking in clinical psychopharmacology trials and 
epidemiological studies. In a validation study (Sheehan et al., 2010), the MINI-KID generated 
reliable and valid psychiatric diagnoses for children and adolescents and does so in a third of the 
time as the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime 
Version. The MINI-KID Standard Version for DSM-5 assesses the 30 most common and 
clinically relevant disorders or disorder subtypes in pediatric mental health. With this version, 
the child and parent are interviewed together. The MINI-KID should be completed by an 
individual who has experience in the evaluation of pediatric patients with ADHD and the scale, 
and may include physicians, or licensed psychologists/clinicians. All individuals performing this 
assessment must be preapproved by the sponsor or designee.
7.2.3
Efficacy
7.2.3.1
Attention-deficit/Hyperactivity Rating Scale 
The ADHD-RS-5 Child, Home Version (DuPaul et al. 2016), the primary efficacy measure, is 
completed by the clinician and will be administered at baseline (Visit 2) and each subsequent 
visit up to and including Visit 6/ET to capture the ADHD symptoms within each study period. 
The ADHD rating scale was developed to measure the behaviors of children with ADHD and is 
commonly used in clinical studies of ADHD (Buitelaar et al. 2007; Döpfner et al. 2006;
Kratochvil et al. 2001; Michelson et al. 2001; Spencer et al. 2001). The ADHD-RS-5 consists of 
18 items designed to reflect current symptomatology of ADHD based on DSM-5 criteria. Each 
item is scored on a 4-point scale ranging from 0 (reflecting no symptoms) to 3 (reflecting severe 
symptoms) with total scores ranging from 0-54. The 18 items may be grouped into 2 subscales: 
hyperactivity/impulsivity (9 items) and inattentiveness (9 items).
The ADHD-RS-5 should be completed by a clinician experienced in the evaluation of children 
with ADHD. Since the ADHD-RS-5 is an important measure for guidance in dosing decisions, 
the ADHD-RS-5 must be performed by an individual who is experienced with the scale. All 
individuals performing this assessment must be pre-approved by the sponsor or designee.
The title, version, and date of the ADHD-RS-5 used in this study are included in Appendix 3.
7.2.3.2
Clinical Global Impression
The Clinical Global Impression Scale (Guy 1976) permits a global evaluation of the subject’s 
severity and improvement over time. The Clinical Global Impression has been used extensively 
in clinical studies of ADHD (Michelson et al. 2001; Weiss et al. 2005; Wilens et al. 2001).
The investigator will perform the CGI-S to rate the severity of a subject’s condition on a 7-point 
scale ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill subjects) at the 
baseline visit (Visit 2). Additionally at the baseline visit, the investigator should establish 3 target 
areas of improvement with the subject and the subject’s parent/LAR. 
To generate the targets, an open-ended question such as “If this program of treatment works for 


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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 3 up to and including Visit 6/ET, the investigator will assess the 
subject’s improvement relative to the 3 target areas of improvement recorded at the baseline visit 
(Visit 2), on the CGI-I, a 7-point scale ranging from 1 (very much improved) to 7 (very much 
worse).
The CGI-S and CGI-I should be completed by a clinician experienced in the evaluation of 
children with ADHD. Since the CGI-I is an important measure for guidance in dosing decisions, 
the CGI-I must be performed by a principal investigator or sub-investigator who is 
medically/clinically responsible for the subject and experienced with the scale. All individuals 
performing this assessment must be pre-approved by the sponsor or designee.
The title, version, and date of the CGI-S and the CGI-I used in this study are included in 
Appendix 3. 
7.2.4
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 and parent/LAR 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 2) if 
more than 32 days have elapsed since the physical examination completed as part of the 
screening visit (Visit 1) was performed. The physical examination will be performed by a 
qualified, licensed individual per local requirements (eg, physician, physician assistant, or nurse 
practitioner).
A full physical examination is composed of a review of the following body systems:

General appearance

Skin

Head, Eyes, Ears, Nose, and Throat


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
Spine/Neck/Thyroid

Respiratory

Cardiovascular

Abdomen (including liver and kidneys)

Musculoskeletal

Neurological
If an abbreviated physical examination is required at the baseline visit (Visit 2), a review of the 
body systems will include the following:

General Appearance

Respiratory

Cardiovascular
Abnormalities identified at the screening visit (Visit 1) will be documented in the subject’s 
source documents. Changes after the screening visit (Visit 1) will be captured as AEs, as 
determined by the investigator.
7.2.4.3
Adverse Event Collection
At each study visit, parent/LAR and/or subject will be questioned in a general way to ascertain if 
AEs have occurred since the previous visit (eg, “Have you had any health problems since your 
last visit?”). Adverse events are collected from the time informed consent is signed. (Refer to 
Section 8.) This information should be collected prior to the completion of assessments at all 
study visits. In addition, any symptoms/conditions reported during assessments and deemed to be 
clinically significant by the investigator will be assessed as AEs.
7.2.4.4
Vital Signs (Including Height and Weight)
Measurements of oral or tympanic temperature and sitting respiratory rate will be performed at 
the screening visit (Visit 1) and/or baseline (Visit 2) 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 seated for a minimum of 3 minutes.
Blood pressure will be determined by an age-appropriate cuff (the same unit and same arm 
should be used throughout the study). A blood pressure cuff appropriate for the subject’s arm 
length and girth should be used for all blood pressure measurements. The age-appropriate cuff 
should be approximately two-thirds the length/width of the subject’s arm (from elbow to 
shoulder). All blood pressure measurements should be taken using the same arm and be 
performed by the same site personnel (if possible) throughout the study. 
The age-appropriate cuff will obtain 3 measurements with approximately 2 minutes in between 
each collection for blood pressure and pulse and report the average of the 3 measurements for 


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each parameter. The 3 individual measurements, time collected, and averaged reading should be 
recorded in the source. 
Height will be captured at the screening visit (Visit 1). 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 should be used for all 
weight measurements. Weight should be measured in pounds or kilograms without shoes and 
with light clothing and should be recorded to the nearest 0.1 pound or 0.1 kilogram. 
Any clinically significant deviations from screening (Visit 1) vital signs which are deemed 
clinically significant in the opinion of the investigator are to be recorded as an AE.
7.2.4.5
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 
2) with results reviewed before enrolling the subject in the study if more than 32 days have 
elapsed since the clinical laboratory assessments completed as part of the screening visit (Visit 1) 
were performed. 
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 Aminotransferase
Urate
Phosphorus
Blood Urea Nitrogen
Alanine Aminotransferase
Total Bilirubin


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Sodium
Creatinine
Alkaline Phosphatase
Glucose
Potassium
Albumin
Gamma Glutamyl Transferase
Protein
Thyrotropin
Lactate Dehydrogenase
Thyroxine, Free
Hematology
A blood sample (~4 mL) for hematology will be taken to assess the following parameters:
Hemoglobin
Neutrophils
Hematocrit
Lymphocytes
Red Blood Cells
Monocytes
Platelets
Eosinophils
White Blood Cell count – total and 
differential 
Basophils
Mean Corpuscular Hemoglobin
Neutrophils Band Form
Mean Corpuscular Hemoglobin Concentration
Mean Corpuscular Volume
Urinalysis
A urine sample (~10 mL) for urinalysis will be collected to assess the following parameters:
Glucose
pH
Specific Gravity
Urobilinogen
Blood
Color
Ketones
Leukocyte Esterase
Protein
Nitrite
Bilirubin
If urinalysis detects protein and/or blood, a microscopic examination will be conducted. The microscopic 
examination will consist of red blood cells, white blood cells, casts, and bacteria.


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7.2.4.6
Urine Drug Screen
A urine drug and alcohol screen will be conducted at the screening visit (Visit 1). As a reminder, 
a urine drug screen should be repeated prior to the baseline visit (Visit 2) if more than 32 days 
have elapsed since the screening visit (Visit 1).
Urine samples (~10 mL) will be collected for this testing and will be evaluated at the central 
laboratory. The following drugs/drug classes will be tested:
Urine Drug Screen
Cocaine
Cannabinoids
Phencyclidine
d-amphetamine
Benzodiazepines class
Barbiturates class
Opiates class
Propoxyphene
Methaqualone
Methadone
Methamphetamine
The urine drug screen must be negative at the screening visit (Visit 1) for the subject to be 
eligible to enroll in the study.
If the subject has a positive urine drug screen at the screening visit (Visit 1) that the investigator 
is able to attribute to a medication that has been prescribed to the subject, the urine drug screen 
must be repeated prior to the baseline visit (Visit 2) and must be negative so the investigator can 
verify that the disallowed medication which caused a positive result at the screening visit 
(Visit 1) has been discontinued prior to the baseline visit (Visit 2). 
7.2.4.7
Pregnancy Test
A serum -HCG pregnancy test is performed on all females of child-bearing potential at the 
screening visit (Visit 1). Additionally, the serum pregnancy test must be repeated at the baseline 
visit (Visit 2) if greater than 32 days have elapsed since the screening visit (Visit 1). The results 
must be reviewed by the investigator before the subject can be randomized. 
A urine pregnancy test is performed on all females of child-bearing potential at the baseline visit 
(Visit 2), and at the final visit (Visit 6/ET), or if pregnancy is suspected, or on withdrawal of the 
subject from the study.
7.2.4.8
Electrocardiogram 
A 12-lead ECG will be performed at the screening visit (Visit 1), Visit 4, and Visit 6/ET. At 
screening, 3 ECGs taken approximately 3 minutes apart will be collected; if >32 days have 
passed since screening, these ECGS will be collected in triplicate at Visit (Visit 2) to ensure 
appropriate baseline intervals are established. Additional ECGs may be performed during the 
study at the investigator’s discretion.  


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All ECGs will be performed after 3 minutes of rest using the central ECG provider’s equipment 
and will be sent to the central ECG provider electronically.
The initial interpretation of the ECG, normal or abnormal and clinical significance, will be 
performed immediately after collection to ensure the safety of each subject. An ECG tracing will 
then be evaluated by a cardiologist at a central ECG reading vendor and returned to the site with 
a determination of normal or abnormal. Upon review of the report from this vendor, the 
investigator will re-evaluate the clinical significance of the ECG while taking into consideration 
all other safety data available for the subject.
Although a central ECG reader is being used for this study, the eligibility of the subject is based 
on the investigator’s assessment of the ECG. If abnormal and significant results are observed 
following assessment by the central reader, the investigator, in consultation with the appointed 
CRO medical monitor, reconfirms subject eligibility to continue.
All ECGs transmitted to the central ECG reader will be analyzed. If the central ECG reader 
receives multiple ECGs, the first readable ECGs will be analyzed as the scheduled ECG. Every 
ECG transmitted to the central ECG reader will have corresponding source document data 
collected. No ECG should be deleted by study site personnel. All ECGs must be transmitted to 
the central provider regardless of quality, results, or number of ECGs taken at a respective visit.
7.2.4.9
Children’s Sleep Habits Questionnaire  
The CSHQ is a tool designed to screen for the most common sleep problems in children and 
consists of 33 items for scoring and several extra items intended to provide administrators with 
other potentially useful information about respondents. The instrument evaluates the child’s 
sleep based on behavior within 8 different subscales: bedtime resistance, sleep onset delay, sleep 
duration, sleep anxiety, night wakings, parasomnias, sleep disordered breathing, and daytime 
sleepiness. The CSHQ will be conducted at each visit to the site starting with the baseline visit 
(Visit 2) and will be completed by the subject’s parent/LAR. 
7.2.4.10 Post Sleep Questionnaire 
The PSQ is a 7-item questionnaire typically used to assess sleep quality with pharmacologic 
treatment. The questionnaire collects data on average time to sleep, sleep latency, frequency of 
interrupted sleep, duration of interrupted sleep, total sleep time and sleep quality over the last 
week. The PSQ will be completed by the parent/LAR with the subject and the responses will be 
reviewed by the clinician during the study visit. The PSQ will be completed at Baseline (Visit 2), 
and each visit through Visit 6/ET. The title, version, and date of the PSQ version used in this 
study are included in Appendix 3.
7.2.4.11 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.


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The C-SSRS contains 2 required items pertaining to suicidal ideation, 4 required items pertaining 
to suicidal behavior, and 1 required item pertaining to nonsuicidal self-injurious behavior. There 
are 8 additional suicidal ideation items and 2 additional suicidal behavior items which are 
completed in cases of positive responses for other items, as well as 2 items for completed suicide 
and suicide behavior present during the interview. Thus, there is a maximum of 19 items to be 
completed.
The C-SSRS must be performed by an individual who is medically responsible for the subject. 
All individuals performing this assessment must be preapproved by the sponsor or delegated 
vendor.
Two versions of the C-SSRS are used in this study:

The “baseline” version will be administered at the screening visit (Visit 1) and will be 
completed for all subjects.

The “since last visit” version will be completed for all subjects at all study visits after the 
screening visit (Visit 1).
The title, version, and date of the C-SSRS “Baseline” version and the C-SSRS “since last visit” 
version used in this study are included in Appendix 3.
7.2.4.12 Suitability of the Subject to Remain in the Study 
At each visit (except for Visit 6/ET) starting with the baseline visit (Visit 2), the investigator will
assess the subject’s ability to continue in the study. The investigator or a medically qualified
designee will review all available safety information (including sleep behavior, weight and BMI) 
and will evaluate for the presence of insomnia or decreased appetite potentially leading to weight 
loss. In cases where the subject has clinically significant decreases in appetite or insomnia, the 
investigator should intervene as necessary based on clinical judgment (eg, diet, behavioral 
interventions, sleep hygiene) and consider discontinuation of treatment if necessary. In any cases 
where a subject has clinically significant and persistent sleep difficulties (eg, the CSHQ score of 
≥41 for 2 consecutive weeks since the beginning of treatment) or has had ≥7% weight loss the 
investigator must discuss the case with the medical monitor and assess whether it’s in the best 
interest for the subject to remain in the study. The evaluation and decision should also be clearly 
documented in the subject’s source notes.
As part of the assessment of the subject’s suitability to remain in the study the investigator 
should also assess the subject’s current potential for suicide, suicidal ideation, self-harm, or harm 
to others, as well as psychiatric disorders. The investigator should make this assessment by 
conducting a clinical interview with the subject and by reviewing of all other relevant sources 
available, including results of the C-SSRS. Any subject who has 1 or more positive responses 
must undergo further evaluation to ensure that they are not in any way at risk. As part of this 
assessment, if appropriate, the investigator should discuss risk factors for suicide with the 
subject. Where a subject has suffered an accidental injury, the investigator should ensure that this 
was a true accidental injury, rather than an episode of self-harming or a suicide attempt.


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The investigator should pay particular attention to:

Any ‘yes’ response to Items 2, 3, 4, or 5 on the C-SSRS or any suicidal behavior.
The subject’s source notes should clearly document that the assessment of continued suitability 
including assessment of the subject’s appetite, weight loss, insomnia and current potential risk of 
suicide, suicidal ideation, feelings of hopelessness, drug use, self-harm, or harm to others has 
taken place and should contain the decision on whether the subject is suitable to continue in the 
study.
7.2.5
Others
No clinical pharmacology, pharmacodynamic, pharmacogenomics, or health-related quality of 
life assessments will be performed.
7.2.6
Volume of Blood to be Drawn From Each Subject
Table 3:
Volume of Blood to be Drawn From Each Subject
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Safetya
Biochemistry and 
Choriogonadotropin 
Beta (-HCG)b
3
2
6
Hematology a
2
2
4
Total mL
10
-HCG= beta human chorionic gonadotropin 
a Biochemistry and hematology clinical laboratory tests will be repeated at baseline if 32 days or longer have elapsed since the 
screening visit (Visit 1).
b-HCG testing for females of childbearing potential only.
During this study, it is expected that approximately 10 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 10 mL. When more than 1 blood assessment is to be done at the time 
point/period, if they require the same type of tube, the assessments may be combined. If a 
catheter is used, the first 1 mL of blood from each sampling will be discarded.


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8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, Recording of Adverse Events
An AE is any untoward medical occurrence in a clinical investigation subject administered a 
pharmaceutical product and that does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product (ICH 
Guidance E2A 1995). 
All AEs are collected from the time the informed consent is signed until the defined follow-up 
period stated in Section 7.1.3. This includes events occurring during the screening phase of the 
study, regardless of whether or not investigational product is administered. Where possible, a 
diagnosis rather than a list of symptoms should be recorded. If a diagnosis has not been made, 
then each symptom should be listed individually. All AEs should be captured 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 pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after first 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded on the appropriate CRF).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.


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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
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.


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8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an AE 
if the change is clinically relevant or if, during treatment with the investigational product, a shift 
of a parameter is observed from a normal value to an abnormal value, or a further worsening of 
an already abnormal value. When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing treatment 
or after the end of treatment with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values which were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Pregnancy
All pregnancies are to be reported from the time informed consent is signed until the defined 
follow-up period stated in Section 7.1.3.
Any report of pregnancy for any female study participant must be reported within 24 hours to the 
Shire Pharmacovigilance Department using the Shire Investigational and Marketed Products 
Pregnancy Report Form. A copy of the Shire Investigational and Marketed Products Pregnancy 
Report Form (and any applicable follow-up reports) must also be sent to the CRO/Shire Medical 
Monitor using the details specified in the emergency contact information section of the protocol. 
The pregnant female study participant must be withdrawn from the study.
Every effort should be made to gather information regarding the pregnancy outcome and 
condition of the infant. It is the responsibility of the investigator to obtain this information within 
30 calendar days after the initial notification and approximately 30 calendar days post partum. 
Pregnancy complications such as spontaneous abortion/miscarriage or congenital abnormality 
are considered SAEs and must be reported using the Shire Clinical Trial Serious Adverse Event 
Form. Note:  An elective abortion is not considered an SAE.
In addition to the above, if the investigator determines that the pregnancy meets serious criteria, 
it must be reported as an SAE using the Shire Clinical Trial Serious Adverse Event Form as well 
as the Shire Investigational and Marketed Products Pregnancy Report Form. The test date of the 
first positive serum/urine -HCG test or ultrasound result will determine the pregnancy onset 
date.


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8.1.7
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 
nonmedical purpose (eg, to alter one’s state of consciousness or get high) in a manner that 
may be detrimental to the individual and/or society.

Misuse – Intentional use of investigational product other than as directed or indicated at 
any dose (Note: this includes a situation where the investigational product is not used as 
directed at the dose prescribed by the protocol).

Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding a prespecified total daily dose of 1 capsule of the product. 

Medication Error – An error made in prescribing, dispensing, administration, and/or use 
of an investigational product. For studies, medication errors are reportable to the sponsor 
only as defined 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 the unassigned treatment is/are always reportable 
as a medication error.
The administration and/or use of an expired investigational product should be considered as a 
reportable medication error. 
All investigational product provided to pediatric subjects should be supervised by the 
parent/LAR/caregiver.
8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the SHP465 investigator’s brochure which 
the sponsor has provided under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire 
Pharmacovigilance Department and the CRO/Shire Medical Monitor within 24 hours of the 
first awareness of the event. 


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Note: The 24-hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors (see Section 8.1.7) unless they result in an SAE. 
The investigator must complete, sign, and date the Shire Clinical Trial Serious Adverse Event 
Form and verify the accuracy of the information recorded on the form with the corresponding 
source documents (Note:  Source documents are not to be sent unless requested) and fax or 
e-mail the form to the Shire Pharmacovigilance Department. A copy of the Shire Clinical Trial 
Serious Adverse Event Form (and any applicable follow-up reports) must also be sent to the 
CRO/Shire Medical Monitor using the details specified in the emergency contact information 
section of the protocol.
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death.

Is life-threatening. Note: The term ‘life-threatening’ in the definition of “serious” refers to 
an event in which the subject was at risk of death at the time of the event; it does not refer 
to an event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note: 
Hospitalizations, which are the result of elective or previously scheduled surgery for 
pre-existing conditions, which have not worsened after initiation of treatment, should not 
be classified as SAEs. For example, an admission for a previously scheduled ventral hernia 
repair would not be classified as an SAE; however, complication(s) resulting from a 
hospitalization for an elective or previously scheduled surgery that meet(s) serious criteria 
must be reported as SAE(s).

Results in persistent or significant disability/incapacity.

Is a congenital abnormality/birth defect.

Is an important medical event. Note: Important medical events that may not result in death, 
be life-threatening, or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the subject and may require medical or 
surgical intervention to prevent 1 of the outcomes listed in this definition. Examples of 
such medical events include allergic bronchospasm requiring intensive treatment in an 
emergency room or at home; blood dyscrasias or convulsions that do not result in inpatient 
hospitalization; or the development of drug dependency or drug abuse. 
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3, and must be reported 
to the Shire Pharmacovigilance Department and the CRO/Shire Medical Monitor within 24 hours 
of the first awareness of the event. 


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In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire 
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 reported by the subject after signing the informed consent
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have fatal checked as an outcome with the date of death recorded as the resolution date. For 
all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, the 
action taken with the investigational product should be recorded as “dose not changed” or “not 
applicable” (if the subject never received investigational product).
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical CRO is responsible for notifying the relevant regulatory authorities 
and central IRBs of related, unexpected SAEs.
In addition the clinical CRO is responsible for notifying active sites of all related, unexpected 
SAEs occurring during all interventional studies across the SHP465 program. 
The investigator is responsible for notifying the local IRB, local EC, or the relevant local 
regulatory authority of all SAEs that occur at his or her site as required.


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9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the 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 as soon as possible after he subject's visit to ensure 
accuracy and completeness of data.
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, investigational product serum 
concentrations, 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, any data that may unblind study team personnel 
will be presented as blinded information or otherwise will not be made available. If applicable, 
unblinded data may be made available to quality assurance representatives for the purposes of 
conducting independent drug audits. 
9.4
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent. 
The SAP will provide the statistical methods and definitions for the analysis of the efficacy and 
safety data, as well as describe the approaches to be taken for summarizing other study 
information such as subject disposition, demographics and baseline characteristics, 
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.


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The SAP will be finalized prior to unblinding to preserve the integrity of the statistical analysis 
and study conclusions. 
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 
9.5
Data Monitoring Committee
An external independent Data Monitoring Committee (DMC) was set up to review the data 
pertaining to safety and tolerability of the study therapy for the duration of this program, which 
includes studies SHP465-112, SHP465-308, and SHP465-309. The DMC will review the data 
pertaining to safety and tolerability of the study therapy. Confidentiality of the unblinded DMC 
analyses is a critical concern and to address this, an unblinded independent reporting team will 
be identified within a CRO. The independent reporting team will have no involvement in the 
conduct of the study. Further details regarding the DMC can be found in the DMC charter, which 
will be available before the administration of investigational product. 
9.6
Planned Interim Analysis
A blinded interim analysis at the late stage of the trial (when approximately 75% of all 
randomized subjects have either completed or discontinued from the study) will be performed to 
reassess the sample size in case of an underestimated variability postulated at the design stage.
Using the cumulative real data, a blinded, pooled analysis of both treatment groups for 
estimating variability will be conducted. If the re-estimated pooled standard deviation is larger 
than the 14 postulated at the design stage, the final total number of subjects to be enrolled will be 
calculated using the re-estimated pooled standard deviation together with the assumed treatment
difference of 11.9 (Friede and Kieser 2006). If the re-estimated pooled standard deviation is 
smaller than 14, the sample size will not be adjusted.
9.7
Sample Size Calculation and Power Considerations
The sample size planned at study initiation was estimated for the primary comparison of SHP465 
at 6.25 mg with placebo by using nQuery Advisor 7.0. 
Approximately 60 subjects will be randomized in a 1:1 ratio to SHP465 at 6.25 mg and placebo 
to achieve 52 completers for the study (26 in each treatment group) and 85% power for the 
primary efficacy analysis at the 2-sided 0.05 significance level. The sample size planned is 
estimated based on the primary comparison between SHP465 at 6.25 mg and placebo on the 
primary efficacy endpoint, change from baseline in ADHD-RS-5 total score at Visit 6 (Week 4). 
Assumptions for the calculation include the true mean difference of 11.9 with the common 
standard deviation (SD) of 14 for the primary efficacy endpoint, for an effect size of 0.85, and a 
dropout rate of 15%.


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The effect size of 0.85 is low compared with that observed in recently completed study 
(SHP465-305) of children and adolescents aged 6-17 years with ADHD treated with SHP465. 
The SHP465-305 study yielded an effect size of 0.93 in children aged 6-12 years (101 subjects).
9.8
Study Population
The screened set will consist of all subjects who have provided consent.
The randomized set will consist of all subjects in the screened set for whom a randomization 
number has been assigned.
The safety 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 set who have at least 
1 post-dose ADHD-RS-5 Total Score.
9.9
Efficacy Analyses
All efficacy analyses will be performed using the FAS. All statistical tests will be 2-sided 
hypothesis tests. Also, all confidence intervals will be 2 sided with 95% coverage, unless stated 
otherwise. The primary and key secondary analyses will be conducted based on the entire age 
group in the FAS.
Handling of missing data rules will be described in the SAP.
9.9.1
Primary Efficacy Endpoint
The primary efficacy endpoint is defined as the change from baseline of the ADHD-RS-5 Total 
Score at Visit 6 (Week 4). The baseline ADHD-RS-5 Total Score is the last value obtained prior 
to taking the first dose of investigational product, usually at Visit 2. 
The primary efficacy analysis will be conducted over the FAS for the change from baseline in 
the ADHD-RS-5 Total Scores, including all assessments from Visit 3 (Week 1) up to Visit 6 
(Week 4). The primary efficacy endpoint will be analyzed by using the linear mixed-effects 
model for repeated measures (MMRM) with treatment group, visit, age group (6-8 years vs. 
9-12 years), and the interaction of treatment group with visit as factors, baseline ADHD-RS-5 
Total Score as a covariate, and the interaction of baseline ADHD-RS-5 Total Score with visit 
adjusted in the model. The primary contrast of interest will be at Visit 6 (Week 4) for SHP465 
6.25 mg compared with placebo at the 2-tailed significance level of 0.05.
The null and alternative hypotheses of the primary efficacy analysis will be the following:

Null hypothesis: There is no difference in primary endpoint mean change from baseline at 
Visit 6 (Week 4) in ADHD-RS-5 total scores between SHP465 6.25 mg and placebo

Alternative hypothesis: There is a difference in primary endpoint mean change from baseline 
at Visit 6 (Week 4) in ADHD-RS-5 total scores between SHP465 6.25 mg and placebo.


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As the primary efficacy analysis (MMRM) relies on the assumption that the missing data 
mechanism follows the MAR (missing-at-random) scenario, sensitivity analyses to examine the 
effect of data that are missing not at random and the robustness on the results of the primary 
analysis will be conducted. One sensitivity analysis model assumes that a subject on SHP465 
6.25 mg treatment with missing data follows the distribution of the placebo responses, ie, the 
means and the intrasubject correlations based on the placebo responses will apply. Another 
sensitivity analysis model assumes that subjects who drop out perform worse than MAR by a 
penalty. The details of the sensitivity analysis methods will be specified in the SAP. 
The observed and change from baseline ADHD-RS-5 Total Score will be summarized at each 
applicable visit using the number of subjects, mean, standard deviation, median, minimum, and 
maximum values.
9.9.2
Key Secondary Efficacy Endpoints
The key secondary efficacy endpoint, CGI-I, 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 primary contrast of interest will be at Visit 6 (Week 4) for SHP465 6.25 mg
compared with placebo at the 2-tailed significance level of 0.05. Appropriate sensitivity analyses 
to explore the effect of data that are missing not at random on the results of the key secondary 
efficacy analysis will be specified in the SAP.
The CGI-I will be summarized at each applicable visit using the number of subjects, mean, 
standard deviation, median, minimum, and maximum values.
The key secondary efficacy measurement will also be analyzed using the proportion of subjects 
with an “improved” CGI-I measurement at Visit 6/ET (Week 4/ET). 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”. If missing data 
exist at the Visit 6 (Week 4) visit, the visit will be imputed by carrying forward the last post 
baseline observation value. The secondary efficacy analysis for the dichotomized CGI-I will be 
conducted to compare SHP465 6.25 mg and placebo on the FAS for the “improved” rate using a 
Cochran-Mantel-Haenszel test stratified by age group and CGI-S value at baseline. 
The observed and dichotomized CGI-I values will be summarized at each applicable visit using 
number of subjects and percentages.
In order to protect the study-wide Type I error at the 2-sided 0.05 level for testing across the 
primary and the key secondary hypotheses, the Fixed-Sequence Test procedure will be applied. 
The hypotheses will be tested in order of the primary (ADHD-RS-5 Total Score) and then the 
key secondary (CGI-I), if significant for the primary, each at the 2-sided 0.05 significance level. 
Both tests in the sequence are based on the MMRM.


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9.9.3
Exploratory Efficacy Endpoints
Each ADHD-RS-5 subscale will be analyzed using a similar model as the primary efficacy 
endpoint and summarized descriptively at each visit by treatment group.
Treatment effect of SHP465 6.25 mg on primary and key secondary measures will be 
estimated using a similar model as the primary efficacy endpoint for each age group (6-8 years 
vs. 9-12 years), sex, race (white and nonwhite), and ethnicity subgroup.
The primary and key secondary data will be descriptively summarized by treatment within each 
sex, race (white and nonwhite), and ethnicity subgroup.
9.10 Safety Analyses
The safety data will be analyzed on the safety set. Safety endpoints include the occurrence of 
TEAEs, vital signs (systolic and diastolic blood pressure, pulse), BMI and weight, ECG results, 
clinical laboratory test results, and responses to CSHQ and C-SSRS.
Exposure to investigational product will be summarized.
Adverse events will be coded using the agreed upon version of the Medical Dictionary for 
Regulatory Activities. Treatment-emergent adverse events 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.
The number of events, incidence, and percentage of TEAEs will be calculated overall, by SOC, 
by preferred term, and by treatment group. Treatment-emergent adverse events will be further 
summarized by severity and relationship to investigational product. Adverse events related to 
investigational product, AEs leading to withdrawal, SAEs, and deaths will be similarly 
summarized/listed.
Vital signs (systolic and diastolic blood pressure, and pulse), weight, height, and BMI including 
potentially clinically important vital signs will be summarized by treatment and visit using the 
appropriate descriptive statistics.
The ECG results including potentially clinically important results will be summarized by 
treatment and visit. 
Clinical laboratory test results will be descriptively presented by treatment group for each visit. 
Shifts of clinical laboratory abnormality from baseline to Visit 6/ET will be presented. Number 
and percent of subjects with potentially clinically important laboratory values will be presented 
by treatment group.


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The PSQ results will be summarized by treatment and visit. Continuous variables, e.g., time to 
go to sleep and time spent awake, will be summarized using number of observations, mean and 
standard deviation, median, and minimum and maximum values. Categorical values, e.g., quality 
of sleep, will be summarized using number of observations and percentages. Detailed analyses of 
the PSQ will be described in the SAP.
The CSHQ results will be summarized by treatment and visit using appropriate descriptive 
statistics.  Detailed analyses of the CSHQ will be described in the SAP.
The C-SSRS results will be summarized and listings of the C-SSRS data will be provided for 
subjects with a positive response.
As the exploratory safety endpoint, the safety data on TEAEs will also be descriptively 
summarized by treatment within each age group (6-8 years vs. 9-12 years), sex, race (white and 
nonwhite), and ethnicity subgroup.
A listing of the C-SSRS data will be provided for subjects with a positive response. A listing of 
clinical laboratory data will be presented for all subjects.
As the exploratory safety endpoints, the safety data on TEAEs, vital signs, ECGs, clinical 
laboratory test results, PSQ and CSHQ will also be descriptively summarized by treatment 
within each age group.


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10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, EU Directive 
2001/20/EC and its updates, and local ethical and legal requirements. 
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996) and any updates, and EU 
Directive 2001/20/EC (2001), as well as all applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and CRFs in accordance with current GCP and the respective local and 
(inter)national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required prior to release of 
investigational product for shipment to the site.
10.1.2
Public Posting of Study Information
The sponsor is responsible for posting appropriate study information on applicable websites. 
Information included in clinical study registries may include participating investigators’ names 
and contact information.
10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for nonpediatric studies as per 
guidance. 
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies and IRBs/ECs are notified as appropriate. 


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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, EU Directive 2001/20/EC (2001), and applicable regulatory 
requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time and appropriately trained 
resources are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and 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.
A coordinating principal investigator is appointed to review the final clinical study report for 
multicenter studies. Agreement with the final clinical study report is documented by the signed 
and dated signature of the principal investigator (single-site study) or coordinating principal 
investigator (multicenter study), in compliance with Directive 2001/83/EC (2001) as amended by 
Directive 2003/63/EC (2003) and ICH Guidance E3 (1996). 
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.
If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.


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Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or for 
multicenter studies, the coordinating principal investigator according to national provisions and 
will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1 Case Report Forms
Case report forms (CRFs) are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
All data sent to the sponsor must be endorsed by the investigator.
The clinical research associate (CRA)/study monitor will verify the contents against the source 
data per the monitoring plan. If the data are unclear or contradictory, queries are sent for 
corrections or verification of data.
10.2.3.2 Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file and original clinical laboratory reports.
All key data must be recorded in the subject’s medical records.
The investigator must permit authorized representatives of the sponsor, the respective national, 
local, or foreign regulatory authorities, the IRB/EC, and auditors to inspect facilities and to have 
direct access to original source records relevant to this study, regardless of media.
The CRA/study monitor (and auditors, IRB/EC or regulatory inspectors) may check the CRF 
entries against the source documents. The consent form includes a statement by which the 
subject agrees to the monitor/auditor from the sponsor or its representatives, national or local 
regulatory authorities, or the IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays etc). These records must be made 
available within reasonable times for inspection and duplication, if required, by a properly 
authorized representative of any regulatory agency (eg, the US FDA, EMA, UK Medicines and 
Healthcare products Regulatory Agency) or an auditor.


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Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3 Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, for example, the US FDA (as well as other US 
national and local regulatory authorities), the EMA, the Medicines and Healthcare products 
Regulatory Agency, other regulatory authorities, the sponsor or its representatives, and the 
IRB/EC for each site.
10.2.3.4 Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in 21 CFR 54 2(b) (1998).
10.2.4
Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation
When using controlled substances, biohazardous material, or substances for infectious diseases, 
the investigator must at all times comply with all local, state, and national laws pertaining to 
registration and reporting with the appropriate regulatory body and control and handling of such 
substances.
10.3
Ethical Considerations
10.3.1
Informed Consent
It is the responsibility of the investigator to obtain written informed consent and assent, where 
applicable from all study subjects prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject and/or the subject’s parent/LAR, as applicable, is requested to 
sign and date the subject informed consent form or a certified translation if applicable, after the 
subject has received and read (or been read) the written subject information and received an 
explanation of what the study involves, including but not limited to: the objectives, potential 
benefits and risk, inconveniences, and the subject’s rights and responsibilities. A copy of the 
informed consent and assent documentation (ie, a complete set of subject information sheets and 
fully executed signature pages) must be given to the subject or the subject’s parent/LAR, as 
applicable. This document may require translation into the local language. Signed consent forms 
must remain in each subject’s study file and must be available for verification at any time.


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Within the source documents, site personnel should document instruction of and understanding 
by the parent/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 
where applicable which was reviewed by the IRB/EC and which received their favorable
opinion/approval. A copy of the IRB/EC’s written favorable opinion/approval of these 
documents must be provided to the sponsor, prior to the start of the study unless it is agreed to 
and documented (abiding by regulatory guidelines and national provisions) prior to study start 
that another party (ie, sponsor or coordinating principal investigator) is responsible for this 
action. Additionally, if the IRB/EC requires modification of the sample subject information and 
consent document provided by the sponsor, the documentation supporting this requirement must 
be provided to the sponsor.
10.3.2
Institutional Review Board or Ethics Committee
It is the responsibility of the investigator to submit this protocol, the informed consent document 
(approved by the sponsor or their designee), relevant supporting information and all types of 
subject recruitment information to the IRB/EC for review, and all must be approved prior to site 
initiation.
Responsibility for coordinating with IRBs/ECs is defined in the investigator agreement.
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 sponsor 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; this can be done by the 
sponsor, the investigator or for multicenter studies the coordinating principal investigator. The 
investigator must also keep the local IRB/EC informed of any serious and significant AEs.
10.4
Privacy and Confidentiality
All US-based sites and laboratories or entities providing support for this study, must, where 
applicable, comply with HIPAA of 1996. A site that is not a covered entity as defined by HIPAA 
must provide documentation of this fact to the CRO.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.


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After subjects have consented to take part in the study, the sponsor and/or its representatives 
reviews their medical records and data collected during the study. These records and data may, in 
addition, be reviewed by others including the following: independent auditors who validate the 
data on behalf of the sponsor; third parties with whom the sponsor may develop, register, or 
market SHP465; national or local regulatory authorities; and the IRB(s) /EC(s) which gave 
approval for the study to proceed. The sponsor and/or its representatives accessing the records 
and data will take all reasonable precautions in accordance with applicable laws, regulations, and 
guidelines to maintain the confidentiality of subjects’ identities.
Subjects are assigned a unique identifying number; however, their initials and date of birth may 
also be collected and used to assist the sponsor to verify the accuracy of the data (eg, to confirm 
that laboratory results have been assigned to the correct subject). 
The results of studies – containing subjects’ unique identifying number, relevant medical 
records, and possibly initials and dates of birth – will be recorded. They may be transferred to, 
and used in, other countries which may not afford the same level of protection that applies within 
the countries where this study is conducted. The purpose of any such transfer would include: to 
support regulatory submissions, to conduct new data analyses to publish or present the study 
results, or to answer questions asked by regulatory or health authorities.
10.5
Study Results/Publication Policy
Shire will endeavor to publish the results of all qualifying, applicable, and covered studies 
according to external guidelines in a timely manner regardless of whether the outcomes are 
perceived as positive, neutral, or negative. Additionally, Shire adheres to external guidelines (eg, 
Good Publication Practices 2) when forming a publication steering committee, which is done for 
large, multicenter Phase 2-4 and certain other studies as determined by Shire. The purpose of the 
publication steering committee is to act as a noncommercial body that advises or decides on 
dissemination of scientific study data in accordance with the scope of this policy.
All publications relating to Shire products or projects must undergo appropriate technical and 
intellectual property review, with Shire agreement to publish prior to release of information. The 
review is aimed at protecting the sponsor’s proprietary information existing either at the 
commencement of the study or generated during the study. To the extent permitted by the 
publisher and copyright law, the principal investigator will own (or share with other authors) the 
copyright on his/her publications. To the extent that the principal investigator has such sole, 
joint or shared rights, the principal investigator grants the sponsor a perpetual, irrevocable, 
royalty- free license to make and distribute copies of such publications.
The term “publication” refers to any public disclosure including original research articles, review 
articles, oral presentations, abstracts and posters at medical congresses, journal supplements, 
letters to the editor, invited lectures, opinion pieces, book chapters, electronic postings on 
medical/scientific websites, or other disclosure of the study results, in printed, electronic, oral or 
other form.


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Subject to the terms of the paragraph below, the investigator shall have the right to publish the 
study results, and any background information provided by the sponsor that is necessary to 
include in any publication of study results, or necessary for other scholars to verify such study 
results. Notwithstanding the foregoing, no publication that incorporates the sponsor’s 
confidential information shall be submitted for publication without the sponsor’s prior written 
agreement to publish, and shall be given to the sponsor for review at least 60 days prior to 
submission for publication. If requested in writing by 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 
current standards. Participation as an investigator does not confer any rights to authorship of 
publications.


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REFERENCES
American Psychiatric Association 2000. American Psychiatric association: Diagnostic and 
statistical manual of mental disorders, fourth edition, text revision. American Psychiatric 
Association, Washington, DC. 
Barkley RA 1998. Developmental course, adult outcome, and clinic-referred ADHD adults. In: 
Attention Deficit Hyperactivity Disorder: A Handbook for Diagnosis and Treatment, second 
edition. Guilford Press: New York, NY; 186-224. 
Biederman J, Faraone S, Milberger S, Curtis S, Chen L, Marrs A, et al. 1996. Predictors of 
persistence and remission of ADHD into adolescence: Results from a four-year prospective 
follow-up study. J Am Acad Child Adolesc Psychiatry; 35(3): 343-51. 
Biederman J and Spencer T 1999. Attention-deficit/hyperactivity disorder (ADHD) as a 
noradrenergic disorder. Biol Psychiatry; 46(9): 1234-42. 
Brown T 2000. Attention-deficit disorders and comorbidities in children, adolescents, and adults. 
American Psychiatric Press Washington DC. 
Buitelaar JK, Michelson D, Danckaerts M, Gillberg G, Spencer TJ, Zuddas A, et al. 2007, A 
randomized, double-blind study of continuation treatment for attention-deficit/hyperactivity 
disorder after 1 year. Biol Psychiatry; 61(5): 694-9. 
Centers for Disease Control and Prevention 2005. Prevalence of Diagnosis and Medication 
Treatment for Attention-Deficit/Hyperactivity Disorder – United States, 2003. MMWR; 
54(34): 842-7. 
Döpfner M, Steinhausen HC, Coghill D, Dalsgaard S, Poole L, Ralston SJ, et al. 2006. Cross-
cultural reliability and validity of ADHD assessed by the ADHD Rating Scale in a pan-
European study. Eur Child Adolesc Psychiatry; 15(Suppl 1): 146–55. 
DuPaul GJ, Power TJ, Anastopoulos AD, Reed R 2016. ADHD rating scale-5 for Children and 
Adolescents: checklists, norms and clinical interpretation: Guilford Press: New York, NY.
Faraone SV, Biederman J, Spencer TJ, Aleardi M 2006. Comparing the efficacy of medications 
for ADHD using meta-analysis. Med Gen Med; 8(4): 4. 
Faraone SVand Biederman J. Neurobiology of attention-deficit hyperactivity disorder 1998. Biol 
Psychiatry; 44(10): 951-8. 
Findling RL, Short EJ, Manos MJ 2001. Developmental aspects of psychostimulant treatment in 
children and adolescents with attention-deficit hyperactivity disorder. J Am Acad Child 
Adolesc Psychiatry; 40(12):1441-7. 
Friede T and Kieser M 2006. Sample Size Recalculation in Internal Pilot Study Designs: A 
Review. Biometrical Journal 48 (4): 537–555.
Guy W, (ed) 1976. Clinical global impressions (CGI). In: ECDEU assessment manual for 
psychopharmacology. Rockville (MD): US Department of Health, Education, and Welfare, 
217-222.


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Kratochvil CJ, Bohac D, Harrington M, Baker N, May D, Burke, WJ 2001. An open-label trial of 
tomoxetine in pediatric attention deficit hyperactivity disorder. J Child Adolesc 
Psychopharmacol; 11(2): 167-70. 
Mannuzza S, Klein RG, Bessler A, Malloy P, LaPadula M 1998. Adult psychiatric status of 
hyperactive boys grown up. Am J Psychiatry; 155(4): 493-8. 
Michelson D, Faries D, Wenicke J, Kelsey D, Kendrick K, Sallee FR et al. 2001. Atomoxetine in 
the treatment of children and adolescents with attention-deficit/hyperactivity disorder: a 
randomized, placebo-controlled, dose-response study. Pediatrics; 108(5): E83.
National Institutes of Health 2004. The fourth report on the diagnosis, evaluation, and treatment
of high blood pressure in children and adolescents. Pediatrics; 114 (2 suppl): 555-76. 
Ostchega Y, Porter KS, Hughes J, Dillon CF, Nwankwo T 2011. Resting pulse rate reference 
data for children, adolescents, and adults: United States, 1999-2008. Natl Health Stat 
Report; (41): 1-16. 
Posner K 2007. Suicidality issues in clinical trials: Columbia suicidal adverse event 
identification in FDA safety analyses. Division of Metabolism and Endocrinology Products 
Advisory Committee Meeting, Food and Drug Administration.
Rowland AS, Lesesne CA, Abramowitz AJ 2002. The epidemiology of attention-
deficit/hyperactivity disorder (ADHD): a public health view. Ment Retard Dev Disabil Res 
Rev; 8(3): 162-70. 
Sheehan DV, Sheehan KH, Shytle RD, Janavs J, Bannon Y, Rogers JE, Milo KM, Stock SL, 
Wilkinson B 2010. Reliability and validity of the Mini International Neuropsychiatric 
Interview for Children and Adolescents (MINI-KID). J Clin Psychiatry; 71(3): 313-26.
Spencer T, Biederman J, Heiligenstein J, Wilens T, Faries D, Prince J, et al. 2001 An open-label, 
dose-ranging study of atomoxetine in children with attention deficit hyperactivity disorder. J 
Child Adolesc Psychopharmacol; 11(3): 251-65. 
Szatmari, P., Offord, D. R. & Boyle, M. H. 1989. Ontario Child Health Study: prevalence of 
attention deficit disorder with hyperactivity. J Child Psychol Psychiatry; 30, 219-30.
Thapar, A. 2003. Attention deficit hyperactivity disorder: New genetic findings, new directions.
In: Behavioral genetics in the postgenomic era. American Psychological Association. 
Washington, DC, pp. 445-462.
Wallis, D., Russell, H. F. & Muenke, M. 2008. Review: Genetics of attention 
deficit/hyperactivity disorder. J Pediatr Psychol, 33, 1085-99.
Weiss M, Tannock R, Kratochvil C, Dunn D, Velez-Borras J, Thomason C, et al. 2005. A 
Randomized, placebo-controlled study of once-daily atomoxetine in the school setting in 
children with ADHD. J Am Acad Child Adolesc Psychiatry; 44(7): 647-55.
Wilens TE and Spencer TJ 2000. The stimulants revisited. Child Adolesc Psychiatr Clin N Am; 
9(3): 573-603.


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Wilens TE, Spencer TJ, Biederman J, Girard K, Doyle R, Prince J, et al. 2001. A controlled 
clinical trial of bupropion for attention deficit hyperactivity disorder in adults. Am J 
Psychiatry; 158(2): 282-8.
Zametkin AJ and Ernst M 1999. Problems in the management of attention-deficit-hyperactivity 
disorder. N Engl J Med; 340(1): 40-6.


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12
APPENDICES




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APPENDIX 2
DIAGNOSTIC CRITERIA/DISEASE CLASSIFICATION
APPENDIX 2.1
DSM-5 CRITERIA FOR ATTENTION 
DEFICIT/HYPERACTIVITY DISORDER  
A. Either (1) or (2):
(1) Six (or more) of the following symptoms of inattention have persisted for at least 
6 months to a degree that is maladaptive and inconsistent with developmental level:
Inattention
a)
often fails to give close attention to details or makes careless mistakes in 
schoolwork, work or other activities
b)
often has difficulty sustaining attention in tasks or play activities
c)
often does not seem to listen when spoken to directly
d)
often does not follow through on instructions and fails to finish schoolwork, 
chores, or duties in the workplace (not due to oppositional behavior or failure to 
understand instructions)
e)
often has difficulty organizing tasks and activities
f)
often avoids, dislikes, or is reluctant to engage in tasks that require sustained 
mental effort (such as schoolwork or homework)
g)
often loses things necessary for tasks or activities (eg, toys, school assignments, 
pencils, books, or tools)
h)
is often easily distracted by extraneous stimuli
i)
is often forgetful in daily activities
(2) Six (or more) of the following symptoms of hyperactivity-impulsivity have persisted for 
at least 6 months to a degree that is maladaptive and inconsistent with developmental level:
Hyperactivity
(a)
often fidgets with hands or feet or squirms in seat
(b)
often leaves seat in classroom or in other situations in which remaining seated is 
expected
(c)
often runs about or climbs excessively in situations in which it is inappropriate 
(in adolescents or adults, may be limited to subjective feelings of restlessness)
(d)
often has difficulty playing or engaging in leisure activities quietly
(e)
is often “on the go” or often acts as if “driven by a motor”
(f)
often talks excessively


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Impulsivity
(g)
often blurts out answers before questions have been completed
(h)
often has difficulty awaiting turn
(i)
often interrupts or intrudes on others (eg, butts into conversations or games)
B. Several inattentive or hyperactive-impulsive symptoms were present prior to age 12 years.
C. 
Several impairments from the symptoms are present in 2 or more settings (eg, at school 
[or work] and at home).
D. 
There is clear evidence of clinically significant impairment in social, academic, or 
occupational functioning.
E.
The symptoms do not occur exclusively during the course of a Pervasive Development 
Disorder, Schizophrenia, or other Psychotic Disorder and are not better accounted for 
by another mental disorder (eg, Mood Disorder, Anxiety Disorder, Dissociative 
Disorder, or a Personality Disorder).
Code based on type:
314.01 Attention-Deficit/Hyperactivity Disorder, Combined Type:
if both Criteria A1 and A2 are met for the past 6 months
314.00 Attention-Deficit/Hyperactivity Disorder, Predominately Inattentive Type:
if Criterion A1 is met but Criterion A2 is not met for the past 6 months
314.01 Attention-Deficit/Hyperactivity Disorder, Predominately Hyperactive-Impulsive 
Type: if Criterion A2 is met but Criterion A1 is not met for the past 6 months
From the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Copyright 2013 
American Psychiatric Association.


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APPENDIX 2.2
BOYS’ STATURE-FOR-AGE AND WEIGHT-FOR-AGE 
PERCENTILES 


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APPENDIX 2.3
BLOOD PRESSURE FOR BOYS BY AGE AND HEIGHT 
PERCENTILE 


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


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APPENDIX 2.4
GIRLS’ STATURE-FOR-AGE AND WEIGHT-FOR-AGE 
PERCENTILES


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APPENDIX 2.5
BLOOD PRESSURE LEVELS FOR GIRLS BY AGE AND 
HEIGHT PERCENTILE 


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


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

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
 
NCT Number:   
NCT03325881 
 
Study Title:  
A Phase 3, Randomized, Double-blind, Multi-center, Placebo-
controlled, Fixed-Dose, Efficacy, and Safety Study of SHP465 in 
Children Aged 6-12 Years with Attention-Deficit/Hyperactivity 
Disorder (ADHD) 
 
Study Number:  
SHP465-309 
 
SAP Version:   
Version 2  
 
SAP Version Date: 
16 August 2018 


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Statistical Analysis Plan
Protocol SHP465-309
Version 2.0/16 Aug 2018
Updates between Version 1.0 and Version 2.0
Section #
Changes
1
Added administrative changes to study protocol
2.5.1
Added a section for updated sample size based on blinded sample size re-estimation
5.4
Clarified definition of the full analysis set by adding the valid baseline ADHD-RS-5 
total score as a requirement.
9
Clarified the exposure and compliance analyses by age group
11.5
Added 2 sensitivity analyses
11.7
Clarified the subgroup analyses
12.1.1
Added “TERMINAL INSOMNIA” to the analysis for insomnia. 
12.2 (Table 3)
Modified the PCI criteria for Mean Corpuscular Hemoglobin (MCH)
12.6
Clarified TEAE summaries by age group
18
Added handling of the urine drug screen


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Statistical Analysis Plan
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TABLE OF CONTENTS
1.
INTRODUCTION ...................................................................................................................7
2.
STUDY DESIGN.....................................................................................................................8
2.1
General Study Design.................................................................................................8
2.2
Randomization ...........................................................................................................9
2.3
Blinding......................................................................................................................9
2.4
Schedule of Assessments .........................................................................................10
2.5
Determination of Sample Size..................................................................................13
2.5.1
Sample Size Update...............................................................................................13
2.6
Multiplicity Adjustments for Type I Error Control..................................................14
3.
OBJECTIVES........................................................................................................................15
3.1
Primary Objective ....................................................................................................15
3.2
Secondary Objectives...............................................................................................15
4.
ESTIMANDS.........................................................................................................................16
4.1
Primary Estimand.....................................................................................................16
4.2
Secondary Estimand.................................................................................................16
5.
SUBJECT POPULATION SETS ..........................................................................................17
5.1
Screened Set .............................................................................................................17
5.2
Randomized Set........................................................................................................17
5.3
Safety Set..................................................................................................................17
5.4
Full Analysis Set ......................................................................................................17
6.
SUBJECT DISPOSITION.....................................................................................................18
7.
PROTOCOL DEVIATIONS .................................................................................................19
8.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ................................20
8.1
Demographic and Other Baseline Characteristics....................................................20
8.2
Medical History........................................................................................................20
9.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE ......................................22
9.1
Exposure to Investigational Product ........................................................................22
9.2
Measurement of Treatment Compliance..................................................................22
10. PRIOR AND CONCOMITANT MEDICATION .................................................................24
11. EFFICACY ANALYSES ......................................................................................................25
11.1
Primary Efficacy Endpoint and Analysis.................................................................25
11.2
Key Secondary Efficacy Endpoint(s) and Analysis .................................................26
11.3
Adjustments for Multiplicity for the Primary and Key Secondary Endpoint...........26
11.4
Sensitivity Analysis Based on Missing Not at Random Assumptions.....................27
11.5
Other Sensitivity Analysis........................................................................................28
11.6
Other Secondary Efficacy Endpoint(s) and Analysis...............................................28


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Statistical Analysis Plan
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11.7
Exploratory Efficacy Endpoint(s) and Analysis.......................................................28
12. SAFETY ANALYSES...........................................................................................................30
12.1
Adverse Events.........................................................................................................30
12.1.1 Adverse Events of Special Interest ........................................................................31
12.2
Clinical Laboratory Variables ..................................................................................34
12.3
Vital Signs (Including Height and Weight)..............................................................37
12.4
Electrocardiogram (ECG).........................................................................................41
12.5
Other Safety Variables .............................................................................................42
12.5.1 Columbia-Suicide Severity Rating Scale (C-SSRS)..............................................42
12.5.2 Post Sleep Questionnaire (PSQ) ............................................................................42
12.5.3 Children’s Sleep Habit Questionnaire (CSHQ).....................................................43
12.6
Exploratory Safety Endpoints ..................................................................................43
13. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES...........44
14. OTHER ANALYSES ............................................................................................................45
15. INTERIM ANALYSIS ..........................................................................................................46
16. DATA MONITORING/REVIEW COMMITTEE ................................................................47
17. COMPUTER METHODS .....................................................................................................48
18. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL ................................................49
18.1
Handling of the Unintentional Urine Drug Screen...................................................49
19. DATA HANDLING CONVENTIONS.................................................................................50
19.1
General Data Reporting Conventions ......................................................................50
19.2
Derived Efficacy Endpoints .....................................................................................50
19.3
Association of Early Termination Assessments to Scheduled Visits.......................50
19.4
Repeated or Unscheduled Assessments of Safety Parameters.................................50
19.5
Missing Dispensed or Returned Date or Number of Capsules of 
Investigational Product.............................................................................................51
19.6
Missing Date Information for Prior or Concomitant Medications...........................51
19.6.1 Incomplete Start Date ............................................................................................51
19.6.2 Incomplete Stop Date.............................................................................................52
19.7
Missing Date Information for Adverse Events ........................................................53
19.8
Missing Severity Assessment for Adverse Events...................................................53
19.9
Missing Relationship to Investigational Product for Adverse Events......................53
19.10
Character Values of Clinical Laboratory Variables .................................................53
20. REFERENCES ......................................................................................................................54
21. TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS..............................55
22. APPENDICES .......................................................................................................................56
22.1
Appendix 1 Algorithms for Sample Size Re-estimation..........................................56
22.2
Appendix 2 Sample SAS Codes...............................................................................57


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LIST OF IN-TEXT TABLES
Table 1
Schedule of Assessments...............................................................................11
Table 2
Psychiatric Events .........................................................................................32
Table 3
Criteria for Potentially Clinically Important Laboratory Tests .....................36
Table 4
Criteria for Potentially Clinically Important Laboratory Tests .....................38
Table 5
Normal Range of Pulse Rate (beats/min) ......................................................39
Table 6
95th Percentile Cut-off Values of Blood Pressure Norms by Sex, Age, 
and Height Percentiles...................................................................................40
Table 7
Criteria for Potentially Clinically Important ECG Values ............................41
LIST OF IN-TEXT FIGURES
Figure 1
Study Design Flow Chart ................................................................................8


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Statistical Analysis Plan
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ABBREVIATIONS
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS-5
Attention-deficit/Hyperactivity Disorder Rating Scale-5
AE
adverse event
ANCOVA
Analysis of covariance
BMI
body mass index
CGI-I
Clinical Global Impressions–Improvement
CGI-S
Clinical Global Impressions–Severity of Illness
CI
confidence interval
CMH
Cochran–Mantel–Haenszel
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
CSHQ
Children’s Sleep Habits Questionnaire
DINFC
date of informed consent
DOB
date of birth
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition
ECG
electrocardiogram
eCRF
electronic case report form
ET
early termination
FAS
full analysis set
FDA
Food and Drug Administration
FoTA
Final on-Treatment Assessment
IWRS
interactive web response system
MAR
missing at random
MCH
mean corpuscular hemoglobin
MCHC
mean corpuscular hemoglobin concentration
MCV
mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MINI-KID
Mini International Neuropsychiatric Interview for Children and Adolescents
MMRM
mixed-effects model for repeated measures
MNAR
missing not at random
PCI
potentially clinically important
PSQ
Post Sleep Questionnaire
QT
QT interval of the cardiac cycle
QTcB
Bazett’s corrected QT interval
QTcF
Fridericia’s corrected QT interval
RBC
red blood cells
REML
restricted maximum likelihood
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOC
system organ class
TEAE
treatment-emergent adverse event
US
United States
WBC
white blood cells
WHO
World Health Organization


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Statistical Analysis Plan
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1.
INTRODUCTION
This statistical analysis plan (SAP) provides a technical and detailed elaboration of the statistical 
analyses of efficacy and safety data as described in the protocol dated 07 September 2017, the 
protocol administrative change #1 dated 20 Oct 2017, and the protocol administrative change #2 
dated 28 Nov 2017. Specifications for tables, figures, and listings are contained in a separate 
document. 




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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.
The actual treatment given to individual subjects is determined by a randomization schedule. 
Subjects who meet all inclusion criteria and none of the exclusion criteria will be randomized in 
a 1:1 ratio to either SHP465 6.25 mg or placebo. Randomization will be stratified to ensure 
approximately 50% of subjects in each age group (6-8 years and 9-12 years), and to facilitate 
balance of treatment allocation within each age group. The study is not powered to detect within 
age stratum treatment effects.
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).
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.
2.3
Blinding
This is a double-blind, placebo-controlled study. All investigational and reference product 
(SHP465 6.25 mg or placebo) will appear identical to protect the study blind.
Data that may potentially unblind the treatment assignment (i.e., 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, 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 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 will be recorded on the IWRS and the source 
documents. Upon breaking the blind, the subject will be 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 to Shire. Code-break information is held by the 
pharmacist/designated person at the site and by the CRO medical monitor/designated person for 


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Statistical Analysis Plan
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the study. There will be a provision for unblinding to ensure adequate treatment of the subject in 
the case of an emergency.
2.4
Schedule of Assessments
Table 1 below presents a schedule of study assessments.






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Statistical Analysis Plan
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2.5
Determination of Sample Size
The primary efficacy endpoint is defined as the change from baseline in the Attention-
deficit/Hyperactivity Disorder Rating Scale Version 5 (ADHD-RS-5) total score at Visit 6 (Week 
4). The baseline ADHD-RS-5 total score is the last value obtained prior to taking the first dose of 
investigational product, usually at Visit 2.
The null hypothesis is that there is no difference in mean change from baseline at Visit 6 (Week 
4) in ADHD-RS-5 total score between SHP465 6.25 mg and placebo, and the alternate 
hypothesis is that there is a difference in mean change from baseline at Visit 6 (Week 4) in 
ADHD-RS-5 total score between SHP465 6.25 mg and placebo.
The sample size was estimated for the primary comparison of SHP465 at 6.25 mg with placebo 
by using nQuery Advisor 7.0. To detect an assumed difference of 11.9 for the change from 
baseline in the ADHD-RS-5 total score between the SHP465 at 6.25 mg treatment group and the 
placebo group with the assumed common standard deviation (SD) of 14, 26 completers per 
group are needed to provide 85% power for a 2-sided t-test with α level of 0.05. This yields a 
total of 52 subjects (26 on active treatment and 26 on placebo). Taking into account an expected 
post-randomization dropout rate of 15%, the randomization target is set at 60 subjects in total.
The assumptions of a treatment difference of 11.9 and a standard deviation of 14.0 corresponds 
to an effect size of 0.85 which is low compared with that in recently completed study (SHP465-
305) of children and adolescents aged 6-17 years with ADHD treated with SHP465. The 
SHP465-305 study yielded an effect size of 0.93 in children aged 6-12 years (101 subjects).
A blinded interim analysis at the late stage of the trial (when approximately 75% of all 
randomized patients have either completed or discontinued from the study) is needed for a 
possible sample size increase in case of an underestimated variability postulated at the design 
stage (see Section 15).
The final total number of subjects randomized between the 2 groups will be calculated in the 
blinded interim analysis, based on the estimate of the pooled variance, as detailed in Section 15. 
The number of subjects could remain at 60, or could potentially be as high as 90, which 
corresponds to the 97.5th percentile of the distribution of the variance estimator based on the true 
standard deviation of 14.0. Note that the total of 90 subjects is not considered a cap. As the final 
sample size is data driven, a higher number, though unlikely, is possible.
2.5.1
Sample Size Update
Following the SAP Section 2.5 and the protocol Section 9.6, a blinded interim analysis for 
sample size re-estimation was performed based on 47 randomized subjects as of 19 March 2018 
(the interim cohort), among which 45 were in the FAS and 43 completed the study. Data of the 
interim cohort were extracted on 27 April 2018, after the collection of all their primary efficacy 
data.
The pooled standard deviation for Visit 6 (Week 4) used for sample size re-estimation was 
calculated using a pooled common variance that was estimated by using blinded cumulative 
primary efficacy data in the interim cohort. Then the final pooled standard deviation was 


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calculated as stated in Section 15 and Appendix 1. The interim analysis results showed a re-
estimated pooled standard deviation of 13.29 which is less than 14 and therefore an increase to 
the sample size was not required.
2.6
Multiplicity Adjustments for Type I Error Control
In order to protect the study-wide Type I error at the 2-sided 0.05 for testing across the primary 
and the key secondary hypotheses, the Fixed-Sequence Test procedure will be used (see Section 
11 for details).


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3.
OBJECTIVES
3.1
Primary Objective
The primary objective of this study is to evaluate the efficacy of SHP465 at 6.25 mg compared to 
placebo as a daily morning dose in children 6-12 years of age (inclusive at the time of consent)
diagnosed with ADHD. The primary measure of efficacy will be the clinician-administered 
ADHD-RS-5 Child Home Version total score.
3.2
Secondary Objectives
Key Secondary:

To assess the efficacy of SHP465 at 6.25 mg compared to placebo using a global clinical 
measure of improvement, the Clinical Global Impression of Improvement (CGI-I) scale.
Secondary:

To evaluate the safety and tolerability of SHP465 at 6.25 mg based on the occurrence of 
treatment-emergent adverse events (TEAEs), evaluation of vital signs (systolic and 
diastolic blood pressure and pulse), weight, height, body mass index (BMI), clinical 
laboratory and electrocardiogram (ECG) results, sleep assessment (Post Sleep 
Questionnaire [PSQ] and Child’s Sleep Habits Questionnaire [CSHQ]), and responses to 
the Columbia Suicide Severity Rating Scale (C-SSRS).


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4.
ESTIMANDS
4.1
Primary Estimand
The primary estimand is the mean change from baseline to Week 4 in ADHD-RS-5 total score 
between active (SHP465 6.25 mg) and placebo groups.

Population: 6-12 year old children with ADHD defined through inclusion and exclusion 
criteria as stated in the protocol

Variable: change from baseline to Week 4 in ADHD-RS-5 total score

Intercurrent event: had patients not discontinued treatment

Population-level summary: difference in mean change of ADHD-RS-5 total score from 
baseline to Week 4 between active (SHP465 6.25 mg) and placebo groups
4.2
Secondary Estimand
The key secondary estimand is the mean CGI-I value at Week 4 between active (SHP465 6.25 
mg) and placebo groups.

Population: 6-12 year old children with ADHD defined through inclusion and exclusion 
criteria as stated in the protocol

Variable: CGI-I value at Week 4

Intercurrent event: had patients not discontinued treatment

Population-level summary: difference in mean CGI-I value at Week 4 between active 
(SHP465 6.25 mg) and placebo groups


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5.
SUBJECT POPULATION SETS
The following subject sets are applicable to this study:
5.1
Screened Set
The Screened Set will consist of all subjects who have provided informed consent.
5.2
Randomized Set
The Randomized Set will consist of all subjects in the Screened Set for whom a randomization 
number has been assigned.
5.3
Safety Set
The Safety Set will consist of all subjects in the Randomized Set who have taken at least 1 dose 
of investigational product.
5.4
Full Analysis Set
The Full Analysis Set (FAS) will consist of all subjects in the Safety Set who have had the 
baseline ADHD-RS-5 total score and at least 1 post-dose ADHD-RS-5 total score.


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6.
SUBJECT DISPOSITION
A listing of all Screen Failures (i.e., 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 (i.e., Screened, Randomized, Safety, FAS) 
will be summarized by treatment group (SHP465 6.25 mg or Placebo) 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 
Treatment period will be presented for each treatment group and overall for the Safety Set. 
Reasons for premature discontinuation from the Treatment period, as recorded on the end of 
study discontinuation page of the electronic case report form (eCRF), will be summarized 
(number and percentage) by treatment group for the Safety Set. The subjects who completed the 
study are those that completed the final scheduled visit (Visit 6) at the end of the Treatment 
period.
In addition, the number and percentage of subjects who completed the study visits will be 
presented by visit for each treatment group and overall for the Safety Set.
All subjects who prematurely discontinued during the Treatment period will be listed by 
discontinuation reason for the Randomized Set.
Follow-up information, new (post-treatment) AEs and new (post-treatment) medication, will be 
listed for the Safety Set.


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7.
PROTOCOL DEVIATIONS
Protocol deviations and violations will be recorded by the site separately from the clinical 
database. The CRO/Shire will classify the protocol deviations and violations per the agreed 
protocol violation and deviation management plan. The Shire study team will review the protocol 
deviations and their classification throughout the study and before treatment unblinding and 
database lock.
Decisions of the review will include:

Accuracy of protocol deviations and violations categorization.
For any criteria for protocol deviations that can be completely implemented by a computer 
program, the detailed algorithm will be agreed upon. Details of such algorithms will be included 
in the derived dataset specifications and finalized before treatment unblinding.
Confirmed protocol violations and protocol deviations will be documented in the Protocol 
Violation/Deviation tracker for the study. Protocol deviations/violations will be summarized by 
category and site for each treatment group (SHP465 6.25 mg and Placebo) and overall, for the 
Safety Set. Protocol deviations/violations will be listed for the Randomized Set.


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8.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
8.1
Demographic and Other Baseline Characteristics
Descriptive summaries of demographic and baseline characteristics will be presented by 
treatment group (SHP465 6.25 mg and Placebo) and overall for the Safety Set and FAS.
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 following demographic characteristics will be summarized in the following order in the 
tables: age, sex, ethnicity, race, weight, height and body mass index (BMI). In addition, other 
baseline characteristics such as years since diagnosis of ADHD, ADHD Subtype, baseline 
ADHD-RS-5 total score, and baseline CGI-S will be summarized.
Age, weight, height, BMI, years since diagnosis of ADHD, ADHD-RS-5 total score will be 
summarized as continuous variables using number of subjects, mean and SD, median, and 
minimum and maximum values, while age (categorical), sex, ethnicity, race, and Baseline 
ADHD Subtype and CGI-S will be summarized as categorical variables using number of subjects 
and percentages for each category. All summarized values will be taken from the Screening Visit 
(Visit 1), except for baseline ADHD-RS-5 total score, baseline CGI-S, height, and weight. In 
addition, baseline weight and baseline height will be summarized in both conventional and 
international system of units.
Age will be calculated as the difference between date of birth (DOB) and date of informed 
consent (DINFC), truncated to months, using the following:

Age = floor((intck('month',DOB,DINFC) - (day(DINFC) < day(DOB))) / 12)
BMI will be calculated using one of the following:

Weight in pounds * 703 / (Height in inches)2

Weight in kilograms / (Height in meters)2
Number of years since diagnosis of ADHD will be based on the date of informed consent. 
Demographics and baseline characteristics will be listed for the Safety Set.
In addition, demographics and baseline characteristics tables will be repeated by age group (6-8 
years and 9-12 years).
8.2
Medical History
Medical history will be collected at the Screening Visit (Visit 1) and will be listed for the Safety
Set.


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The psychiatric diagnosis will be established with Mini International Neuropsychiatric Interview 
for Children and Adolescents (MINI-KID) at the Screening Visit (Visit 1) and will be listed for 
the Safety Set.
ADHD non-medication treatment history, behavioral therapy history, collected at the Screening 
Visit (Visit 1) will be listed for the Safety Set.


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9.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
9.1
Exposure to Investigational Product
Exposure to double-blind investigational product for the Safety Set will be summarized by visit 
for each treatment group and age group. The following statistics will be calculated by visit for 
the investigational product:

Days of dosing: number of days on which dose information was available and non-zero

Total dose (mg) for SHP465: total number of capsules taken × dose level

Average daily dose (mg/day) for SHP465: the total dose / total days of dosing

Cumulative dose (mg) for SHP465: sum of total dose since start of treatment

Duration of exposure in weeks: the total days of dosing / 7
An appropriate statistical summary will be applied to present for each of the above statistical 
quantities.
Subjects will be categorized in 1 week increments by their overall duration of exposure in days 
and will be presented using subject counts and percentages.
In addition, person-time (overall total exposure in days) will be derived for SHP465.  It is 
calculated as total number of days in which SHP465 was taken for each subject (total days of 
dosing for the Treatment period), and then sum over all subjects for the Treatment period.
All dosing information, for example, total dose, average daily dose and cumulative dose, will be 
listed.
If a 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 subjects who are lost in the follow up after the Baseline Visit (Visit 2), 
it will not be assumed that any of the investigational products has been ingested unless there is a 
post-baseline safety assessment. Subjects who do not return the investigational product but return 
to the site for the following visit will have the dose return information entered into the database 
on the scheduled visit.
9.2
Measurement of Treatment Compliance
Investigational product dosing compliance during the treatment period is defined as the total 
number of capsules actually taken by a subject during that period divided by the total number of 
capsules expected to be taken during the same period multiplied by 100. The total number of 
capsules actually taken is calculated by the total number of capsules dispensed minus the number 
of capsules returned. If a bottle is not returned, the number of capsules returned for that bottle 
will be imputed to zero. The number of capsules expected to be taken is calculated as the number 
of days the subject was in the treatment period multiplied by the number of capsules to be taken 
per day during the treatment period. Compliance rates will be calculated separately for SHP465
6.25 mg and placebo.


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Summary statistics for investigational product compliance will be presented by treatment group 
(SHP465 6.25 mg and Placebo) and by age group during the treatment period for the Safety Set. 
The investigation product treatment compliance will be categorized as <80%, 80-120%, or 
>120%. The category 80-120% is considered compliant. Categorical data will be presented for 
the Safety Set.
Calculated compliance data for each subject will be listed.


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10.
PRIOR AND CONCOMITANT MEDICATION
Version WHODRUG March 2017 of the WHO drug dictionary will be used to classify prior and 
concomitant medications by preferred term.
Prior medication is defined as any medication taken prior to the date of first dose of 
investigational product.
Concomitant medication is defined as any medication with a start date prior to the date of the 
first dose of investigational product and continuing after the first dose of investigational product 
or with a start date between the dates of the first dose and last dose of investigational product, 
inclusive.
Any medication with a start date after the date of the last dose of investigational product (post-
treatment) will not be considered a concomitant medication.
Both prior and concomitant medication usage will be summarized separately by the number and 
percentage of subjects receiving each medication within each preferred term by treatment group 
(SHP465 6.25 mg and Placebo) and overall for the Safety Set. Medications can be counted both 
as prior and concomitant medication. Multiple medication usage by a subject in the same 
category will be counted only once for the purpose of the summaries.
For ADHD medication history collected at the Screening Visit (Visit 1), version WHODRUG
March 2017 of the World Health Organization (WHO) drug dictionary will be used to classify 
ADHD medications by preferred term. ADHD medication history will be summarized separately 
by the number and percentage of subjects receiving each medication within each preferred term 
by treatment group (SHP465 6.25 mg and Placebo) for the Safety Set. ADHD medication history 
will be listed for the Safety Set.
All prior, concomitant and post-treatment medications will be listed for the Safety Set.


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11.
EFFICACY ANALYSES
All efficacy analyses will be performed using the FAS. All statistical tests will be 2-sided 
hypothesis tests performed at the 0.05 level of significance. All confidence intervals (CI) will be
2-sided 95% CIs, unless stated otherwise. Only post-baseline assessments from Visit 3 (Week 1) 
up to Visit 6 (Week 4) that were collected on or before 2 days after the last dose of double-blind 
investigational product will be analyzed.
11.1
Primary Efficacy Endpoint and Analysis
The primary efficacy endpoint is defined as the change from baseline of the ADHD-RS-5 total 
score at Visit 6 (Week 4). Baseline ADHD-RS total score is defined as the last valid ADHD-RS-
5 total score assessment prior to taking the first dose of double-blind investigational product, 
usually at Visit 2 (Week 0).
The primary efficacy analysis will be conducted on the FAS for the change from baseline for the 
ADHD-RS-5 total score, including all assessments from Visit 3 (Week 1) up to Visit 6 (Week 4). 
The primary efficacy endpoint will be analyzed by using the linear mixed-effects model for 
repeated measures (MMRM) with treatment group (SHP465 6.25 mg and Placebo), visit, age 
group (6-8 years vs. 9-12 years) and the interaction of treatment group with visit as factors, 
baseline ADHD-RS-5 total score as a covariate, and the interaction of baseline ADHD-RS-5 total 
score with visit adjusted in the model.
The REML (restricted maximum likelihood) method of estimation, which is default in SAS, will 
be utilized along with the Kenward-Roger method for estimating the covariance matrix and 
degrees of freedom. The model will use an unstructured covariance type. 
The primary contrast of interest will be at Visit 6 (Week 4) for SHP465 6.25 mg compared with 
placebo.
The null and alternative hypotheses of the primary efficacy analysis are:

Null hypothesis: There is no difference in mean change from baseline at Visit 6 (Week 4) in 
ADHD-RS-5 total score between SHP465 6.25 mg and placebo;

Alternative hypothesis: There is a difference in mean change from baseline at Visit 6 
(Week 4) in ADHD-RS-5 total score between SHP465 6.25 mg and placebo.
Descriptive statistics will be displayed for each treatment group and visit, as well as the least 
squares means and standard errors resulting from the MMRM. To compare SHP465 6.25 mg and 
placebo, the difference of least squares means, the corresponding 95% CI, and the effect size 
(Cohen’s d) at Visit 6 (Week 4), defined as difference of the least squares means divided by the 
square root of the variance estimate at Visit 6 obtained from the SAS-estimated R matrix, will be 
displayed (Cohen, 1988). The p-value and effect size will only be presented for Visit 6 (Week 4).
A corresponding line graph of the least squares means of change from baseline and associated
95% CI in ADHD-RS-5 total score by visit and treatment group will be presented.


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The observed and change from baseline in ADHD-RS total score will be summarized at each 
applicable visit using the number of subjects, mean, SD, median, minimum, and maximum 
values.
The items in the ADHD-RS-5 will also be grouped into 2 subscales: hyperactivity/impulsivity (9 
items for hyperactivity/impulsivity) and inattentiveness (9 items for inattentiveness). Each 
subscale will be analyzed using a similar model as the primary efficacy endpoint and 
summarized descriptively at each visit by treatment group. A corresponding line graph of the 
least squares means of change from baseline and associated 95% CI in ADHD-RS-5 subscale 
scores by visit and treatment group will be presented.
11.2
Key Secondary Efficacy Endpoint(s) and Analysis
The key secondary efficacy endpoint, CGI-I score, will be analyzed using the same analysis 
method (MMRM) as for the primary efficacy endpoint for the Full Analysis Set. The baseline 
CGI-S score will be used as the covariate. The primary contrast of interest will be at Visit 6 
(Week 4) for SHP465 6.25 mg compared with placebo.
The CGI-I will be summarized descriptively at each applicable visit using the number of 
subjects, mean, SD, median, minimum, and maximum values.
As a supportive analysis, the key secondary efficacy measurement will also be analyzed using 
the proportion of subjects with an "improved" CGI-I measurement at Visit 6/ET (Week 4/ET). 
The CGI-I categories will be dichotomized into 2 categories; "very much improved" and "much 
improved" classified as "improved" (CGI-I score of 1 or 2) and all other assessed categories 
grouped together as "not improved" (CGI-I score of >2). If missing data exist at the Visit 6 
(Week 4) visit, the visit will be imputed by carrying forward the last post-baseline observation 
value. The dichotomized CGI-I will be analyzed by comparing SHP465 6.25 mg and placebo on 
the FAS for the proportion of “improved” subjects using a Cochran-Mantel-Haenszel test 
stratified by age group and CGI-S value at baseline.
The observed and dichotomized CGI-I values will be summarized at each applicable visit using 
number of subjects and percentages as well.
A corresponding bar chart showing the percentage of subjects improved by visit and treatment 
group will be presented. CGI-I values and CGI-S values will be listed for FAS.
11.3
Adjustments for Multiplicity for the Primary and Key Secondary Endpoint
In order to protect the study-wide Type I error at the 2-sided 0.05 for testing across the primary 
and the key secondary hypotheses, the Fixed-Sequence Test procedure will be applied. The 
hypotheses will be tested in the order of the primary (ADHD-RS-5 Total Score) and then the 
secondary (CGI-I), if significant for the primary, each at the 2-sided 0.05 significance level. Both 
tests in the sequence are based on the MMRM.


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11.4
Sensitivity Analysis Based on Missing Not at Random Assumptions
The primary efficacy analysis (MMRM) relies on the assumption that the missing data 
mechanism follows the MAR (missing at random) scenario. It is assumed that the probability of 
missing data is unrelated to the value of the variable, after controlling for other variables in the 
data.  The likelihood-based MMRM analysis is considered an appropriate method for the 
statistical analysis under MAR assumptions.
The following 2 sensitivity analysis models will be used to examine robustness of the primary 
analysis results. The sensitivity analysis models assume different MNAR mechanisms and are 
within the pattern-mixture model framework.
Model 1 - Placebo multiple imputations
Rationale: The imputations are based on the distribution of placebo group responses over time. 
The underlying assumption is that a subject on SHP465 6.25 mg treatment with missing data 
follows the distribution of the placebo responses, i.e., the means and the intra-subject 
correlations based on the placebo responses will apply.
The model is implemented in 3 steps: 1. imputations, 2. analysis of complete data sets, and 3. 
inference.  Sample SAS codes are provided in Section 22.
Step 1: Imputations
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 SHP465 6.25 mg treatment group, the other 100 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 sets for imputations within a treatment group will be ordered from 1 
to 100, and combined between the SHP465 6.25 mg treatment group and placebo, for a total of
100 completely imputed data sets.
Step 2: Analysis of complete data sets
The primary endpoint will be analyzed for each of the 100 complete data sets with imputed data 
using an ANCOVA with treatment and age group as the factor and the baseline value as a 
covariate.
Step 3: Inference
The LS mean difference estimates will be averaged and the associated standard errors 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.
Model 2 - Multiple imputations with penalties applied to dropouts
Rationale: The underlying assumption is that subjects who drop out perform worse than MAR by 
a penalty.


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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 
Section 22.
Step 1a: Imputations
Missing data will be multiply imputed for 100 times based on a treatment specific, multivariate 
normal distribution of the response over time 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 Visit 6 (Week 4).  The penalty 
will be a fraction of the estimated SD for the primary endpoint (the square root of the estimated 
element for Visit 6 of the co-variance matrix R from the primary MMRM model): (0*SD), 
(0.25*SD), (0.5*SD), (0.75*SD), and (1*SD).
Step 2 (analysis of complete data sets) and Step 3 (inference) are the same as Steps 2 and 3 
respectively for Model 1.
11.5
Other Sensitivity Analysis
Other sensitivity analyses will be used to examine 2 different issues in this study:
1. Robustness of the key secondary efficacy analysis (MMRM) results for the CGI-I will be 
examined using the 2 sensitivity analysis models described in Section 11.4.
2. Impact of potential unblinding of 10 subjects due to unintentional urine drug screen 
performed erroneously after the final on-treatment assessments (see Section 18.1 for further 
details)
To evaluate whether the potential unblinding modified the efficacy results, sensitivity analyses of 
the primary efficacy (ADHD-RS-5 total score) and key secondary efficacy (CGI-I) analyses will 
be performed, in which these 10 subjects will be excluded from the FAS. The results between the 
primary and key secondary efficacy analyses and the sensitivity analyses will be examined.
11.6
Other Secondary Efficacy Endpoint(s) and Analysis
No other secondary efficacy endpoints are defined for this study.
11.7
Exploratory Efficacy Endpoint(s) and Analysis
The primary efficacy endpoint, change from baseline of the ADHD-RS-5 total score at Visit 6 
(Week 4), will be analyzed separately for age group (6-8 years and 9-12 years), sex group (male 
and female), race group (white and non-white), and ethnicity group, using the same analysis 
method (MMRM) as for the primary efficacy endpoint, with treatment group, visit, age group (6-
8 years vs. 9-12 years) and the interaction of treatment group with visit as factors, baseline 
ADHD-RS-5 total score as a covariate, and the interaction of baseline ADHD-RS-5 total score 
with visit adjusted in the model. The age group will not be included as a factor for the subgroup 


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analysis for age group. ADHD-RS subscales will also be analyzed separately for age group (6-8
years and 9-12 years) using a similar model as the primary efficacy endpoint.
Descriptive statistics will be displayed for each treatment group within each age group, sex 
group, race group, and ethnicity group as well as the least squares means and standard errors 
resulting from the MMRM. To compare SHP465 6.25 mg and placebo, the difference of least 
squares means and the corresponding 95% CI, and the effect size (defined as difference of the 
least squares means divided by the estimated SD from the unstructured covariance matrix) will 
be displayed. The effect size will only be presented for Visit 6 (Week 4). In addition, the ADHD-
RS total score will be summarized at each visit by treatment group for each age group (6-8 years 
and 9-12 years), sex group (male and female), race group (white and non-white), and ethnicity 
group. ADHD-RS subscales will also be summarized at each visit by treatment group and age 
group (6-8 years and 9-12 years).
The key secondary efficacy endpoint, CGI-I score, will be analyzed separately for each age 
group (6-8 years and 9-12 years), sex group (male and female), race group (white and non-
white), and ethnicity using the same analysis method (MMRM) as for the primary efficacy 
endpoint with treatment group, visit, and the interaction of treatment group with visit as factors, 
and baseline CGI-S score used as a covariate, and interaction of the baseline CGI-S score with 
the visit adjusted in the model.


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12.
SAFETY ANALYSES
Safety data will be analyzed for the Safety Set. Safety endpoints include the occurrence of 
TEAEs, vital signs (systolic and diastolic blood pressure, pulse, temperature, and respiration 
rate), height and weight, ECG results, C-SSRS, PSQ, and CSHQ. For each safety endpoint, the 
last value collected before the first dose of double-blind investigational product will be used as 
baseline for all analyses of that safety endpoint. Except for AE data, only post-baseline 
assessments from Visit 2 (Week 0) up to Visit 6 (Week 4) that were collected on or before 2 days 
after the last dose of double-blind investigational product will be analyzed. A Final on-Treatment 
Assessment (FoTA) will be defined as the last valid assessment obtained after Baseline and 
whilst on investigational product (on or before 2 days after the last dose date).
12.1
Adverse Events
Adverse events will be coded using Version 18.0 of Medical Dictionary for Regulatory Activities
(MedDRA).
An AE (classified by preferred term) that occurs during the Treatment period will be considered 
a TEAE if it has a start date on or after the first dose of double-blind investigational product or if 
it has a start date before the date of the first dose of double-blind investigational product, but 
increases in severity on or after the date of the first dose of double-blind investigational product. 
An AE that occurs after more than 3 days of the last dose of double-blind investigational product 
will not be counted as a TEAE. If more than 1 AE with the same preferred term is reported 
before the date of the first dose of double-blind investigational product, then the AE with the 
greatest severity will be used as the benchmark for comparison to the AEs occurring during the 
Treatment period under the preferred term.
An overall summary of the number of subjects with TEAEs in each treatment group will be 
presented, including the number and percentage of subjects with any TEAEs, serious TEAEs, 
TEAEs related to investigational product, TEAEs leading to drug withdrawal, severe TEAEs and 
serious TEAEs leading to death.
The number and percentage of subjects reporting TEAEs in each treatment group will be 
tabulated by system organ class (SOC) and preferred term; by SOC, preferred term, and severity; 
and by SOC, preferred term, and relationship to investigational product. If more than 1 AE 
occurs with the same preferred term for the same subject, then the subject will be counted only 
once for that preferred term using the most severe and most related occurrence for the 
summarization by severity and by relationship to investigational product.
The incidence of common (≥ 2% of subjects in any treatment group) will be summarized by 
preferred term and treatment group, sorted in decreasing frequency for subjects on SHP465 6.25 
mg, and then for placebo. The incidence of TEAEs, serious TEAEs, and TEAEs leading to 
withdrawal will be summarized by SOC, preferred term and treatment group, sorted in 
decreasing frequency for subjects on SHP465 6.25 mg, and then for placebo.
For the Safety Set, listings will be presented for all AEs, TEAEs related to investigational 
product, TEAEs leading to drug withdrawal, and serious TEAEs.


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12.1.1
Adverse Events of Special Interest
Adverse events of special interest will include psychiatric events of interest (categorized as 
psychosis/mania, suicidal, aggression and other events) listed in Table 2. Adverse event terms of 
special interest will be searched across the TEAE data and summarized with the total exposure 
(in subject-days).


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Table 2
Psychiatric Events
Category
Preferred Term/Verbatim term
Signs and/or symptoms of psychosis/mania
Hallucination (any type, including visual, auditory, tactile, 
mixed, etc.)
Delusion (any type including somatic, persecutory, 
grandeur, reference)
Schizophrenia (any type)
Psychotic disorder
Transient psychosis
Acute psychosis
Paranoia
Childhood psychosis
Schizophreniform disorder
Schizoaffective disorder
Catatonia
Mania
Hypomania
Suicidal ideation and behavior
Depression suicidal
Gun shot wound
Intentional self-injury
Non-accidental overdose
Overdose
Self injurious behavior
Self injurious ideation
Self-mutilation
Suicidal ideation
Suicidal attempt
Completed suicide
Aggression and violent behavior
Aggression
Anger
Hostility
Homicidal ideation
Sexual offense
Murder
Imprisonment


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Table 2
Psychiatric Events
Category
Preferred Term/Verbatim term
Miscellaneous psychiatric events (include 
events with serious outcome only)
Abnormal behavior
Agitation
Amnesia
Confusional state
Depressed mood
Depression
Disorientation
Emotional disorder
Emotional distress
Feeling abnormal
Memory impairment
Mood altered
Mood swings
Personality change
Thinking abnormal
Anxiety
Fearfulness
Phobia
Panic attack
Sleep disturbance
Tics
Obsessive or compulsive behavior
Trichotillomania
A separate listing will be provided for AEs of special interest.
Adverse events of particular interest include insomnia (including AEs with preferred terms of
‘INSOMNIA’, ‘INITIAL INSOMNIA’, ‘MIDDLE INSOMNIA’, and ‘TERMINAL 
INCOMNIA’), weight decrease and decreased appetite. The preferred terms for these 3 AEs will 
be reviewed prior to database lock to determine which will be used to identify them.
For each of these 3 AEs, the following information will be presented by treatment group:

Number and percentage of subjects reporting the TEAE

Number of TEAEs

Summary of onset day of first TEAE: The onset day of first TEAE is calculated as 
(onset date of first TEAE-date of first dose) + 1 for subjects who experienced the TEAE

Summary of duration of TEAE while on study drug: The duration of each event is the 
number of days from the onset of the TEAE, while on study drug during SHP465 6.25 
mg, until the earlier of the end date of the TEAE or the date of last dosing + 3 days (if 
the date of last dosing is missing, the date of last day on study will be used). TEAEs 
that either overlap in time, or are adjacent in time will be merged into one TEAE only 
for the purposes of calculating duration of event. If a subject has multiple TEAEs that 


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are not overlapping or adjacent in time, the durations will be averaged for that subject. 
Summary statistics are then based on the averaged subject durations. The calculated 
duration only includes the duration of TEAEs.

Number and percentage of mild, moderate and severe TEAEs: Overlapping TEAEs 
with different preferred terms are counted as multiple TEAEs.

Summary of the number of TEAEs per subject: Overlapping TEAEs with different 
preferred terms are counted as multiple TEAEs.

Number and percentage of TEAEs that: 

Resolved while on study drug 

Ongoing

Dose interrupted

Dose withdrawn (and other action categories related to dose)

TEAEs leading to discontinuation

Number of subjects who discontinued investigational product due to the event
Also, for each of these 3 AEs, the following information will be presented by week:

Number of subjects in the study

Number and percentage of subjects with the TEAE

Number of TEAEs

Number and percentage of subjects who discontinued due to the TEAE

umber and percentage of mild, moderate and severe TEAEs. If a subject has more than 
one TEAE in the same week, then the worst severity is counted.
Where, Week 1 includes TEAEs that start after Visit 2 (Baseline) through Visit 3 (Week 1), 
Week 2 includes TEAEs that start after Visit 3 (Week 1) through to Visit 4 (Week 2), Week 3 
includes TEAEs that start after Visit 4 (Week 2) through to Visit 5 (Week 3), and Week 4 
includes TEAEs that start after Visit 5 (Week 3) through to Visit 6 (Week 4).
In addition, for each subject, all occurrences of each of these 3 AEs will be listed separately by 
treatment group, subject, start date and stop date. The information presented will include: 
subject, sex, age, race, ethnicity, preferred term/adverse event, start date, stop date, onset day, 
study visit, last dose date, duration/imputed duration of TEAE (days), SAE, severity, effect on 
dosing and treatment for AE.
12.2
Clinical Laboratory Variables
Descriptive statistics for clinical laboratory values (in SI units) and changes from Baseline to 
Visit 6/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:


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Biochemistry and Endocrinology
Total cholesterol
Calcium
Aspartate aminotransferase
Uric acid
Phosphorus
Blood urea nitrogen
Alanine aminotransferase
Total bilirubin
Sodium
Creatinine
Alkaline phosphatase
Glucose
Potassium
Albumin
Gamma-glutamyl transferase
Total protein
Thyroid-stimulating hormone
Lactate dehydrogenase
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
Urinalysis
Glucose
pH
Specific gravity
Urobilinogen
Blood
Color
Ketones
Leukocyte esterase
Protein
Nitrate
Bilirubin
Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis. At a minimum the microscopic examination will consist of red blood cells, white 
blood cells, casts, and bacteria.
Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 3. The number and percentage of subjects with post-
baseline PCI values will be tabulated.  The percentages will be calculated relative to the number 
of subjects with available baseline values and at least 1 post-baseline assessment.  The numerator 
is the total number of subjects with at least 1 post-baseline PCI value.  A supportive listing of 
subjects with post-baseline PCI values will be provided including the subject number, baseline, 
and post-baseline values.


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Table 3
Criteria for Potentially Clinically Important Laboratory Tests
Parameter 
PCI Criteria 
Biochemistry 
Cholesterol-H 
>300mg/dl** (>7.8mmol/L) 
Glucose, serum 
<55mg/dl or >160mg/dl (<3.1mmol/L or >8.9mmol/L) 
Bilirubin, total 
>1.5 x ULN 
Transaminase, SGOT, AST 
>3 x ULN 
Transaminase, SGPT, ALT 
>3 x ULN 
Gamma Glutamyl Transpeptidase (GGT) 
>3 x ULN 
Alkaline phosphatase 
>2.5 x ULN 
Lactate dehydrogenase (LDH) 
>3 x ULN* 
Sodium 
<130mEq/L (grade 3) or >150mEq/L (mmol/L) 
Potassium, serum/plasma 
<3mEq/L (grade 3) or >5.5mEq/L (mmol/L) 
Calcium 
<8mg/dl or >11.5mg/dl (<2mmol/L or >2.9mmol/L) 
Phosphorus, inorganic 
<2.5mg/dl or >7.0mg/dl** (<0.8mmol/L or 
>2.3mmol/L) 
Uric acid, serum 
>10mg/dl (>0.6mmol/L or >594.8μmol/L) 
Thyroid Stimulating Hormone (TSH) ~ 
< 0.35 μIU/ml or > 6 μIU/mL (0.35mIU/L or >6mIU/L) 
Blood Urea nitrogen (BUN) 
>2.5 x ULN* (or alternatively >30mg/dl**, 
>10.7mmol/L) 
Creatinine, serum 
>1.5 x ULN (or alternatively >2mg/dl**, >176.8μmol/L) 
Albumin 
<3g/dl (<30g/L) 
Total protein, plasma or serum 
<5g/dl* or >9g/dl* (<50g/L or >90g/L) 
Hematology 
Hemoglobin (He.) 
<10g/dl (<100g/L) 
Hematocrit 
<32% or >45% (<0.32 or >0.45 Fraction of 1)
Red Blood Cells (RBC) 
male: <2.5 x106/μL; female: <2.0 x106/μL 
(male: <2.5 x 10^12/L; female: <2.0 x 10^12/L) 
Mean Corpuscular Hemoglobin (MCH) 
< LLN or > 32pg 
Mean Corpuscular Volume (MCV) 
< 70fL or > 110fL 
Mean Corpuscular He. Concentration (MCHC) 
< 28g/dL or > 41g/dL (<280g/L or >410g/L) 
Platelet count 
<75 x 109/L or >500 x 109/L 
White Blood Cell Count (WBC) 
<3 x 109/L or >16 x 109/L 
Bands 
> 5% 
Neutrophils 
< 15% 
Eosinophils 
> 10% 
Basophils 
> 15% 
Lymphocytes 
> 80% 
Monocytes 
> 40% 
ANC (%neutrophils x WBC count) 
<1.3x10e9/L 
Urinalysis 
Glucose 
Positive Value (excluding trace) 
Blood 
Positive Value (excluding trace) 
Ketones 
Positive Value (excluding trace) 
Protein 
Positive Value (excluding trace) 
Bilirubin 
Positive Value (excluding trace) 


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Table 3
Criteria for Potentially Clinically Important Laboratory Tests
Parameter 
PCI Criteria 
Leukocyte Esterase 
Positive Value (excluding trace) 
Nitrite 
Positive Value (excluding trace) 
*The NCI has not specified a value, Shire physicians have agreed on lab values provided. 
** Values taken from the Reviewer Guidance, Conducting a Clinical Safety Review of a New Product Application and Preparing 
a Report on the Review, Table 7.1.7.3.2.1 pp 70-72. US DHHS FDA CDER, February 2005. 
~These values were taken from Clinical Laboratory Diagnostics, ed. L. Thomas, MD, Frankfurt, Germany, 1998. 
ULN: Upper limit of normal value provided by the laboratory; LLN: Lower limit of normal value provided by the laboratory
All laboratory data will be listed for the Safety Set.
12.3
Vital Signs (Including Height and Weight)
The averaged values of the 3 measurements collected for blood pressure and pulse at each visit 
will be used for all summaries and determination of PCIs. 
Descriptive statistics for vital signs (sitting systolic and diastolic blood pressure, pulse, height,
weight, and BMI) and their changes from baseline at each post-baseline visit and FoTA will be 
presented by treatment group. In the case of multiple assessments at post-baseline visits, the first 
readable value at the visit will be used in the summary tables. 
Additionally, figures with the mean change from baseline ±SD of the vital signs values (sitting 
systolic and diastolic blood pressure, and pulse) will be presented by treatment group and visit. 
Height, weight, and BMI will also be converted to percentile values based on the subject’s age 
and sex at each visit and summarized categorically (<5th, 5th to <95th, and ≥95th) at each visit 
and at the FoTA. Post-baseline shifts in height, weight, and BMI percentile category (<5th, 5th to 
<95th, and ≥95th) from baseline will be summarized at each visit and at the FoTA. In addition, z-
scores for height, weight, and BMI will be based on the subject’s age at each visit and will be 
summarized categorically (<-2, ≥-2 to <-1, ≥-1 to <1, ≥1 to <2, and ≥2) at each visit and at the 
FoTA. Percentiles and z-scores will be derived using the CDC growth charts (Kuczmarski et al,
2002). 
Vital sign values will be considered PCI if they meet the criteria listed in Table 4. The number 
and percentage of subjects with PCI post-baseline values will be summarized by visit and 
treatment group. The percentages will be calculated relative to the number of subjects with 
baseline and at least 1 post-baseline assessment. The numerator is the total number of subjects 
with at least 1 PCI post-baseline vital sign value. A supportive listing of subjects with post-
baseline PCI values will be provided including the subject number, site, baseline, and post-
baseline PCI values. A listing of all AEs for subjects with post-baseline PCI vital sign values will 
also be provided. In addition, for pulse, the number and percentage of subjects with at least 1 
post-baseline value that fall within the categories >50-<100, 100-<110 and ≥110 beats/minute, 
will also be summarized by treatment group.
Measurements of oral or tympanic temperature, sitting respiratory rate will be performed at the 
Screening Visit (Visit 1) only.


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Table 4
Criteria for Potentially Clinically Important Laboratory Tests
Vital Sign Parameter 
PCI Criteria 
Weight Loss (kg) 
≥7% of weight (determined at baseline) 
Systolic BP (mmHg), seated 
>120* 
>120* on 2 or more consecutive visits 
>10 increase from baseline 
>10 increase from baseline on 2 or more consecutive visits 
>120* and increase >10 from baseline 
>120* and increase >10 from baseline on 2 or more 
consecutive visits 
Diastolic BP (mmHg), seated 
>80* 
>80* on 2 or more consecutive visits 
>10 increase from baseline 
>10 increase from baseline on 2 or more consecutive visits 
>80* and increase >10 from baseline 
>80* and increase >10 from baseline on 2 or more 
consecutive visits 
Pulse (beats/minute) 
<=50* 
<=50* and decrease >15 from baseline
>=100* 
>=100* on 2 or more consecutive visits 
>=100* and increase >15 from baseline 
>=100* and increase >15 from baseline on 2 or more 
consecutive visits 
Temperature (tympanic) 
>38.0°C (100.4°F) 
Temperature (oral) 
>37.5°C (99.5°F) 
Respiratory Rate (breaths per minute) 
<10 or >24 
~Given the pharmacological effect of the drugs used in ADHD and based on experience gained in previous ADHD trials, the 
focus is on rise of blood pressure only. 
*The NCI has not specified a value, Shire physicians have agreed on values provided. 
Pulse rate (beats per minute) will be considered abnormal if a value is lower than the 1st 
percentile or higher than the 99th percentile cut-off values listed in Table 5. 


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Table 5
Normal Range of Pulse Rate (beats/min)
Age
1st Percentile
99th Percentile
Males
6-8 years
59
114
9-11 years
56
110
12 years
52
108
Females
6-8 years
61
117
9-11 years
58
113
12 years
54
110
Source: National health statistics report: Resting Pulse Rate Reference Data for Children, Adolescents, and Adults: United 
States, 1999–2008
https://www.cdc.gov/nchs/data/nhsr/nhsr041.pdf
The number and percentage of subjects with abnormal pulse rate values for at least 1 post-
baseline assessment will be tabulated by treatment group for the lower than the 1st percentile and 
higher than the 99th percentile cut-off values, respectively, for males and females separately. The 
denominator will be the number of subjects in the Safety Set (per gender) with at least 1 post-
baseline pulse measurement. The numerator is the total number of subjects with at least 1 
abnormal pulse record. A supportive listing of subjects with abnormal pulse rate values will be 
provided.
In addition, following the US Department of Health and Human Services standards, blood 
pressure values higher than the 95th percentile determined by sex, age, and height percentiles 
will be considered abnormal. The cut-off values are presented in Table 6. 


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Table 6
95th Percentile Cut-off Values of Blood Pressure Norms by Sex, Age, and 
Height Percentiles
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Age 
(y)
Percentile of Height
Percentile of Height
Boys
5%
10%
25%
50%
75%
90%
95%
5%
10%
25%
50%
75%
90%
95%
6
109
110
112
114
115
117
117
72
72
73
74
75
76
76
7
110
111
113
115
117
118
119
74
74
75
76
77
78
78
8
111
112
114
116
118
119
120
75
76
77
78
79
79
80
9
113
114
116
118
119
121
121
76
77
78
79
80
81
81
10
115
116
117
119
121
122
123
77
78
79
80
81
81
82
11
117
118
119
121
123
124
125
78
78
79
80
81
82
82
12
119
120
122
123
125
127
127
78
79
80
81
82
82
83
Girls
6
108
109
110
111
113
114
115
72
72
73
74
74
75
76
7
110
111
112
113
115
116
116
73
74
74
75
76
76
77
8
112
112
114
115
116
118
118
75
75
75
76
77
78
78
9
114
114
115
117
118
119
120
76
76
76
77
78
79
79
10
116
116
117
119
120
121
122
77
77
77
78
79
80
80
11
118
118
119
121
122
123
124
78
78
78
79
80
81
81
12
119
120
121
123
124
125
126
79
79
79
80
81
82
82
Source: National Heart Lung and Blood Institute; May 2004
http://www nhlbi nih.gov/guidelines/hypertension/child_tbl.htm
The number and percentage of subjects with any post-baseline blood pressure values higher than 
the 95th percentile (exclusive) will be tabulated by treatment group and by age group. The 
denominator will be the number of subjects in the Safety Set (per gender) with at least 1 post-
baseline blood pressure measurement. The numerator will be the total number of subjects with at 


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least 1 blood pressure value higher than the 95th percentile. A supportive listing of all subjects 
with abnormal blood pressure values will be provided.
All vital signs data will be listed for the Safety Set.
12.4
Electrocardiogram (ECG)
Electrocardiogram results and change from baseline will be summarized at each visit and at the 
FoTA by treatment group. If there are multiple assessments for the interpretation at any visit, the 
worst interpretation will be used in the summary tables. For the interval parameters at post-
baseline visits, the first readable result will be used if there are multiple assessments.
For the ECG interval parameters, baseline is defined as the average of all valid ECG 
measurements as the last assessment obtained prior to the first dose of the investigational 
product. For the ECG interpretation, baseline will be the ECG with the worst interpretation 
obtained at the baseline Visit (Visit 2), providing this is prior to the first dose of the 
investigational product.
PCI criteria will be applied to all ECG data at each visit including any repeat/unscheduled 
assessments and presented by visit and treatment group. PCI criteria are defined in Table 7.
Table 7
Criteria for Potentially Clinically Important ECG Values
ECG Parameter 
Outlier Criteria 
ECG result 
Shift from a normal baseline to an abnormal finding or from 
an abnormal baseline to a new abnormal finding 
Heart rate 
≤50 beats/minute* or ≥100 beats/minute* 
PR interval (increase) 
≥200 msec* 
QRS interval 
≥120 msec* 
QTcF/QTcB 
≥450 msec* and <480 msec* 
≥480 msec* and <500 msec* 
≥ 500msec* 
QT/QTc from Baseline 
≥30 msec* and <60 msec* 
≥60 msec* 
*The NCI has not specified a value, Shire physicians have agreed on values provided. 
ECG=electrocardiogram; QTcB=Bazett’s corrected QT interval; QTcF=Fridericia’s corrected QT interval 
The number and percentage of subjects with post-baseline PCI values will be tabulated.  The 
percentages for the observed value criteria will be calculated relative to the number of subjects 
with at least 1 post-baseline assessment available per parameter and visit. The percentages for 
the change from baseline criteria will be calculated relative to the number of subjects with 
available baseline and at least 1 post-baseline assessment per parameter and visit.  The numerator 
is the total number of subjects with at least 1 PCI post-baseline ECG value.
Additionally, a summary table showing the number and percentage of subjects with the Central 
Reader’s assessment of the ECG result as normal, abnormal or unable to evaluate, and the 
investigator’s assessment of abnormal ECG results as not clinically significant or clinically 
significant at each visit and at the FoTA by treatment group will be produced. A shift table 


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showing the change in evaluation from baseline to the FoTA by treatment group will also be 
produced.
Listings of ECG data including the central reader’s assessment and investigator's interpretation 
by individual subject will be produced. Separate listings will be produced for subjects with ECG 
results meeting the PCI criteria. Data from unscheduled visits will be listed, but not summarized.
12.5
Other Safety Variables
12.5.1
Columbia-Suicide Severity Rating Scale (C-SSRS)
The C-SSRS is a semi-structured interview that captures the occurrence, severity, and frequency 
of suicide-related thoughts and behaviors during the assessment period. The interview includes 
definitions and suggested questions to solicit the type of information needed to determine if a 
suicide-related thought or behavior occurred.
The C-SSRS contains two required items pertaining to suicidal ideation, four required items 
pertaining to suicidal behavior, and one required item pertaining to non-suicidal self-injurious 
behavior. There are eight additional suicidal ideation items and two additional suicidal behavior 
items which are completed in cases of positive responses for other items, as well as two items for 
suicide and suicide behavior present during the interview. Most items are rated on a dichotomous 
scale (yes or no) or 3- or 5-point Likert scale. In addition, the total number of attempts (including 
interrupted and aborted attempts) is recorded. In the event of a positive categorical response the 
interviewer can provide text or narrative that further describes the thought or behavior.
Two versions of the C-SSRS are used in this study:

The “Baseline” version will be administered at the Screening Visit (Visit 1) and will be 
completed for all subjects.

The “Since Last Visit” version will be completed for all subjects at all study visits after the 
Screening Visit (Visit 1).
Listings of the C-SSRS data will be provided for subjects with a positive response.
12.5.2
Post Sleep Questionnaire (PSQ)
The PSQ is a 7-item questionnaire typically used to assess sleep quality with pharmacologic 
treatment. The questionnaire collects data on average time to sleep, sleep latency, frequency of 
interrupted sleep, duration of interrupted sleep, total sleep time and sleep quality over the last 
week. The PSQ will be completed by the parent/LAR with the subject and the responses will be 
reviewed by the clinician during the study visit. The PSQ will be completed at Baseline (Visit 2), 
and each visit through Visit 6/ET.
The PSQ results will be summarized by treatment and visit. Continuous variables, for example,
time to go to sleep and time spent awake, will be summarized using number of subjects, mean 
and standard deviation, median, and minimum and maximum values. Categorical values, for 
example, quality of sleep, will be summarized using number of subjects and percentages for each 
category.


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All PSQ data will be listed for the Safety Set.
12.5.3
Children’s Sleep Habit Questionnaire (CSHQ) 
The Child’s Sleep Habits Questionnaire (CHSQ) consists of 33 items for scoring and several 
extra items intended to provide administrators with other potentially useful information about 
respondents. 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.
1. Bedtime resistance (sum of the responses for Goes to bed at same time, Falls asleep in own 
bed, Falls asleep in other’s bed, Needs parent in room to sleep, Struggles at bedtime and 
Afraid of sleeping alone)
2. Sleep-onset delay (Falls asleep in 20 minutes item)
3. Sleep duration (sum of the responses for Sleeps too little, Sleeps the right amount and Sleeps 
same amount each day)
4. Sleep anxiety (sum of the responses for Needs parent in room to sleep, Afraid of sleeping in 
the dark, Afraid of sleeping alone and Trouble sleeping away)
5. Night wakings (sum of the responses for Moves to other’s bed in night, Awakes once during 
night and Awakes more than once)
6. Parasomnias (sum of the responses for Wets the bed at night, Talks during sleep, Restless 
and moves a lot, Sleepwalks, Grinds teeth during sleep, Awakens screaming, sweating and 
Alarmed by scary dream)
7. Sleep-disordered breathing (sum of the responses for Snores loudly, Stops breathing and 
Snorts and gasps)
8. Daytime sleepiness (sum of the responses for Wakes by himself, Wakes up in negative mood, 
Others wake child, Hard time getting out of bed, Takes long time to be alert, Seems tired, 
Watching TV and Riding in car)
Total sleep disturbance score is sum of the 8 subscale scores minus Needs parent in room to 
sleep and Afraid of sleeping alone (as Needs parent in room to sleep and Afraid of sleeping alone
are included in two subscales (1 and 4) and need to be included once).
Total sleep disturbance score, each subscale score and each individual item will be summarized 
using descriptive statistics (n, mean, SD, minimum, median, and maximum) at each visit (and 
Visit 6/ET) by treatment group. All CSHQ data will be listed for the Safety Set.
12.6
Exploratory Safety Endpoints
Safety data for TEAEs, vital signs, ECGs, clinical laboratory test results, PSQ, and CSHQ will 
be descriptively summarized by treatment within each age group (6-8 years and 9-12 years).
TEAEs will also be descriptively summarized for overall AEs, AEs by SOC and PT, frequently 
occurring AEs within each sex group (male and female), race group (white and non-white), and 
ethnic group.


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13.
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
Pharmacokinetic and pharmacodynamics data will not be collected for this study.


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14.
OTHER ANALYSES
No other analyses are planned for this study.


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15.
INTERIM ANALYSIS
In order to maintain sufficient study power to detect a clinically meaningful treatment effect for 
the primary efficacy endpoint, a blinded interim analysis at the late stage of the trial (when 
approximately 75% of all randomized subjects have either completed or discontinued from the 
study) will be performed to reassess the sample size in case of an underestimated variability 
postulated at the design stage.
Using the cumulative real data, a blinded, pooled analysis of both treatment groups for 
estimating variability will be conducted. If the re-estimated pooled standard deviation is larger 
than the 14 postulated at the design stage, the final total number of subjects to be enrolled will be 
calculated using the re-estimated pooled standard deviation together with the assumed treatment 
difference of 11.9 (Friede et al, 2006). If the re-estimated pooled standard deviation is smaller 
than 14, the sample size will not be adjusted. Using the pooled common variance estimated to do 
a blinded sample size re-estimation does not inflate the Type I error. The details for estimating 
the pooled SD are included in Appendix 1.


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16.
DATA MONITORING/REVIEW COMMITTEE
An external independent Data Monitoring Committee (DMC) was set up to review the data 
pertaining to safety and tolerability of the study therapy for the duration of this program, which 
includes studies SHP465-112, SHP465-308, and SHP465-309. The DMC will review the data 
pertaining to safety and tolerability of the study therapy. Active surveillance for insomnia and 
decreased appetite leading to weight loss are included. Confidentiality of the unblinded DMC 
analyses is a critical concern and to address this, an unblinded independent reporting team will 
be identified within a CRO. The independent reporting team will have no involvement in the 
conduct of the study. Further details regarding the DMC can be found in the DMC charter, which 
will be available before the administration of investigational product. 


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17.
COMPUTER METHODS
Statistical analyses will be performed using Version 9.3 (or newer) of SAS  on a suitably 
qualified environment.


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18.
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
18.1
Handling of the Unintentional Urine Drug Screen
At the end of this study, after completing the final on-treatment efficacy and safety assessments, 
urine drug screens were erroneously performed for one subject at last visit (Visit 6) and 9
subjects who were rolled over to the long-term safety extension study (SHP465-308). Thus, the 
site and vendor personnel might have been unblinded to treatment drug information of these 
subjects although a quick action was taken to remove and restrict access to the urine drug screen 
results. To assess any compromise to data integrity following the potential unblinding for the ten 
(10) subjects, Shire and PPD study teams performed a thorough investigation of data collected 
for study primary efficacy, secondary efficacy and safety analyses, including eCOA data 
collected on the ERT devices and data entered into the EDC.
This investigation showed no patterns of data changes or data integrity concerns which would be 
indicative of actions based on unblinded information. It was concluded that there was no 
evidence of the introduction of bias that would affect the aggregate data reported. In addition, 
Shire respects the value for each subject participant in the study, therefore decided to include all 
subjects in the final study analysis.
As a conservative measure to evaluate whether the potential unblinding modified the efficacy 
results due to the unintentional urine drug screen, sensitivity analyses of the primary efficacy 
(ADHD-RS-5 total score) and key secondary efficacy (CGI-I) analyses will be performed, in 
which these 10 subjects were excluded from the FAS (see Section 11.5). 


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19.
DATA HANDLING CONVENTIONS
19.1
General Data Reporting Conventions
Continuous variables will be summarized using the following descriptive statistics:  n, mean, 
median, SD, minimum, and maximum. Unless specified otherwise, summary statistics will be 
presented to 1 more significant digit than the raw data. The minimum and maximum values will 
be presented to the same number of decimal places as the raw data; the mean and median will be 
presented to 1 more decimal place than the raw data; and the SD and standard error will be 
presented to 2 more decimal places than the raw data.
Categorical and count variables will be summarized by the number of subjects (n) and the 
percent of subjects in each category.  Percentages will be presented to 1 decimal place.
P-values will generally be presented to 4 decimal places; values less than 0.001 will be presented 
as <0.001.
19.2
Derived Efficacy Endpoints
The ADHD-RS-5 total score will be calculated as the sum of the individual items from the 
ADHD-RS-5. The ADHD-RS-5 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 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 to 54. As specified in Section 
11.1, the 18 items will also be grouped into 2 subscales: hyperactivity/impulsivity (9 items for 
hyperactivity/impulsivity) and inattentiveness (9 items for inattentiveness), with subscale scores 
ranging from 0-27.
A missing individual item in the ADHD-RS-5 is imputed as follows (DuPaul et al., 2016):  if 
only 1 single item is missing in a given subscale, the mean score for all other items in the 
subscale for the specific visit is imputed as the score rounded up to the nearest integer for the 
missing score. The total score is computed as the sum of the imputed subscale scores.  If more 
than 1 item is missing in a subscale then the subscale score and total score would be missing.
19.3
Association of Early Termination Assessments to Scheduled Visits
For purposes of reporting early termination assessments during the study, each early termination 
visit will be assigned the next nominal visit number after the last completed visit. This rule 
applies to both efficacy variables (e.g., ADHD-RS-5 total score) and safety variables (e.g., vital 
signs) that are analyzed and/or summarized by visit.
19.4
Repeated or Unscheduled Assessments of Safety Parameters
If a subject has repeated assessments before the start of double-blind investigational product, 
then the results from the final assessment made prior to the start of double-blind investigational 
product will be used as baseline.


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If a subject has repeated assessments at any post-baseline visit, the first recorded assessment will 
be assigned to the visit for generating descriptive statistics. For vital signs (sitting systolic and 
diastolic blood pressure, and pulse), this will be the average of the 3 measurements from the first 
recorded assessment.
If final on-treatment safety assessments are repeated or unscheduled, the last post-baseline 
assessment will be used as the final on-treatment assessment for generating descriptive statistics. 
For vital signs (sitting systolic and diastolic blood pressure, and pulse), this will be the average 
of the 3 measurements from the last post-baseline assessment.
However, all post-baseline assessments will be used for PCI value determination and all 
assessments will be presented in the data listings.
All repeat and unscheduled visits will be listed.
19.5
Missing Dispensed or Returned Date or Number of Capsules of Investigational
Product
When the date of the last dose of double-blind investigational product is missing for a subject in 
the Safety Set, all efforts should be made to obtain the date from the investigator. If it is still 
missing after all efforts, then the last visit date when investigational product was returned will be 
used in the calculation of investigational product exposure.
19.6
Missing Date Information for Prior or Concomitant Medications
For prior or concomitant medications, incomplete (i.e., partially missing) start date and/or stop 
date will be imputed.  When the start date and the stop date are both incomplete for a subject, 
impute the start date first.
19.6.1
Incomplete Start Date
The following rules will be applied to impute the missing numerical fields. If the stop date is 
complete and the imputed start date is after the stop date, then the start date will be imputed 
using the stop date.
Missing day and month

If the year of the incomplete start date is the same as the year of the date of the first dose of 
double-blind investigational product, then the day and month of the date of the first dose of 
double-blind 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 
double-blind 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 double-
blind investigational product, then 01 January will be assigned to the missing fields.


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Missing month only

The day will be treated as missing and both month and day will be replaced according to the 
above procedure.
Missing day only

If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of double-blind investigational product, then the day of the date of the 
first dose of double-blind 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 double-blind 
investigational product or if both years are the same but the month is before the month of the 
date of the first dose of double-blind 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 double-blind investigational 
product or if both years are the same but the month is after the month of the date of the first 
dose of double-blind investigational product, then the first day of the month will be assigned 
to the missing day.
19.6.2
Incomplete Stop Date
The following rules will be applied to impute the missing numerical fields.  If the date of the last 
dose of double-blind investigational product is missing, then replace it with the last visit date.  If 
the imputed stop date is before the start date (imputed or non-imputed start date), then the 
imputed stop date will be equal to the start date.
Missing day and month

If the year of the incomplete stop date is the same as the year as of the date of the last dose 
of double-blind investigational product, then the day and month of the date of the last dose 
of double-blind 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 
double-blind 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 double-
blind investigational product, then 01 January will be assigned to the missing fields.
Missing month only

The day will be treated as missing and both month and day will be replaced according to the 
above procedure.
Missing day only

If the month and year of the incomplete stop date are the same as the month and year of the 
date of the last dose of double-blind investigational product, then the day of the date of the 
last dose of double-blind 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 double-blind investigational 
product or if both years are the same but the month is before the month of the date of the last 


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dose of double-blind 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 double-blind investigational product or 
if both years are the same but the month is after the month of the date of the last dose of 
double-blind investigational product, then the first day of the month will be assigned to the 
missing day.
19.7
Missing Date Information for Adverse Events
For AEs, incomplete (i.e., partially missing) start dates will be imputed and will follow the same 
rules as in Section 19.6.1.  Incomplete stop dates will not be imputed.
19.8
Missing Severity Assessment for Adverse Events
If severity is missing for an AE starting prior to the date of the first dose of double-blind 
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 double-blind 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.
19.9
Missing Relationship to Investigational Product for Adverse Events
If the relationship to investigational product is missing for an AE starting on or after the date of 
the first dose of double-blind 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.
19.10 Character Values of Clinical Laboratory Variables
The actual values of clinical laboratory variables as reported in the database will be presented in 
data listings.  No coded values (e.g., when a character string is reported for a numerical variable) 
are necessary.


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20.
REFERENCES
Cohen J, 1988. Statistical Power Analysis for the Behavioral Sciences, Second Edition. 
Hillsdale, NJ: Lawrence Earlbaum Associates. 
DuPaul GJ, Power TJ, Anastopoulos AD, Reid R, 2016. ADHD Rating Scale-5 for Children and 
Adolescents: Checklists, Norms, and Clinical Interpretation, New York, NY: Guilford Press. 
Friede T, Kieser M, 2006. Sample Size Recalculation in Internal Pilot Study Designs: A Review. 
Biometrical Journal 48 (4): 537-55. 
Kuczmarski RJ, Ogden CL, Guo SS, et al., 2002. 2000 CDC growth charts for the United States: 
Methods and development. National Center for Health Statistics, Vital Health Stat 11(246).


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21.
TABLE OF CONTENTS FOR FIGURES, TABLES, AND LISTINGS
Table of contents for figures, tables and listings will be documented separately.


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22. APPENDICES 
22.1 
Appendix 1 Algorithms for Sample Size Re-estimation 
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 details: 
• Ignoring treatment difference and applying the formula below to estimate the pooled sample 
variance, which is an unbiased estimate of the variance.  
 
𝑆𝑝𝑜𝑜𝑙𝑒𝑑
2
 = 
1
 𝑛1−1 ∑(𝑋𝑖𝑗− 
𝑖,𝑗
 𝑋ത )2, 
 
where 𝑛1 is total number of subjects who either completed or discontinued from the study at 
the time point of the sample size re-estimation. 𝑖=1,2; 𝑗=1,⋯,𝑛1𝑖 and 𝑛1= 𝑛11+ 𝑛12.  
• Let ∆∗be the alternative hypothesis of treatment mean difference that is pre-specified as 11.9, 
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 et al, 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 et al, 2006). 


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22.2
Appendix 2 Sample SAS Codes
Mixed Model Repeated Measures (MMRM)
Proc mixed  /* select derived data set */ ;
Class trt subjid visit agegp;
Model chg = trt visit agegp 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;
Mixed Model Repeated Measures (MMRM) for subgroup analysis
Proc mixed  /* select derived data set */ ; Class trt 
subjid visit;
Model chg = trt visit trt*visit base base*visit / ddfm=kr; Repeated visit / 
subject=subjid type=UN;
by subgroup;
/* LSMean, Estimate, and/or LSMestimate statement(s) */
/* Data output or object delivery statement(s) */
Run;
Analysis of Covariance (ANCOVA)
Proc glm /* select derived data set */ ;
Class trt ;
Model chg = trt agegp base/alpha=.05; 
Lsmeans trt/stderr pdiff;
/* Data output or object delivery statement(s) */ 
Run;
Missing Not at Random (MMNAR) Sensitivity Analysis
Model 1: Placebo Multiple Imputation
* Step 1;
proc mi data=unimputed out=discard nimpute=200 seed=309 noprint;
where treatment=1; * where 1 stands for placebo;
var baseline chy1-chy4;
mcmc outest=posteriors; * here we pick up the PLA posteriors;
run;
* 100 posteriors for the placebo, rest for SHP465 6.25 mg;
data posteriors(type=est);
set posteriors;


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if 1<=_imputation_<=100 then do; * assign placebo posteriors ;
treatment=1;
end;
if 100<_imputation_<=200 then do; * assign posteriors to SHP465 6.25 mg;
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-chy4;
mcmc inest=posteriors; * here we use the placebo posteriors;
run;
* Step 2;
data endpoint; 
set imputed;
endpoint=chy4; 
run;
proc sort data=endpoint;
by _imputation_;
run;
proc glm data=endpoint;
by _imputation_;
class treatment agegp;
model endpoint = baseline treatment agegp / solution;
lsmeans treatment;
estimate 'SHP465 6.25 mg 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;


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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=(Chy4 =.);
run;
proc sort data=unimputed;
by treatment;
run;
proc mi data=unimputed out=imputed nimpute=&nimpute seed=309 noprint;
by treatment;
var baseline chy1-chy4;
run;
%let SD=10;
* This will be replaced by the estimated SD[chy5] 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, 0.75 and 1) as per SAP;
data imputed;
set imputed;
if missing then chy4=chy4+ &penalty; * + or -, depending on the measure;
run;
* Step 2 (analysis of completed data sets) and Step 3 (inference) are the same as Steps 2 and 3 respectively for 
Model 1.