Clinical trial NCT03327402
Conditions: Attention Deficit Hyperactivity Disorder (ADHD)
Keywords: SHP465 ADHD Hyperactivity
Sponsor: Shire
Start date: 2018-03-13; Completion date: 2018-10-05
Enrollment: 24 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this study is to evaluate the pharmacokinetics (PK), safety, and tolerability of SHP465 in children aged 4 to 5 years with ADHD after multiple daily doses of 6.25 milligram (mg) SHP465

Detailed description:

Arms: arm 1: Participants will receive SHP465 capsule at a dose of 6.25 mg, orally once daily for 4 weeks.
Interventions: intervention 1: SHP465
Intervention descriptions: intervention 1: SHP465 capsule will be administered at a dose of 6.25 mg, orally once daily for 4 weeks. SHP465 is comprised of sulfate salts of dextroamphetamine and amphetamine, with dextroamphetamine saccharate and amphetamine aspartate monohydrate, which provide a composite enantiomer ratio of 3:1 d-amphetamine to l-amphetamine.

Protocol documents:
Prot_000.pdf: 
PROTOCOL: SHP465-112
TITLE:
A Phase 1 Open-label Study of the Safety, Tolerability, and 
Pharmacokinetics of d- and l-Amphetamine after Multiple Daily Doses
of SHP465 6.25 mg Administered in Children Aged 4 to 5 years with 
Attention-Deficit/Hyperactivity Disorder
DRUG:
SHP465
IND:
66,329
EUDRACT NO.:
Non-EUDRACT
SPONSOR: 
Shire Development LLC
300 Shire Way, Lexington, MA 02421 US
PRINCIPAL/
COORDINATING
INVESTIGATOR:
TBD
PROTOCOL 
HISTORY:
Original Protocol: 15 Sep 2017
This document contains confidential and proprietary information of Shire and is disclosed pursuant to 
confidentiality and nondisclosure obligations. This information should be used solely for the purposes for which 
it was provided and should not be copied, shared with, or disclosed to any third party without the express written 
consent of Shire.
 








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


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TABLE OF CONTENTS
PROTOCOL SIGNATURE PAGE .................................................................................................2
EMERGENCY CONTACT INFORMATION................................................................................3
PRODUCT QUALITY COMPLAINTS..........................................................................................5
LIST OF TABLES.........................................................................................................................10
ABBREVIATIONS .......................................................................................................................11
STUDY SYNOPSIS ......................................................................................................................13
STUDY SCHEDULE ....................................................................................................................20
1
BACKGROUND INFORMATION.......................................................................................24
1.1
Indication and Current Treatment Options...............................................................24
1.2
Product Background and Clinical Information ........................................................25
2
STUDY OBJECTIVES AND PURPOSE ..............................................................................26
2.1
Rationale for the Study.............................................................................................26
2.2
Study Objectives ......................................................................................................26
2.2.1
Primary Objective......................................................................................26
3
STUDY DESIGN ...................................................................................................................26
3.1
Study Design ............................................................................................................26
3.2
Duration and Study Completion Definition .............................................................27
3.3
Sites and Regions .....................................................................................................28
4
STUDY POPULATION.........................................................................................................28
4.1
Inclusion Criteria......................................................................................................28
4.2
Exclusion Criteria.....................................................................................................29
4.3
Reproductive Potential .............................................................................................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 ...................................................................33
5.1
Prior Treatment ........................................................................................................34
5.2
Concomitant Treatment............................................................................................34
5.2.1
Permitted Treatment...................................................................................34
5.2.2
Prohibited Treatment .................................................................................34
6
INVESTIGATIONAL PRODUCT ........................................................................................35
6.1
Identity of Investigational Product...........................................................................35


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6.1.1
Blinding the Treatment Assignment..........................................................35
6.2
Administration of Investigational Product ...............................................................35
6.2.1
Allocation of Subjects to Treatment ..........................................................35
6.2.2
Dosing........................................................................................................36
6.2.3
Unblinding the Treatment Assignment......................................................37
6.3
Labeling, Packaging, Storage, and Handling ...........................................................37
6.3.1
Labeling .....................................................................................................37
6.3.2
Packaging...................................................................................................37
6.3.3
Storage .......................................................................................................38
6.4
Drug Accountability.................................................................................................38
6.5
Subject Compliance..................................................................................................39
7
STUDY PROCEDURES........................................................................................................40
7.1
Study Schedule.........................................................................................................40
7.1.1
Screening and Washout Period..................................................................41
7.1.2
Treatment Period........................................................................................42
7.1.3
Follow-up Period .......................................................................................42
7.1.4
Additional Care of Subjects after the Study ..............................................43
7.2
Study Evaluations and Procedures ...........................................................................43
7.2.1
Demographic and Other Baseline Characteristics .....................................43
7.2.1.1
Mini International Neuropsychiatric Interview for Children and 
Adolescents (MINI-KID) .......................................................................43
7.2.1.2
Clinical Global Impressions.......................................................................44
7.2.1.3
The ADHD-Rating Scale-5........................................................................44
7.2.2
Safety .........................................................................................................44
7.2.2.1
Medical and Medication History ...............................................................45
7.2.2.2
Physical Examination (Including Height and Weight)..............................45
7.2.2.3
Adverse Event Collection ..........................................................................46
7.2.2.4
Vital Signs..................................................................................................46
7.2.2.5
Clinical Laboratory Evaluations ................................................................47
7.2.2.6
Drug and Alcohol Screen...........................................................................48
7.2.2.7
Electrocardiogram......................................................................................48
7.2.2.8
Columbia-Suicide Severity Rating Scale...................................................49
7.2.2.9
Children’s Sleep Habits Questionnaire......................................................50
7.2.2.10
Post Sleep Questionnaire ...........................................................................50
7.2.2.11
Suitability of the Subject to Remain in the Study......................................50
7.2.3
Pharmacokinetic Procedures......................................................................51
7.2.3.1
Blood Sample Collection and Handling Procedures..................................51
7.2.3.2
Shipment of Plasma Pharmacokinetic Samples.........................................52


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7.2.3.3
Plasma Drug Assay Methodology .............................................................52
7.2.4
Volume of Blood to be Drawn from Each Subject....................................53
8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT ....................................54
8.1
Definition of Adverse Events, Period of Observation, and Recording of 
Adverse Events.........................................................................................................54
8.1.1
Severity Categorization..............................................................................54
8.1.2
Relationship Categorization.......................................................................55
8.1.3
Outcome Categorization ............................................................................55
8.1.4
Symptoms of the Disease under Study ......................................................55
8.1.5
Clinical Laboratory and Other Safety Evaluations ....................................55
8.1.6
Abuse, Misuse, Overdose, and Medication Error......................................56
8.2
Serious Adverse Event Procedures ..........................................................................57
8.2.1
Reference Safety Information....................................................................57
8.2.2
Reporting Procedures.................................................................................57
8.2.3
Serious Adverse Event Definition .............................................................57
8.2.4
Serious Adverse Event Collection Time Frame.........................................58
8.2.5
Serious Adverse Event Onset and Resolution Dates .................................58
8.2.6
Fatal Outcome............................................................................................58
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, 
and Site Reporting......................................................................................58
9
DATA MANAGEMENT AND STATISTICAL METHODS...............................................59
9.1
Data Collection.........................................................................................................59
9.2
Clinical Data Management.......................................................................................59
9.3
Statistical Analysis Process......................................................................................59
9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee......60
9.4.1
Data Monitoring Committee......................................................................60
9.5
Sample Size Calculation and Power Considerations................................................60
9.6
Study Population ......................................................................................................61
9.7
Pharmacokinetic Analyses .......................................................................................61
9.7.1
Pharmacokinetic Analysis..........................................................................61
9.7.1.1
Statistical Analysis of Pharmacokinetic Parameters..................................62
9.8
Safety Analyses........................................................................................................62
10 SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES...........................................63
10.1
Sponsor’s Responsibilities .......................................................................................63
10.1.1
Good Clinical Practice Compliance...........................................................63
10.1.2
Public Posting of Study Information..........................................................63
10.1.3
Submission of Summary of Clinical Study Report to Competent 
Authorities of Member States Concerned and Ethics Committees............64


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10.1.4
Study Suspension, Termination, and Completion......................................64
10.2
Investigator’s Responsibilities .................................................................................64
10.2.1
Good Clinical Practice Compliance...........................................................64
10.2.2
Protocol Adherence and Investigator Agreement......................................64
10.2.3
Documentation and Retention of Records.................................................65
10.2.3.1
Case Report Forms.....................................................................................65
10.2.3.2
Recording, Access, and Retention of Source Data and Study 
Documents..............................................................................................65
10.2.3.3
Audit/Inspection.........................................................................................66
10.2.3.4
Financial Disclosure...................................................................................66
10.2.4
Compliance to all Local, State, and National Controlled-substance 
Biohazard and Infectious Disease Regulations and Legislation................66
10.3
Ethical Considerations..............................................................................................66
10.3.1
Informed Consent/Assent...........................................................................66
10.3.2
Institutional Review Board or Ethics Committee......................................67
10.4
Privacy and Confidentiality......................................................................................67
10.5
Study Results/Publication Policy .............................................................................68
11 REFERENCES .......................................................................................................................70
12
APPENDICES ........................................................................................................................73
Appendix 1
PROTOCOL HISTORY............................................................................74
Appendix 2
DIAGNOSTIC CRITERIA/DISEASE CLASSIFICATION.....................75
Appendix 2.1 DIAGNOSTIC AND STATISTICAL MANUAL OF MENTAL 
DISORDERS, FIFTH EDITION CRITERIA............................................75
Appendix 2.2 BOYS’ STATURE-FOR-AGE AND WEIGHT-FOR-AGE 
PERCENTILES .........................................................................................77
Appendix 2.3 BLOOD PRESSURE LEVELS FOR BOYS BY AGE AND 
HEIGHT PERCENTILE............................................................................78
Appendix 2.4 GIRLS’ STATURE-FOR-AGE AND WEIGHT-FOR-AGE 
PERCENTILES .........................................................................................79
Appendix 2.5 BLOOD PRESSURE LEVELS FOR GIRLS BY AGE AND 
HEIGHT PERCENTILE............................................................................80
Appendix 3
SCALES AND ASSESSMENTS ..............................................................81


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LIST OF TABLES
Table 1:
Schedule of Assessments for Rich Pharmacokinetic Sampling Portion .......20
Table 2:
Schedule of Assessments for Sparse Pharmacokinetic Sampling 
Portion ...........................................................................................................22
Table 3:
Common Excluded Treatments and Associated Washout Period 
Relative to Baseline Visit..............................................................................35
Table 4:
Volume of Blood to be Drawn from Each Subject (Rich 
Pharmacokinetic Sample Subset) ..................................................................53
Table 5:
Volume of Blood to be Drawn from Each Subject (Sparse 
Pharmacokinetic Sample Subset) ..................................................................53
Table 6:
Estimates of Clearance and Volume of Distribution for d-
Amphetamine and l-Amphetamine................................................................60


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ABBREVIATIONS
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS-5
Attention-Deficit/Hyperactivity Disorder Rating Scale-5
AE
adverse event
AUC0-∞
area under the curve extrapolated to infinity
AUClast
area under the curve from the time of dosing to the last measurable concentration
AUC0-t
area under the curve from time 0 to the last time point of sample collection
AUC0-5
area under the curve from time 0 predose to 5 hours postdose
AUC5-t
area under the curve from time 5 hours to the last time point of sample collection
AUCtau
area under the concentration curve over the dosing interval (24 hours), at steady state 
BMI
body mass index
CGI-S
Clinical Global Impressions – Severity of Illness
CL/F
total body clearance for extravascular administration
Cmax
maximum concentration occurring at tmax
CSHQ
Children’s Sleep Habits Questionnaire
Ctrough
trough plasma concentration (the predose concentrations collected at steady state)
CRA
clinical research associate
CRC
clinical research center
CRF
case report form
CRO
contract research organization
C-SSRS
Columbia-Suicide Severity Rating Scale
DMC
data monitoring committee
DSM-5
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition
EC
ethics committee
ECG
electrocardiogram
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HIPAA
Health Insurance Portability and Accountability Act
IB
investigator’s brochure
ICH
International Council for Harmonisation
IRB
institutional review board
LAR
legally authorized representative
MINI-KID
Mini International Neuropsychiatric Interview for Children and Adolescents
PK
pharmacokinetic(s)
PSQ
Post Sleep Questionnaire
SAE
serious adverse event
SAP
statistical analysis plan
T3
tri-iodothyronine
T4
thyroxine


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t1/2
terminal half-life
TEAE
treatment-emergent adverse event
tmax
time of maximum observed concentration sampled during a dosing interval
US
United States
VF/ss
apparent volume of distribution at steady state
Vz/F
volume of distribution associated with the terminal slope following extravascular 
administration
z
the first order rate constant associated with the terminal phase of elimination


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STUDY SYNOPSIS
Protocol number: SHP465-112
Drug: SHP465, mixed salts of a single-entity amphetamine
Title of the study: A Phase 1 Open-label Study of the Safety, Tolerability, and Pharmacokinetics of d- and 
l-Amphetamine after Multiple Daily Doses of SHP465 6.25 mg Administered in Children Aged 4 to 5 years with 
Attention-Deficit/Hyperactivity Disorder
Number of subjects (total and for each treatment arm): Approximately 24 subjects are expected to be enrolled to 
ensure that 10 subjects will complete the rich pharmacokinetic (PK) sampling portion of the study and an additional 
10 subjects will complete the sparse PK sampling portion of the study. Enrollment will be stratified by gender to 
ensure that at least 2 of the 10 subjects in the rich PK sampling portion of the study and at least 3 of the 10 subjects 
in the sparse PK sampling portion of the study expected to complete the study are females.
Investigators: Multicenter study
Sites and Regions: Approximately 10 sites in the United States will participate in this study
Study period (planned): 2017-2018
Clinical phase:
1
Objectives:
Primary: To evaluate the pharmacokinetics (PK), safety, and tolerability of SHP465 in children aged 4 to 5 years 
with attention-deficit/hyperactivity disorder (ADHD) after SHP465 multiple daily doses of 6.25 mg.
Rationale:
The proposed clinical study is being conducted to provide information on SHP465 PK, safety, and tolerability after 
4 weeks of SHP465 administration at a daily dose of 6.25 mg in preschool children aged 4 to 5 years with ADHD.
Investigational product, dose, and mode of administration:

There will be one SHP465 dose level of 6.25 mg used in this study.

SHP465 6.25 mg will be given once daily for 28 days (±1 day) at 8:00 AM (±1 hour).

Investigational product will be taken by either swallowing the capsule whole or sprinkling the capsule content
onto 1 tablespoon of applesauce and ingesting the entire mixture immediately without chewing.
Methodology:
The study will be a Phase 1, open-label, multiple-dose, PK, safety, and tolerability study in children aged 4 to 
5 years diagnosed with ADHD. Enrollment will be stratified by gender to ensure that at least 2 of the 10 subjects
expected to complete the rich PK sampling portion of the study and at least 3 of the 10 subjects expected to 
complete the sparse PK sampling portion of the study are females. Subjects for the rich PK sampling portion of the 
study will be enrolled first. Once the required number of subjects is achieved, enrollment in the sparse PK sampling 
group will begin.
Screening Period (Includes Washout Period)
Subjects will be assessed for eligibility during the screening period. The duration of the screening period will be a 
maximum of 32 days. If subjects are currently taking ADHD medication, they are required to discontinue their 
current ADHD medication at least 7 days prior to the first dose of investigational product on Day 1 of Week 1 
(washout period).
Following the screening visit, eligible subjects will return to the clinical research center (CRC) on Day 1 of Week 1 
to reconfirm eligibility criteria and enter into the treatment phase.
If more than 32 days have elapsed since the screening evaluations were completed, then the following evaluations 
must be repeated at baseline (prior to the first dose of investigational product on Day 1 of Week 1): vital signs, 
clinical laboratory evaluations, blood pressure, electrocardiograms (ECGs), weight, and height. The physical 
examination will be abbreviated with a review of the following body systems: general appearance, respiratory, and 
cardiovascular.
 
 


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Treatment Period
The subject will receive SHP465 6.25 mg as a daily dose for 28 days (±1 day).
PK Sample Collection
Subjects should be adequately hydrated before blood draws. Caffeinated drinks should be avoided. Details on fasting 
and hydration are provided in Section 6.2.2.
Rich PK Sample Scheme (9 Samples/Subject) Collection
Predose PK samples will be collected on Day 1 of Week 1, and serial blood samples for PK analysis will be drawn 
prior to dosing on Day 7 of Week 4 (within 60 minutes prior to dosing) and up to 48 hours after administration of 
the investigational product.
On Day 7 of Week 4, subset of subjects in the rich PK sampling portion will be required to remain at the CRC 
through 8 hours postdose. Following completion of the 8-hour PK sample collection, per investigator’s discretion, 
subjects will have the option to remain at or leave the CRC. If they leave the CRC, subjects will either return to the
CRC on Days 7, 8, and 9 of Week 4 for the 12-hour, 16-hour, 24-hour, and 48-hour postdose blood sample 
collections or, if the option is available at their clinical site, a qualified person may visit the subject for the 12-hour, 
16-hour, and 24-hour postdose blood sample collections, but they must return to the clinic for the 48-hour blood
sample collection.
Sparse PK Sample Scheme (4 Samples/Subject) Collection
Predose PK samples will be collected on Day 1 of Weeks 1 to 3 and on Day 8 of Week 4 (24 hours after dosing on 
Day 7 of Week 4) for subjects in the sparse PK sampling subset.
The end-of-study assessments will be performed at the last clinic visit: on Day 9 of Week 4 (approximately 48 hours 
after the last dose of investigational product) for subjects in the rich PK sampling portion and on Day 8 of Week 4 
(approximately 24 hours after the last dose of investigational product) for subjects in the sparse PK sampling portion 
of the study.
Follow-up
At the last clinic visit, subjects and their parent/legally authorized representative (LAR) will be offered to rollover 
into the SHP465-308 study. If subjects agree and their parent/LAR signs the informed consent form, this will end 
their participation in the SHP465-112 study. If they do not want to participate in the SHP465-308 study, follow-up 
contact (study visit/telephone call) will be conducted. For those subjects with ongoing adverse events (AEs), a 
mandatory in-person follow-up visit at the CRC will occur 7 days (±2 days) following the subject’s last dose of 
investigational product to collect information on any ongoing or new AEs, serious AEs (SAEs), or concomitant 
medications, as appropriate.
At the investigator’s discretion, for those subjects with no ongoing AEs at the time of the last scheduled assessment, 
a telephone call initiated by the CRC staff or in-person follow-up visit at the CRC will occur 7 days (±2 days) 
following the subject’s last dose of investigational product to collect information on any new AEs, SAEs, or 
concomitant medications, as appropriate.
Inclusion and exclusion criteria:
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the following criteria (including test 
results).
1.
Subject is a male or female aged 4 years to 5 years inclusive at the time of consent.
2.
Subject and parent/LAR are willing and able to fully comply with all of the testing and requirements defined in
the protocol. Specifically, the parent/LAR must be available at approximately 8:00 AM (±1 hour) to administer
the dose of investigational product at the time points specified in the protocol.
3.
Subject’s parent/LAR must sign the informed consent form, and there must be documentation of assent (if
applicable) by the subject in accordance with the International Council for Harmonisation Good Clinical
Practice Guideline E6 (2016) and any updates, and applicable regulations, before starting any study-related
procedures.


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4.
Subject satisfies the following ADHD criteria during the screening period:

Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 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

Has an ADHD Rating Scale-5 Child, Home Version Total Score of ≥28 for boys and ≥24 for girls

Has a Clinical Global Impressions – Severity of Illness score ≥4.
5.
Subject functions at an age-appropriate level intellectually, as determined by the investigator.
6.
Subject has undergone an adequate course of nonpharmacological treatment OR the subject has a severe
enough condition to consider enrollment without undergoing prior nonpharmacological treatment, based on the
investigator’s judgment OR has never taken ADHD medication OR has taken ADHD medication with
unacceptable efficacy and/or tolerability.
7.
Subject has the ability to take investigational product by either swallowing the capsule whole or sprinkling the
capsule contents in applesauce and ingesting the entire mixture immediately without chewing.
8.
Subject has lived with the same parent/LAR for at least 6 months.
Exclusion Criteria
Subjects are excluded from the study if any of the following exclusion criteria are met:
1.
Prior enrollment or participation in the study.
2.
Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any excipients in the
investigational product.
3.
Subject cannot swallow a pill and/or applesauce, or has an allergy to applesauce.
4.
Subject is currently taking or has taken ADHD medication with acceptable efficacy and tolerability.
5.
Subject has taken ADHD medication within 7 days prior to the administration of investigational product.
6.
Subject has used any medication (including over-the-counter, herbal, or homeopathic preparations) within
30 days prior to the administration of investigational product or 5-half-lives, whichever is longer, with the
exception of the following:

Thyroid medication

Intermittent use of nonsteroidal anti-inflammatory drugs or acetaminophen for minor aches and pains

As needed use of a beta-agonists inhaler for mild asthma or exercise induced bronchospasm

Over-the-counter nonsedating antihistamines such as fexofenadine (ALLEGRA®, Sanofi), loratadine
(CLARITIN®, Schering-Plough), or cetirizine hydrochloride (ZYRTEC®, McNeil-PPC) for allergies.

Subject has continuously used oral corticosteroids ≥7 days in 3 months prior to investigational product
dosing. If continuous use was <7 days, 1 month of washout prior to dosing of investigational product is
required.
7.
Within 30 days prior to the administration of investigational product:

Subject has used an investigational product.
R
If the elimination half-life of the previous study’s investigational product was less than 6 days, then the
last dose of the previous investigational product should be 30 days prior to the first dose of SHP465.
R
If the elimination half-life of the previous study’s investigational product was greater than 6 days, then
the last dose of the previous investigational product should be 5 half-lives prior to the dose of SHP465.
8.
Subject has glaucoma.


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9.
Subject has a known family history of sudden cardiac death or ventricular arrhythmia.
10. 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.
11. Subject has any clinically significant ECG or clinically significant laboratory abnormalities at the first screening
visit based on the investigator’s judgment. A single retest of laboratory parameters is allowed based on the
investigator’s judgment.
12. Subject has Marfan’s syndrome.
13. Subject has a blood pressure ≥95th percentile for age, sex, and height at the screening visit.
14. Subject has a height 5th percentile for age and sex at the first screening visit.
15. Subject has a weight 5th percentile for age and sex at the first screening visit.
16. Subject has current abnormal thyroid function test results, defined as abnormal thyroid-stimulating hormone,
thyroxine, and tri-iodothyronine at the first screening visit. Treatment with a stable dose of thyroid medication
for at least 3 months is permitted.
17. Subject has a history of seizures (other than infantile febrile seizures).
18. 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 positive family history of these disorders in first- or
second-degree relatives

Pervasive developmental disorder

Obsessive-compulsive disorder

A serious tic disorder, or a family history of Tourette disorder

Substance abuse or dependence disorder

Any other disorder that in the opinion of the investigator contraindicates SHP465 or amphetamine
treatment or confounds safety assessments.
19. Subject is currently considered a suicide risk in the opinion of the investigator, has previously made a suicide
attempt, or has a prior history of or is currently demonstrating active suicidal ideation.
20. Subject has a history of physical, sexual, or emotional abuse.
21. Subject has a primary sleep disorder (eg, sleep apnea, narcolepsy).
22. Subject has a history or is currently diagnosed with an eating disorder.
23. Subject has a clinically important abnormality on the urine drug and alcohol screen (excluding the subject’s
current ADHD stimulant, if applicable) at the first screening visit.
24. Subject lives with anyone who currently abuses stimulants or cocaine, based on the investigator’s judgment.
25. 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.
26. Subject has any additional condition(s) such as any significant illness or unstable medical condition that, in the
investigator's opinion, would prohibit the subject from completing the study and /or could lead to difficulty
complying with the protocol.


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Maximum duration of subject involvement in the study:

Each subject’s maximum duration of participation is expected to be approximately 9 weeks. The study will be
completed in approximately 12 months.

Screening period:

A maximum of 32 days before the first dose of investigational product

If applicable, this includes a washout period that is to start 7 days before the first dose of investigational
product.

Treatment Period: Total duration for the treatment period is approximately 30 days for subjects in the rich
PK sampling portion of the study and 29 days for subjects in the sparse PK sampling portion of the study.

Follow-up contact: At the last clinic visit, subjects and their parent/LAR will be offered to rollover into the
SHP465-308 study. If subjects agree and their parent/LAR signs the informed consent form, this will end their
participation in the SHP465-112 study. If they do not want to participate in the SHP465-308 study, follow-up
contact will be conducted approximately 1 week (7 days [±2 days]) following the last dose of investigational
product.
Sample size and power calculations:
To objectively justify the sample size for PK sampling and PK sampling scheme for this study, the following 
precision is recommended in the Food and Drug Administration guidance, General Clinical Pharmacology: 
Considerations for Pediatric Studies for Drugs and Biological Products.
The sample size for traditional rich PK sampling for noncompartmental analysis is calculated to achieve 80% 
probability (power), to assure the 95% confidence interval of the point estimate of the geometric mean of clearance 
is within 60% to 140% of the estimate of the clearance. Although the range (60%, 140%) is not symmetric to 1, the 
lower confidence interval bound is within (60%, 140%) (1/1.4=0.714) as long as the upper bound is ≤1.4.
The available data in the following table are from Shire’s completed study (SHP465-111) with an ADHD pediatrics 
population and show the reported apparent clearance (CL/F) and volume of distribution (Vz/F) for the 
d-amphetamine and l-amphetamine of SHP465 after oral administration of 12.5 mg in children aged 6 to 12 years 
and 25 mg in adolescents aged 13 to 17 years.
Estimates of Clearance and Volume of Distribution for G-Amphetamine and O-Amphetamine
CV (%)
SHP465 12.5 mg
Children (6 to 12 years)
SHP465 25 mg
Adolescents (13 to 17 years)
CL/F (L/h)
Vz/F (L)
CL/F (L/h)
Vz/F (L)
d-Amphetamine
25.0
28.5
23.7
18.4
l-Amphetamine
26.9
32.2
28.4
22.0
CV=coefficient of variation 
Source: SHP465-111 Clinical Study Report Tables 9-1 and 9-4.


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The sample size estimates use the within-subject l-amphetamine variability of 32.2%, since it is numerically bigger. 
Applying the methods from the manuscript by Wang et al., 2012, sample size estimations with related probability 
for corresponding coefficients of variation are provided as follows:
CV (%)
Number of Subjects Required
Probability of the Point Estimate 
Within the Prespecified Interval (%)
18.4
5
89
22.0
5
80
23.7
6
88
25.0
6
82
26.9
7
89
28.4
7
88
28.5
7
88
32.2
8
90
CV=coefficient of variation
Based on these data, the PK analysis will need at least 8 subjects in total to provide reliable PK parameter estimates.
Endpoints and statistical analysis:
Analysis Populations
The screened set will consist of all subjects who have provided informed consent.
The enrolled set will consist of all subjects who have been assigned a subject identification number.
The safety set will consist of all enrolled subjects who have taken at least 1 dose of investigational product.
The PK set will consist of all subjects in the safety set for whom at least 1 postdose PK blood sample was collected.
Pharmacokinetic Endpoints
Pharmacokinetic parameters will be determined from the plasma concentration-time data for d-amphetamine and 
l-amphetamine by noncompartmental analysis using Phoenix® WinNonlin® (Certara, Princeton, NJ) Version 6.4 or 
higher.
The PK parameters will include, but not be limited to:

AUC0-∞
Area under the curve extrapolated to infinity

AUC0-t
Area under the curve from time 0 to the last time point of sample collection

AUC0-5
Area under the curve from time 0 predose to 5 hours postdose

AUC5-t
Area under the curve from time 5 hours to the last time point of sample collection

AUClast
Area under the curve from the time of dosing to the last measurable concentration

AUCtau
Area under the concentration curve over the dosing interval (24 hours) at steady state

CL/F
Total body clearance for extravascular administration

Cmax
Maximum concentration occurring at tmax

Ctrough
Trough plasma concentration (the predose concentrations collected at steady state)

t1/2
Terminal half-life

tmax
Time of maximum observed concentration sampled during a dosing interval

VF/ss
Apparent volume of distribution at steady state

Vz/F
Volume of distribution associated with the terminal slope following extravascular administration

z
The first order rate constant associated with the terminal phase of elimination


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There will be no inferential statistical analysis of the PK data. Summary descriptive statistics (number of 
observations, mean, standard deviation, coefficient of variation, median, maximum, minimum and geometric mean) 
will be determined for all PK parameters. Plasma concentrations at each nominal sampling time will also be 
summarized using descriptive statistics.
Safety Endpoints
Safety will be assessed by treatment-emergent AEs (TEAEs), vital signs (systolic and diastolic blood pressure, pulse 
rate, respiratory rate, and body temperature), 12-lead ECGs, weight, height, clinical laboratory tests (biochemistry, 
hematology, and urinalysis), Post Sleep Questionnaire (PSQ), and a validated sleep questionnaire (Children’s Sleep 
Habits Questionnaire [CSHQ]).
Additionally, the Columbia-Suicide Severity Rating Scale (C-SSRS) scale will capture the safety of SHP465 related 
to suicidality.
The safety endpoints will be summarized with descriptive statistics for the safety set.
Baseline is defined as the last assessment prior to the first dose of investigational product. Potentially clinically 
important findings will also be summarized or listed. The potentially clinically important values will be defined in 
the statistical analysis plan.
Weight, height, BMI, vital signs, ECG, PSQ, and CSHQ will be summarized. The C-SSRS results will be 
summarized and a listing of the C-SSRS data will be provided for subjects with a positive response.
Adverse events will be coded using the agreed-upon version of the Medical Dictionary for Regulatory Activities. 
The number of events, incidence, and percentage of TEAEs will be calculated overall, by system organ class, and by 
preferred term. Treatment-emergent AEs will be further summarized by severity and relationship to investigational 
product. Adverse events related to investigational product, AEs leading to withdrawal, SAEs, and deaths will be 
similarly summarized/listed.


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STUDY SCHEDULE
Table 1:
Schedule of Assessments for Rich Pharmacokinetic Sampling Portion
Assessment Day
Screening and Washout
Week 1
to 3
Week 4
Follow-upa
D -32
to D -8
D -7
to D -1
Washout
D 1 D 2-7 D 1 D 2-6
D 7
D 8b
D 9
/ETb
Treatment Week 4 Time Point (h)
Predosec
0
2
5
8
12
16
24
48
Informed Consent & Assent
X
Inclusion/Exclusion Criteria
X
Xd
Demographics
X
Medical & Medication History (Includes 
Prior Medications and Procedures)e
X
Physical Examination
X
Xf
Xf
Xg
Xh
Vital Signsi
X
X
X
X
X
Xh
Weightj
X
X
X
X
Xh
Heightj
X
Xh
Biochemistry, Hematology, and Urinalysis
X
Xh
TSH, T4, and T3
X
Xh
Urine Drug and Alcohol Screen
X
12-lead ECGi
X
X
X
X
Xh
C-SSRS Baseline Version
X
C-SSRS Since Last Visit Version
X
X
X
Xh
MINI-KID
X
ADHD-RS-5 Child, Home Version
X
Clinical Global Impressions – Severity of 
Illness
X
CSHQ
X
X
X
X
Xh
PSQ
X
X
X
X
Xh
Eligibility Confirmation
Xd
Investigational Product Dispensed
X
X
Investigational Product Administration 
Xk
Xl
Xk
Xl
Xk,m


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Table 1:
Schedule of Assessments for Rich Pharmacokinetic Sampling Portion
Assessment Day
Screening and Washout
Week 1
to 3
Week 4
Follow-upa
D -32
to D -8
D -7
to D -1
Washout
D 1 D 2-7 D 1 D 2-6
D 7
D 8b
D 9
/ETb
Treatment Week 4 Time Point (h)
Predosec
0
2
5
8
12
16
24
48
Pharmacokinetic Sample Collection 
Xn
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
ADHD-RS-5=Attention-Deficit/Hyperactivity Disorder Rating Scale-5; CRC=clinical research center; C-SSRS=Columbia-Suicide Severity Rating Scale; CSHQ=Children's Sleep 
Habits Questionnaire; D=day; ECG=electrocardiogram; ET=Early Termination; h=hours; MINI-KID=Mini International Neuropsychiatric Interview for Children and Adolescents; 
PSQ=Post Sleep Questionnaire; TSH=thyroid-stimulating hormone; T3=tri-iodothyronine; T4=thyroxine.
a 
Follow-up contact will be conducted approximately 1 week (7 days [±2 days]) following the last dose of investigational product.
b
Day 8 and Day 9 may be conducted on an out-patient basis.
c
These assessments should be performed within 2 hours prior to dose administration with the exception of the pharmacokinetic sample, which should be collected within 
60 minutes prior to dosing.
d
Inclusion/exclusion criteria and eligibility confirmation must be reviewed at the CRC on Day 1 of Week 1.
e
Medical and medication history will include a detailed description of the subject’s psychiatric diagnosis and a lifetime history of pharmacologic therapies for ADHD and other 
disorders.
f
A brief physical examination will be performed prior to dosing on Day 1.
g
A brief physical examination will be performed prior to dosing on Day 7 of Week 4.
h
An attempt to perform these assessments and procedures will be made for any subjects who withdraw or are removed from the study. 
i
Subjects should be resting in a sitting position for at least 5 minutes prior to collecting vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature). Subjects should be resting in a supine position for at least 5 minutes prior to collecting ECGs. If an invasive procedure was conducted prior to blood pressure, 
ECG and respiratory rate recording, the subject should be resting for 15 minutes.
Blood pressure and pulse will be measured at each visit. Measurements of blood pressure and pulse will be performed 3 times (with at least 2 minutes in between each 
collection) using the provided age-appropriate cuff. The average of each set of 3 measurements will be used to determine continued participation in the study.
Temperature and respiratory rate will be collected at the screening visit and ET visit only.
Measurement of blood pressure and pulse will be performed 3 times (with at least 2 minutes in between each collection) using the provided age-appropriate cuff.
j
Height and weight to be measured without shoes and with light clothing using a stadiometer for height and calibrated scale for weight.
k
Dosing will be done at the CRC.
l
Dosing will be done at the home.
m
Subjects should fast for 2 hours prior to dose administration on Day 7 of Week 4 and for 2 hours postdose. At 2 hours postdose on Day 7, subjects will be allowed to consume a 
light breakfast, ie, a single serving of cereal with up to 8 ounces of skim milk. Starting at 4 hours postdose on Day 1, for lunch and dinner, subjects will receive a standardized 
moderate fat meal. Subjects will be allowed snacks starting after lunch.
n
To be sampled predose on Week 1 only.
Whenever possible, the same individual should complete/rate consistently the following scales and questionnaires as appropriate: ADHD-RS-5 Child, Home Version; Clinical 
Global Impressions - Severity of Illness; Post Sleep Questionnaire; and Children’s Sleep Habits Questionnaire.


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Table 2:
Schedule of Assessments for Sparse Pharmacokinetic Sampling Portion
Assessment Day
Screening and Washout
Week 1 to 3
Week 4
Follow-upa
D -32
to D -8
D -7 to D -1
Washout
D 1
D 2-7
D 1
D 2-7
D 8
/ET
Informed Consent & Assent
X
Inclusion/Exclusion Criteria
X
Xb
Demographics
X
Medical & Medication Historyc
X
Physical Examination
X
Xd
Xd
Xe
Vital Signsf
X
X
X
Xe
Weightg
X
X
X
Xe
Heightg
X
Xe
Biochemistry, Hematology, and Urinalysis
X
Xe
TSH, T4, and T3
X
Xe
Urine Drug and Alcohol Screen
X
12-lead ECGf
X
X
Xe
C-SSRS Baseline Version
X
C-SSRS Since Last Visit Version
X
X
Xe
MINI-KID
X
ADHD-RS-5 Child, Home Version
X
Clinical Global Impressions – Severity of Illness
X
CSHQ
X
X
X
Xe
PSQ
X
X
X
Xe
Eligibility Confirmation
Xb
Investigational Product Dispensed
X
X
Investigational Product Administration 
Xh
Xi
Xh
Xi
Pharmacokinetic Sample Collection - Predose
X
X
Concomitant Medications
X
X
X
X
X
X
Xe
X
Adverse Events
X
X
X
X
X
X
Xe
X
ADHD-RS-5=Attention-Deficit/Hyperactivity Disorder Rating Scale-5; CRC=clinical research center; C-SSRS=Columbia-Suicide Severity Rating Scale; CSHQ=Children's Sleep 
Habits Questionnaire; D=day; ECG=electrocardiogram; ET=Early Termination; h=hours; MINI-KID=Mini International Neuropsychiatric Interview for Children and Adolescents; 
PSQ=Post Sleep Questionnaire; TSH=thyroid-stimulating hormone; T3=tri-iodothyronine; T4=thyroxine.
a
Follow-up contact will be conducted approximately 1 week (7 days [±2 days]) following the last dose of investigational product.
b
Inclusion/exclusion criteria and eligibility confirmation must be reviewed at the CRC on Day 1 of Week 1.


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Table 2:
Schedule of Assessments for Sparse Pharmacokinetic Sampling Portion
Assessment Day
Screening and Washout
Week 1 to 3
Week 4
Follow-upa
D -32
to D -8
D -7 to D -1
Washout
D 1
D 2-7
D 1
D 2-7
D 8
/ET
c
Medical and medication history will include a detailed description of the subject’s psychiatric diagnosis and a lifetime history of pharmacologic therapies for ADHD and other 
disorders.
d
A brief physical examination will be performed prior to dosing on Day 1 of Weeks 1 to 4.
e
An attempt to perform these assessments and procedures will be made for any subjects who withdraw or are removed from the study.
f
Subjects should be resting in a sitting position for at least 5 minutes prior to collecting vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature). Subjects should be resting in a supine position for at least 5 minutes prior to collecting ECGs. If an invasive procedure was conducted prior to blood pressure, 
ECG and respiratory rate recording, the subject should be resting for 15 minutes.
Blood pressure and pulse will be measured at each visit.
Temperature and respiratory rate will be collected at the screening visit and ET visit only.
g
Height and weight to be measured without shoes and with light clothing using a stadiometer for height and calibrated scale for weight.
h
Dosing will be done at the CRC.
i
Dosing will be done at the home.


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1
BACKGROUND INFORMATION
SHP465 is a once daily, sustained-release, single-entity mixed amphetamine salt product for oral 
administration. The product was previously referred to as SPD465; however, it is now being 
studied under the code of SHP465. The amphetamine salt combination found in SHP465 is 
comprised of sulfate salts of dextroamphetamine and amphetamine, with dextroamphetamine 
saccharate and amphetamine aspartate monohydrate, which provide a composite enantiomer ratio 
of 3:1 d-amphetamine to l-amphetamine.
SHP465 capsule contains 3 types of drug-releasing beads providing immediate release, pulsatile 
delayed release, and delayed sustained release of the mixed amphetamine salts. The immediate 
release bead comprises a drug-layered sphere which releases rapidly in the stomach. The 
pulsatile delayed-release bead includes an additional pH sensitive polymer coating which is 
insoluble under gastric pH conditions but is soluble above pH 5.5, thereby releasing drug in the 
small intestine. The delayed sustained-release bead includes a pH sensitive polymer coating with 
an additional coating of a sustained-release polymer; this combination begins releasing drug once 
the gastrointestinal track reaches pH 7.0 or above.
Amphetamines are noncatecholamine sympathomimetic amines with central nervous system 
stimulant activity. The primary mechanism of action is to increase synaptic concentrations of 
monoamine neurotransmitters, thereby indirectly enhancing noradrenergic, dopaminergic 
neurotransmission in the central nervous system (Heal et al., 2013). Amphetamine increases the 
availability of biogenic amines (primarily dopamine and norepinephrine) in central nerve 
synapses through multiple actions, including stimulating neurotransmitter release into the nerve 
terminal and inhibiting reuptake from the synapse. These actions may be the basis of its 
therapeutic actions in attention-deficit/hyperactivity disorder (ADHD); however, the mode of 
therapeutic action in ADHD is not known.
1.1
Indication and Current Treatment Options 
The exact etiology of ADHD is unknown. Extensive research has suggested that neurotransmitter 
deficits (Arnsten, 2001), genetics (Arnsten, 2001; Brown, 2003), environment (Kahn et al., 
2003), and perinatal complications (Bhutta and Anand, 2002) may all be contributing factors. 
The hypothesized mechanism of action of effective medications in ADHD is to raise 
neurotransmitter levels (specifically norepinephrine and/or dopamine, or their precursors) at the 
synapse either by facilitating neurotransmitter release from the synapse or by decreasing 
neurotransmitter reuptake by binding or activating the postsynaptic receptor (Kratochvil et al., 
2003; Wang et al., 2007).
According to the Diagnostic and Statistical Manual of Mental Disorders, ADHD has 3 subtypes: 
hyperactive/impulsive, inattentive, and combined, and individuals with ADHD may manifest 
considerably different symptomology depending on sex, disorder subtype, and the presence of 
comorbid disorders.
Compared with nonstimulants, stimulant medications (ie, amphetamine or methylphenidate) 
produce the most robust improvements in symptom expression across all age ranges 
(Spencer et al., 1996). 


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Furthermore, stimulant medications have a rapid onset of action, within 1 hour to 2 hours of 
dosing, compared with nonstimulants (eg, atomoxetine), which can require dosing for up to 
4 weeks to 6 weeks to achieve maximal therapeutic benefit (Wilens et al., 2002).
Nonpharmacologic measures (psychological, educational, and social) can also be beneficial, and 
psychosocial treatments for adults with ADHD have been studied (Safren et al., 2004; Greenfield 
and Hechman, 2005). Comorbid psychiatric and learning disorders are common in adults with 
ADHD, and appropriate evaluation, diagnosis, and treatment are recommended (Weiss and 
Murray, 2003).
Importantly, symptoms may not only manifest throughout the day. Many patients continue to 
have residual symptoms lasting into the evening hours (Greenfield and Hechman, 2005). Adult 
patients may benefit from symptom relief into the evening hours for such activities as planning 
and organizing, or professional activities (eg, professional work at night), spousal/parental 
responsibilities, and driving. Similarly, impairments in nighttime activities are recognized in the 
pediatric population, which may need coverage all day and into the evening as well (eg, to do 
homework and to participate in family/social activities).
The impairments in psychosocial academic and occupational functioning associated with ADHD 
may arise from underlying chronic deficiencies in executive function (Brown, 1996). In general, 
the term executive function is used to describe a set of cognitive abilities that control and 
regulate judgments and behaviors which are necessary for goal-directed behavior; however, the 
specific definition of executive functioning varies and is debated. Understanding and treating 
executive functioning deficits is increasingly considered an unmet medical need in ADHD. 
1.2
Product Background and Clinical Information
SHP465 and its prototypes have been evaluated in 1641 subjects in 16 clinical studies, of which 
13 clinical studies were in adult subjects aged 18 years to 55 years and 3 clinical studies were in 
pediatric subjects aged 6 years to 17 years. The SHP465 clinical development program has 
shown that doses of 12.5 mg to 50 mg in adult subjects and 12.5 mg 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-amphetamine and l-amphetamine are similar.
Acceptable safety and tolerability profiles observed were consistent with the types of side effects
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).


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Always refer to the latest version of the SHP465 investigator’s brochure (IB) for the overall 
risk/benefit assessment and the most accurate and current information regarding the drug 
metabolism, pharmacokinetics (PK), efficacy, and safety of SHP465.
2
STUDY OBJECTIVES AND PURPOSE
2.1
Rationale for the Study
The proposed clinical study is being conducted to provide information on SHP465 PK, safety,
and tolerability after 4 weeks of SHP465 administration at a daily dose of 6.25 mg in preschool 
children aged 4 to 5 years with ADHD.
2.2
Study Objectives
2.2.1
Primary Objective
To evaluate the PK, safety, and tolerability of SHP465 in children aged 4 to 5 years with ADHD 
after SHP465 multiple daily doses of 6.25 mg.
3
STUDY DESIGN
3.1
Study Design
The study will be a Phase 1, open-label, multiple-dose, PK, safety, and tolerability study in 
children aged 4 to 5 years diagnosed with ADHD. Enrollment will be stratified by gender to 
ensure that at least 2 of the 10 subjects expected to complete the rich PK sampling portion of the 
study and at least 3 of the 10 subjects expected to complete the sparse PK sampling portion of 
the study are females. Subjects for the rich PK sampling portion of the study will be enrolled 
first. Once the required number of subject is achieved, enrollment in the sparse PK sampling 
group will begin.
Subjects will be assessed for eligibility during the screening period. The duration of the 
screening period will be a maximum of 32 days. If subjects are currently taking ADHD 
medication, they are required to discontinue their current ADHD medication at least 7 days prior 
to the first dose of investigational product on Day 1 of Week 1 (washout period). 
Following the screening visit, eligible subjects will return to the clinical research center (CRC) 
on Day 1 of Week 1 to reconfirm eligibility criteria and enter into the treatment phase.
If more than 32 days have elapsed since the screening evaluations were completed, then the 
following evaluations must be repeated at baseline (prior to the first dose of investigational 
product on Day 1 of Week 1): vital signs, clinical laboratory evaluations, blood pressure, 
electrocardiograms (ECGs), weight, and height. The physical examination will be abbreviated 
with a review of the following body systems: general appearance, respiratory, and 
cardiovascular.
The PK of d-amphetamine and l-amphetamine will be evaluated in this study, according to the 
schedule in Table 1 (rich PK sample subset) and Table 2 (sparse PK sample subset). 


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Rich PK Sample Scheme (9 Samples/Subject) Collection
Predose PK samples will be collected on Day 1 of Week 1, and serial blood samples for PK 
analysis will be drawn prior to dosing on Day 7 of Week 4 (within 60 minutes prior to dosing) 
and up to 48 hours after administration of the investigational product.
On Day 7 of Week 4, subset of subjects in the rich PK sampling portion will be required to 
remain at the CRC through 8 hours postdose. Following completion of the 8-hour PK sample 
collection, per investigator’s discretion, subjects will have the option to remain at or leave the 
CRC. If they leave the CRC, subjects will either return to the CRC on Days 7, 8, and 9 of 
Week 4 for the 12-hour, 16-hour, 24-hour, and 48-hour postdose blood sample collections or, if 
the option is available at their clinical site, a qualified person may visit the subject for the 
12-hour, 16-hour, and 24-hour postdose blood sample collections, but they must return to the 
clinic for the 48-hour blood sample collection.
Sparse PK Sample Scheme (4 Samples/Subject) Collection
Predose PK samples will be collected on Day 1 of Weeks 1 to 3 and on Day 8 of Week 4 
(24 hours after dosing on Day 7 of Week 4) for subjects in the sparse PK sampling subset.
3.2
Duration and Study Completion Definition
Each subject’s maximum duration of participation is expected to be approximately 9 weeks. The 
study will be completed in approximately 12 months.

Screening period:

A maximum of 32 days before the first dose of investigational product

If applicable, this includes a washout period that is to start 7 days before the first dose of
investigational product.

Treatment Period: Total duration for the treatment period is approximately 30 days for
subjects in the rich PK sampling portion of the study and 29 days for subjects in the sparse
PK sampling portion of the study.

Follow-up contact: At the last clinic visit, subjects and their parent/legally authorized
representative (LAR) will be offered to rollover into the SHP465-308 study. If subjects agree
and their parent/LAR signs the informed consent form, this will end their participation in the
SHP465-112 study. If they do not want to participate in the SHP465-308 study, follow-up
contact will be conducted approximately 1 week (7 days [±2 days]) following the last dose of
investigational product.
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.


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3.3
Sites and Regions
The study will be conducted in approximately 10 sites in the US.
4
STUDY POPULATION
Each subject and parent/LAR must participate in the informed consent/assent process, and the 
parent/LAR must provide written informed consent/assent before any procedures specified in the 
protocol are performed.
4.1
Inclusion Criteria
The subject will not be considered eligible for the study without meeting all of the following 
criteria (including test results):
1. Subject is a male or female aged 4 years to 5 years inclusive at the time of consent.
2. Subject and parent/LAR are willing and able to fully comply with all of the testing and
requirements defined in the protocol. Specifically, the parent/LAR must be available at
approximately 8:00 AM (±1 hour) to administer the dose of investigational product at the time
points specified in the protocol.
3. Subject’s parent/LAR must sign the informed consent form, and there must be
documentation of assent (if applicable) by the subject in accordance with the International
Council for Harmonisation (ICH) Good Clinical Practice (CGP) Guideline E6 (2016) and any
updates, and applicable regulations, before starting any study-related procedures.
4. Subject satisfies the following ADHD criteria during the screening period:

Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
criteria for a primary diagnosis of ADHD (any subtype) based on a detailed psychiatric
evaluation using the Mini International Neuropsychiatric Interview for Children and
Adolescents (MINI-KID)

Has an ADHD Rating Scale-5 (ADHD-RS-5) Child, Home Version Total Score of
≥28 for boys and ≥24 for girls

Has a Clinical Global Impressions-Severity of Illness (CGI-S) score ≥4.
5. Subject functions at an age-appropriate level intellectually, as determined by the investigator.
6. Subject has undergone an adequate course of nonpharmacological treatment OR the subject
has a severe enough condition to consider enrollment without undergoing prior
nonpharmacological treatment, based on the investigator’s judgment OR has never taken
ADHD medication OR has taken ADHD medication with unacceptable efficacy and/or
tolerability.
7. Subject has the ability to take investigational product by either swallowing the capsule whole
or sprinkling the capsule contents in applesauce and ingesting the entire mixture immediately
without chewing.
8. 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. Prior enrollment or participation in the study.
2. Subject has a documented allergy, hypersensitivity, or intolerance to amphetamine or to any
excipients in the investigational product.
3. Subject cannot swallow a pill and/or applesauce, or has an allergy to applesauce.
4. Subject is currently taking or has taken ADHD medication with acceptable efficacy and
tolerability.
5. Subject has taken ADHD medication within 7 days prior to the administration of
investigational product.
6. Subject has used any medication (including over-the-counter, herbal, or homeopathic
preparations) within 30 days prior to the administration of investigational product or
5 half-lives, whichever is longer, with the exception of the following:

Thyroid medication

Intermittent use of nonsteroidal anti-inflammatory drugs or acetaminophen for minor
aches and pains

As needed use of a beta-agonists inhaler for mild asthma or exercise induced
bronchospasm

Over-the-counter nonsedating antihistamines such as fexofenadine (ALLEGRA®, Sanofi),
loratadine (CLARITIN®, Schering-Plough), or cetirizine hydrochloride (ZYRTEC®,
McNeil-PPC) for allergies.

Subject has continuously used oral corticosteroids ≥7 days in 3 months prior to
investigational product dosing. If continuous use was <7 days, 1 month of washout prior
to dosing of investigational product is required.
7. Within 30 days prior to the administration of investigational product:

Subject has used an investigational product.
R
If the elimination half-life of the previous study's investigational product was less
than 6 days, then the last dose of the previous investigational product should be
30 days prior to the first dose of SHP465.
R
If the elimination half-life of the previous study's investigational product was greater
than 6 days, then the last dose of the previous investigational product should be
5 half-lives prior to the dose of SHP465.
8. Subject has glaucoma.
9. Subject has a known family history of sudden cardiac death or ventricular arrhythmia.


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10. 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.
11. Subject has any clinically significant ECG or clinically significant laboratory abnormalities
at the first screening visit based on the investigator’s judgment. A single retest of laboratory
parameters is allowed based on the investigator’s judgment.
12. Subject has Marfan’s syndrome.
13. Subject has a blood pressure ≥95th percentile for age, sex, and height at the screening visit
(Appendix 2.3 and Appendix 2.5).
14. Subject has a height 5th percentile for age and sex at the first screening visit (Appendix 2.2
and Appendix 2.4).
15. Subject has a weight 5th percentile for age and sex at the first screening visit.
16. Subject has current abnormal thyroid function test results, defined as abnormal
thyroid-stimulating hormone, thyroxine (T4), and tri-iodothyronine (T3) at the first screening
visit. Treatment with a stable dose of thyroid medication for at least 3 months is permitted.
17. Subject has a history of seizures (other than infantile febrile seizures).
18. 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 illness, psychosis/schizophrenia, or positive family history of these disorders in
first- or second-degree relatives

Pervasive developmental disorder

Obsessive-compulsive disorder

A serious tic disorder, or a family history of Tourette disorder

Substance abuse or dependence disorder

Any other disorder that, in the opinion of the investigator, contraindicates SHP465 or
amphetamine treatment or confounds efficacy or safety assessments.
19. Subject is currently considered a suicide risk in the opinion of the investigator, has
previously made a suicide attempt, or has a prior history of or is currently demonstrating
active suicidal ideation.
20. Subject has a history of physical, sexual, or emotional abuse.
21. Subject has a primary sleep disorder (eg, sleep apnea, narcolepsy).
22. Subject has a history or is currently diagnosed with an eating disorder.


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23. Subject has a clinically important abnormality on the urine drug and alcohol screen
(excluding the subject's current ADHD stimulant, if applicable) at the first screening visit.
24. Subject lives with anyone who currently abuses stimulants or cocaine, based on the
investigator’s judgment.
25. 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.
26. Subject has any additional condition(s) such as any significant illness or unstable medical
condition that, in the investigator's opinion, would prohibit the subject from completing the
study and /or could lead to difficulty complying with the protocol.
4.3
Reproductive Potential
Contraception is not applicable as no female subjects in this study are of childbearing potential. 
All female subjects in this study are premenarchal, less than age 9 years, and Tanner Stage 1.
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 early withdrawal 
evaluations listed in Table 1 and Table 2 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 also be recorded in the 
source document.
Subjects who discontinue may be replaced at the discretion of the investigator and sponsor to 
ensure at least 10 completers in each of the PK sampling portions of the study (of which at least 
2 subjects in the rich PK sample subset and at least 3 subjects in the rich PK sample subset 
should be female).
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 in Sections 4.4.1.1 and 4.4.1.2.


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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).
Increases in blood pressure (both systolic and diastolic) from the 50th to the 95th percentile 
(representative of a change of 2 standard deviations) range from 17 mmHg to 20 mmHg for both 
boys and girls in this age range. Based on this range, an increase of >15 mmHg from the baseline 
visit (predose on Day 1) was selected for this protocol. 
If there are elevations in the average systolic and/or diastolic blood pressure based on the 
following defined criteria, further assessment will be required (average is of 3 readings with 
approximately 2 minutes between readings):

Elevations in average (of 3 readings) sitting systolic blood pressure defined as an increase of
>15 mmHg from the baseline visit (predose on Day 1) or an average (of 3 readings) sitting
systolic blood pressure value ≥95th percentile for age, sex, and height percentile.

Elevations in average (of 3 readings) sitting diastolic blood pressure defined as an increase of
>15 mmHg from the baseline visit (predose on Day 1) or an average (of 3 readings) sitting
diastolic blood pressure value ≥95th percentile for age, sex, and height percentile.
The investigator will discuss each subject who meets any criterion with the medical monitor, and 
a joint decision between the investigator and the medical monitor will be made regarding 
continued participation in the study.
If the subject is allowed to remain in the study, an unscheduled visit will be conducted the next 
business day. If a visit cannot be conducted the next business day, the subject may be 
discontinued from the study.
At the unscheduled visit, 3 individual measurements will be obtained, and the average of the 
3 blood pressure measurements for each parameter will be reported. The investigator will notify 
the medical monitor of the results, and, if the previously met criteria remain, the subject will be 
discontinued from the study. 
Any subject with a systolic or diastolic blood pressure value <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). 
An elevation in the average (of 3 readings) sitting pulse, defined as >126 bpm, equivalent to the 
99th percentile for this age range, requires further assessment. 


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The investigator will discuss each subject meeting this criterion with the medical monitor, and a 
joint decision between the investigator and the medical monitor will be made regarding 
continued participation in the study.
If the subject is allowed to remain in the study, an unscheduled visit will be conducted the next 
business day. If a visit cannot be scheduled the next business day, the subject may be 
discontinued from the study. 
At the unscheduled visit, the investigator will notify the medical monitor of the results, and if the 
pulse is still >126 bpm, the subject will be discontinued from the study. 
Any subject with a pulse rate ≥126 bpm may be discontinued from the study based upon the 
clinical judgment of the investigator regarding the subject’s safety.
4.4.2
Reasons for Discontinuation
The reason for withdrawal must be determined by the investigator and recorded in the subject’s 
medical record and on the case report form (CRF). If a subject is withdrawn for more than 
1 reason, each reason should be documented in the source document and the most clinically 
relevant reason should be entered on the CRF.
Reasons for discontinuation include but are not limited to:

Adverse event (AE)

Protocol violation

Withdrawal by subject or parent/LAR

Lost to follow-up

Blood pressure and/or pulse criteria for discontinuation 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 or parent/LAR in the 
event that any subject is lost to follow-up at any time point prior to the last scheduled contact 
(office visit or telephone contact). At least 1 of these documented attempts must include a written 
communication sent to the subject’s last known address via courier or mail (with an 
acknowledgement of receipt request) asking that they return to the site for final safety 
evaluations and return any unused investigational product.
5
PRIOR AND CONCOMITANT TREATMENT
All nonstudy treatment (including but not limited to herbal treatments, vitamins, and 
nonpharmacological treatment such as behavioral treatment) received within 30 days prior to the 
screening visit (Day -1) (or PK equivalent of 5 half-lives, whichever is longer) and through the 
final study contact (including the protocol-defined follow-up period) must be recorded in the 
source document.


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5.1
Prior Treatment
Prior treatment includes all treatment (including but not limited to herbal treatments, vitamins, 
nonpharmacological treatment, such as behavioral treatment) received within 30 days (or PK 
equivalent of 5 half-lives, whichever is longer) of the date of the administration of 
investigational product. Prior treatment information must be recorded in the source document.
5.2
Concomitant Treatment 
Concomitant treatment refers to all treatment taken between the dates of the administration of 
investigational product and the end of the follow-up period, inclusive. Concomitant treatment 
information must be recorded in the source document.
5.2.1
Permitted Treatment
Subjects should refrain from taking any medications (excluding those medications that are 
permitted) during the course of the study. Any medication which is considered necessary for the 
subject’s safety and well-being may be given at the discretion of the investigator. The 
administration of all medications (including investigational products) must be listed in the source 
documents.
Medications permitted during the study are listed as follows:

Stable (ie, for at least 3 months prior to the screening visit) dose of thyroid medication

Stable (ie, for at least 1 month prior to the screening visit) dose of bronchodilator inhalers
(however, oral beta-agonists and oral corticosteroids are prohibited)

Any medications that do not affect blood pressure, heart rate, or the central nervous system,
and which are considered necessary for the subject's welfare, may be administered at the
discretion of the investigator

Nonsedating antihistamines such as fexofenadine (eg, ALLEGRA, Sanofi), loratadine
(eg, CLARITIN, Schering-Plough), and cetirizine hydrochloride (eg, ZYRTEC, McNeil PPC)

Over-the-counter nonstimulant cold remedies

A topical numbing agent may be used to assist in the drawing of blood.
5.2.2
Prohibited Treatment
Table 3 details the washout period for common prior treatments that are excluded medications 
for this study.


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Table 3:
Common Excluded Treatments and Associated Washout Period Relative to 
Baseline Visit
Minimum Number of Days 
Before Baseline Visit
Treatment
7
14
30
Psychostimulants, amphetamines, and amphetamine-like agents
X
Antihypertensivesa
X
Methylxanthines (theophylline and aminophylline)
X
Antihistamines (centrally and peripherally active)
X
Herbal preparations (including melatonin)
X
Sedatives, anxiolytics, antipsychoticsa
X
Monoamine oxidase inhibitors (MAOIs)a
X
Antidepressantsa
X
Clonidine and guanfacine
X
Selective noradrenaline reuptake inhibitors and noradrenaline reuptake inhibitorsa
X
Cytochrome P450 2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine, ritonavir)
X
Alkalinizing agents (eg, sodium bicarbonate, acetazolamide, some thiazides)
X
Acidifying agents (eg, guanethidine, reserpine, glutamic acid hydrochloride, 
ascorbic acid, ammonium chloride, sodium acid phosphate, methenamine salts)
X
a
These medications may signal that an exclusionary diagnosis is present. The medical monitor should be consulted prior to 
instructing a subject to discontinue one of these medications for this study. Baseline visit is considered as predose on Day 1.
6
INVESTIGATIONAL PRODUCT
6.1
Identity of Investigational Product
The test product is SHP465, which will be provided in 6.25 mg capsule form. The product was 
previously referred to as SPD465 and is registered with the Drug Enforcement Agency as 
SPD465; however, it is now being studied under the code of SHP465. The drug will be labeled 
with SHP465 (SPD465). Additional information is provided in the current SHP465 IB.
6.1.1
Blinding the Treatment Assignment
Not applicable.
6.2
Administration of Investigational Product
6.2.1
Allocation of Subjects to Treatment
This is an open-label, single-sequence, 1-period, multiple-dose, PK, safety, and tolerability 
study.


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Subject numbers are assigned to all subjects as they consent/assent 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. This will be a 4-digit 
number starting at 0001.
A 4-digit subject number, starting at 1001, will be allocated immediately prior to dosing after 
eligibility has been determined. If a subject number is allocated incorrectly, the study monitor 
must be notified as soon as the error is discovered. Once a subject number has been assigned, 
that number must not be used again if, for example, a subject is withdrawn from the study. For 
enrolled subjects, the subject number will be the identifying number used throughout the CRF.
If a unique identifier is allocated incorrectly, the clinical research associate (CRA)/study monitor 
must be notified as soon as the error is discovered.
Investigational product packaging identification numbers, separate from 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.
6.2.2
Dosing
There will be one SHP465 dose level of 6.25 mg used in this study. 
On Day 1 of each week (Weeks 1-4), all subjects will report to the CRC approximately 2 hours 
prior to the time of dosing for predose evaluations. The dose will be administered daily as a 
single dose for 28 days (±1 day) at 8:00 AM (±1 hour). Doses on Day 1 of each week 
(Weeks 1-4) will be administered in the CRC. The parent/LAR will be dispensed a bottle 
containing the remaining doses for that week. The same parent/LAR should be available daily to 
dispense the dose of investigational product for the study duration.
For all subjects, investigational product will be taken by either swallowing the capsule whole or 
sprinkling the capsule contents onto 1 tablespoon of applesauce. 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. A single capsule cannot be split. The empty 
gelatinous capsule should be discarded. 
On Day 7 of Week 4, subjects in the rich PK sampling subset will report to the CRC for dosing 
approximately 2 hours prior to dose administration. Subjects should fast for 2 hours prior to dose 
administration and for 2 hours postdose, and the site should record the timing and composition of 
the last meal consumed by the subject. Subjects in the rich PK sampling portion will be required 
to remain at the CRC through 8 hours postdose. At 2 hours postdose, subjects will be allowed to 
consume a light breakfast, eg, a single serving of cereal with up to 8 ounces of skim milk. 
Subjects should be well hydrated while at the CRC for PK draws. Water or other clear liquids 
should be given ad libitum. Caffeinated beverages should not be consumed for 2 hours prior to 
dosing and until 12 hours after the postdose PK sample is obtained.


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6.2.3
Unblinding the Treatment Assignment
Not applicable.
6.3
Labeling, Packaging, Storage, and Handling
6.3.1
Labeling
Labels containing study information and pack identification are applied to the investigational 
product(s) container.
All investigational product is labeled with a minimum of the following:

protocol number

medication identification number (if applicable)

dosage form (including product name and quantity in pack)

directions for use, storage conditions, expiry date (if applicable)

batch number and/or packaging reference

the statements “For clinical trial use only” and/or “CAUTION: New Drug – Limited by
Federal (or US) Law to Investigational Use,” and “Keep out of reach of children,”

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:
SHP465 capsules are packaged in 9-count high density polyethylene bottles with child resistant 
closures.


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Changes to sponsor-supplied packaging prior to dosing may not occur without full agreement in 
advance by the sponsor.
6.3.3
Storage
The investigator has overall responsibility for ensuring that investigational product is stored in a 
secure, limited-access location. Limited responsibility may be delegated to the pharmacy or 
member of the study team, but this delegation must be documented. Investigational products are 
distributed by the pharmacy or nominated member of the study team. The pharmacist/nominated 
team member will enter the unique subject identifier and initials on the investigational product 
bottle/carton labels as they are distributed.
Investigational product must be stored in accordance with labeled storage conditions. 
Temperature monitoring is required at the storage location to ensure that the investigational 
product is maintained within an established temperature range. The investigator is responsible 
for ensuring that the temperature is monitored throughout the duration of the study and that 
records are maintained; the temperature should be monitored continuously by using either an 
in-house system, a mechanical recording device such as a calibrated chart recorder, or by manual 
means, such that both minimum and maximum thermometric values over a specific time period 
can be recorded and retrieved as required. Such a device (ie, certified minimum/maximum
thermometer) would require manual resetting upon each recording. The sponsor must be notified 
immediately upon discovery of any excursion from the established range. Temperature 
excursions will require site investigation as to cause and remediation. The sponsor will determine 
the ultimate impact of excursions on the investigational product and will provide supportive 
documentation as necessary. Under no circumstances should the product be dispensed to subjects 
until the impact has been determined and the product is deemed appropriate for use by the 
sponsor.
The sponsor should be notified immediately if there are any changes to the storage area of the 
investigational product that could affect the integrity of the product(s), eg, fumigation of a 
storage room.
All controlled-substance investigational product for the sponsor’s studies must be stored in a 
securely locked, substantially constructed room or cabinet according to all applicable local, state, 
and/or national laws. Limited, controlled access to these investigational products must be 
maintained, as well as chain of custody, for all investigational product movement.
6.4
Drug Accountability
Investigators will be provided with sufficient amounts of the investigational product to carry out 
this protocol for the agreed-upon 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.


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The investigator has overall responsibility for administering/dispensing investigational product. 
Where permissible, tasks may be delegated to a qualified designee (eg, a pharmacist) who is 
adequately trained in the protocol and who works under the direct supervision of the investigator. 
This delegation must be documented in the applicable study delegation of authority form.
The investigator or his/her designee (as documented by the investigator in the applicable study 
delegation of authority form) will administer the investigational product only to subjects 
included in this study following the procedures set out in the study protocol. Each subject will be 
given only the investigational product carrying his/her treatment assignment. All administered 
medication will be documented in the source documents and/or other investigational product 
record.
No investigational product stock or returned inventory from a Shire-sponsored study may be 
removed from the site where originally shipped without prior knowledge and consent by the 
sponsor. If such transfer is authorized by the sponsor, all applicable local, state, and national 
laws must be adhered to for the transfer.
The sponsor or its representatives must be permitted access to review the supplies storage and 
distribution procedures and records.
At the end of the study, or as instructed by the sponsor, all unused stock and empty/used 
investigational product packaging are to be sent to a nominated contractor on behalf of the 
sponsor. Investigational products being returned to the sponsor’s designated contractors must be 
counted and verified by clinical site personnel and the sponsor (or designated contract research 
organization [CRO]). For unused supplies where the original supplied tamper-evident feature is 
verified as intact, the tamper-evident feature must not be broken, and the labeled amount is to be 
documented in lieu of counting. Shipment return forms, when used, must be signed 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
Compliance must be assessed by observation of dosing by the investigator or designee when the 
subject is being dosed in the CRC. In addition, the CRC personnel should perform a
hand-and-mouth check of the subject to assure the investigational product has been ingested. The 
investigator/nominated person will record details on the drug accountability form(s) and/or 
source documents. In addition, details of the dosing time (time, date, dose level) will be captured.


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The parent/LAR will also be provided with a diary with customized questions to record the times 
when the investigational product was given to the child.
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.
Subjects who have taken 80% to 100% of the investigational product are regarded as being 
compliant with the study protocol. Compliance must be assessed by the investigator.
The calculation of medication compliance is as follows:
For whole capsules:
Protocol
by
Prescribed
Capsules
100
Taken
Capsules
Total
Compliance


For capsule contents sprinkled in applesauce:
Protocol
by
Prescribed
Capsules
100
Taken
Doses
Sprinkled
Total
Compliance


To ensure that the maximum amount of capsule contents has been taken when sprinkled onto 
applesauce, the total amount of applesauce used is limited to 1 tablespoon.
When performing the calculation of medication compliance for investigational product, the total 
capsules taken must also include number of capsules not returned by the subject to the site.
7
STUDY PROCEDURES
7.1
Study Schedule
The Schedule of Assessments (Table 1 for the rich PK sample subset and Table 2 for the sparse 
PK sample subset) details all procedures to be completed at each visit and should serve as the 
primary section of the protocol regarding visit-specific study procedures.
The following “priority order” will be in effect at the screening visit:

Medical and medication history and physical examination

Vital signs and ECG

PK blood sampling

Clinical laboratory tests


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
Clinician-completed rating scales and assessments conducted by the site, ie, ADHD-RS-5,
Child, Home Version; CGI-S; MINI-KID; Post Sleep Questionnaire (PSQ); and the
Columbia-Suicide Severity Rating Scale (C-SSRS) must be completed by the same rater
whenever possible.
At all other visits, which require more than one procedure or assessment, the following priority 
order will be in effect:

Spontaneous or solicited AE reporting

Vital signs and ECG

PK blood sampling

Clinical laboratory tests

Physical examination
Additional unscheduled visits and/or assessments may occur as needed for safety 
(eg, unscheduled visits for blood pressure and/or pulse measurements will be conducted as 
described in Section 4.4.1).
NOTE: Blood sampling for PK evaluation must be performed at the precise protocol-scheduled 
time. Actual sampling time(s) must be accurately recorded in the source document.
7.1.1
Screening and Washout Period
Subjects will be screened within 32 days prior to initiation of dosing of the investigational 
product. During the screening period, the eligibility of subjects will be assessed. All screening 
assessments and procedures are to be performed by the principal investigator or a qualified 
designee. A complete list of screening procedures to be performed is provided in Table 1 for the 
rich PK sample subset and Table 2 for the sparse PK sample subset.
The principal investigator or his/her designee must obtain written informed consent and assent
from the subject’s parent/LAR prior to any study-related procedures conducted during the 
screening period. 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.
If subjects are currently taking ADHD medication, they are to discontinue their current ADHD 
medication at least 7 days prior to the first dose of investigational product (please refer to
Section 4.2 for additional information).
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 is the date the parent/LAR 
has signed informed consent for this study.


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A screen failure is a subject who has given informed consent and failed to meet any of the 
inclusion and/or met at least 1 of the exclusion criteria and has not been enrolled or administered 
investigational product(s).
Subjects cannot be rescreened once they have been designated as a definite screen failure. 
Reassessment of subjects who failed specific inclusion/exclusion criteria is not allowed.
7.1.2
Treatment Period
The study will consist of 1 treatment period:

The subject will receive a single 6.25-mg dose of SHP465 once daily for 28 days (±1 day) at
8:00 AM (±1 hour)
The assessments and procedures performed during the study are outlined in Table 1 (rich PK 
sample subset) and Table 2 (sparse PK sample subset).
Rich PK Sample Collection Subset
Predose PK samples will be collected on Day 1 of Week 1, and serial blood samples for PK 
analysis will be drawn prior to dosing on Day 7 of Week 4 (within 60 minutes prior to dosing) 
and up to 48 hours after administration of the investigational product.
On Day 7 of Week 4, subset of subjects in the rich PK sampling portion will be required to 
remain at the CRC through 8 hours postdose. Following completion of the 8-hour PK sample 
collection, per investigator’s discretion, subjects will have the option to remain at or leave the 
CRC. If they leave the CRC, subjects will either return to the CRC on Days 7, 8, and 9 of 
Week 4 for the 12-hour, 16-hour, 24-hour, and 48-hour postdose blood sample collections or, if 
the option is available at their clinical site, a qualified person may visit the subject for the 
12-hour, 16-hour, and 24-hour postdose blood sample collections, but they must return to the 
clinic for the 48-hour blood sample collection.
Sparse PK Sample Collection Subset
Predose PK samples will be collected on Day 1 of Weeks 1 to 3 and on Day 8 of Week 4 for 
subjects in the sparse PK sampling subset.
The end-of-study assessments will be performed at the last clinic visit: on Day 9 of Week 4 
(approximately 48 hours after the last dose of investigational product) for subjects in the rich PK 
sampling portion and on Day 8 of Week 4 (approximately 24 hours after the last dose of 
investigational product) for subjects in the sparse PK sampling portion of the study.
7.1.3
Follow-up Period
At the last clinic visit, subjects and their parent/LAR will be offered to rollover into the 
SHP465-308 study. If subjects agree and their parent/LAR signs the informed consent form, this 
will end their participation in the SHP465-112 study. If they do not want to participate in the 
SHP465-308 study, follow-up contact will be conducted. 


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For those subjects with ongoing AEs, a mandatory in-person follow-up visit at the CRC will 
occur 7 days (±2 days) following the subject’s last dose of investigational product to collect 
information on any ongoing or new AEs, serious AEs (SAEs), or concomitant medications, as 
appropriate.
At the investigator’s discretion, for those subjects with no ongoing AEs at the time of the last 
scheduled assessment, a telephone call initiated by the CRC staff or in-person follow-up visit at 
the CRC will occur 7 days (±2 days) following the subject’s dose of investigational product to 
collect information on any new AEs, SAEs, or concomitant medications, as appropriate. All AEs 
and SAEs that are not resolved at the time of this contact will be followed to closure 
(Section 8.1).
7.1.4
Additional Care of Subjects after the Study
Subjects who have completed the study at Day 9 of Week 4 (rich PK sample subset) or at Day 8 
of Week 4 (sparse PK sample subset) may be evaluated for eligibility to enter a long-term safety 
study of SHP465.
7.2
Study Evaluations and Procedures
7.2.1
Demographic and Other Baseline Characteristics
Demographic characteristics such as age, gender, weight, and height will be collected according 
to Table 1 (rich PK sample subset) and Table 2 (sparse PK sample subset).
Clinician-completed rating scales and assessments conducted by the site, ie, ADHD-RS-5 
Child, Home Version; MINI-KID; CGI-S; and C-SSRS must be completed by the same 
rater whenever possible. The parent/LAR-completed Children’s Sleep Habits 
Questionnaire (CSHQ) and the PSQ must be completed by the same individual whenever 
possible.
7.2.1.1
Mini International Neuropsychiatric Interview for Children and 
Adolescents (MINI-KID)
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. The standard MINI-KID Version 7.0.2 for 
DSM-5 assesses the 30 most common and clinically relevant disorders or disorder subtypes in 
pediatric mental health. With this version, the child and parent are interviewed together. 
Additional symptom questions within each disorder section are asked only if the screen 
questions are positively endorsed. The MINI-KID is the structured psychiatric interview of 
choice for psychiatric evaluation and outcome tracking in clinical psychopharmacology trials 
and epidemiological studies. In a validation study (Sheehan et al., 2010), the MINI-KID 
generated reliable and valid psychiatric diagnoses for children and adolescents and does so in 
one-third of the time as the Kiddie Schedule for Affective Disorders and Schizophrenia 
Present and Lifetime Version. 


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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. 
7.2.1.2
Clinical Global Impressions
The Clinical Global Impressions Scale which measures severity of illness (CGI-S) will be 
performed at the time points described in Table 1. The CGI-S (Guy, 1976) permits a global 
evaluation of the subject’s severity and improvement over time. The CGI-S 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.
The CGI-S will be completed by a clinician trained and experienced in the evaluation of 
preschool children with ADHD.
The title, version, and date of the CGI-S used in this study are included in Appendix 3.
7.2.1.3
The ADHD-Rating Scale-5
The ADHD-RS-5 Child, Home Version (DuPaul et al., 2016) is completed by the clinician and 
will be administered at baseline. 
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 to 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.
7.2.2
Safety
The name and address of each third-party vendor (eg, clinical laboratory) used in this study will 
be maintained in the investigator’s and sponsor’s files.


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Actual safety assessment times will be monitored and recorded. The sponsor’s expectation is that 
the investigator will ensure that every effort is made to perform all assessments at the precise 
protocol-scheduled time. Any safety assessment that deviates from the scheduled assessment 
time set forth in the protocol by more than 30 minutes will be considered a protocol deviation.
7.2.2.1
Medical and Medication History
A complete medical and medication history, as well as demographic information, will be 
performed at the screening visit/time points described in Table 1 (rich PK sample subset) and 
Table 2 (sparse PK sample subset) by a qualified licensed physician, physician’s assistant, or a 
nurse practitioner. The medical history will be reviewed and recorded, including:

Date of birth

Sex

Race and ethnicity

Recent ingestion of medication (30 days prior to entering the screening period)

History of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine,
hematological, neurological, psychiatric, and other diseases
With the consent of the subject’s parent/LAR, medical records from other treatment providers 
should be requested.
7.2.2.2
Physical Examination (Including Height and Weight)
A complete physical examination will be performed at the time points described in Table 1 (rich 
PK sample subset) and Table 2 (sparse PK sample subset) by a qualified licensed physician, 
physician’s assistant, or nurse practitioner.
The physical examination will include a review of the following body systems:

General appearance

Skin

Head, eyes, ears, nose, and throat

Spine/neck/thyroid

Musculoskeletal

Respiratory

Cardiovascular

Neurological

Abdomen (including liver and kidneys)


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Abnormalities identified at the screening visit will be documented in the source documents. 
Changes after the screening visit will be captured as AEs as deemed appropriate by the 
investigator.
Height and weight will be measured at the time points described in Table 1 (rich PK sample 
subset) and Table 2 (sparse PK sample subset). 
A calibrated stadiometer must be used for all height measurements. Height should be measured 
in centimeters or inches without shoes with the subject standing on a flat surface and with the 
chin parallel to the floor. The body should be straight but not rigid. The subject’s height should 
be recorded as accurately as possible and should be recorded to the nearest centimeter or nearest 
inch.
The same calibrated scale must be used for all weight measurements. Weight should be 
measured in kilograms or pounds without shoes and with light clothing and recorded as 
accurately as possible and should be recorded to the nearest 0.1 kg or nearest 0.1 lb. Weight and 
height measuring apparatus should be calibrated/tested prior to study initiation.
7.2.2.3
Adverse Event Collection
At each study visit, subjects will be questioned in a general way to ascertain whether AEs have 
occurred since the previous visit (eg, “Have you had any health problems since your last visit?”). 
This information should be collected before the completion of assessments at all study visits. In 
addition, any symptoms and signs/conditions reported during assessments and deemed to be 
clinically significant by the investigator will be assessed as AEs. Adverse events are collected 
from the time informed consent is signed. (Please refer to Section 8, Adverse and Serious 
Adverse Events Assessment.)
7.2.2.4
Vital Signs
Vital signs, including systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature, will be measured at the times specified in Table 1 (rich PK sample subset) and
Table 2 (sparse PK sample subset). Subjects should be resting in a sitting position for at least 
5 minutes prior to collecting vital signs, legs should be uncrossed, and the back and arm should 
be supported. Measurements of sitting systolic and diastolic blood pressure and pulse will be 
performed 3 times at each time point, with approximately 2 minutes between each measurement; 
both individual measurements and the averaged reading should be recorded in the source 
document.
Blood pressure will be determined by the provided age-appropriate cuff (the same equipment and 
the same arm should be used throughout the study). A blood pressure cuff appropriate for the 
subject’s arm length and girth should be used for all blood pressure measurements. The cuff 
should be approximately two-thirds the length/width of the subject’s arm (from elbow to 
shoulder). All blood pressure measurements should be performed by the same study center 
personnel (if possible) throughout the study.
Pulse rate should be counted for 1 minute.


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Any deviations from baseline in vital signs which are deemed clinically significant in the opinion 
of the investigator are to be recorded as an AE.
Respiratory Rate
The subject should be in a comfortable position. The observer should hold the extremity of the 
subject as a distraction for the subject (ie, pretending he/she is taking the subject’s radial pulse) 
and count the respiration for 1 minute. 
Body Temperature
An electronic/chemical dot thermometer in the axilla or an infrared tympanic thermometer 
should be used for measuring the temperature. The thermometer should be left in position for 
sufficient time to gain an accurate reading, according to the manufacturer’s instructions. The 
same method of obtaining temperature should be used throughout the study in a given subject.
7.2.2.5
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 is/are 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 time points indicated in Table 1 (rich 
PK sample subset) and Table 2 (sparse PK sample subset) and include the following:
Biochemistry
Blood samples (2 mL) for serum biochemistry will be collected into a serum separator tube at the 
time points described in Table 1 (rich PK sample subset) and Table 2 (sparse PK sample subset). 
The following parameters will be assessed:
Sodium
Total protein
Potassium
Total CO2 (bicarbonate)
Glucose 
Albumin
Blood urea nitrogen
Aspartate transaminase 
Creatinine
Alanine transaminase 
Calcium
Gamma glutamyl transferase 
Chloride
Alkaline phosphatase 
Thyroid-stimulating hormone
Total bilirubin 
Thyroxine (T4 total)
Uric acid
Tri-iodothyronine (T3)
Phosphorus


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Hematology
Blood samples (1 mL) for hematology will be collected into a K2EDTA plastic tube at the time 
points described in Table 1 (rich PK sample subset) and Table 2 (sparse PK sample subset). The 
following parameters will be assessed:
Hemoglobin
Total neutrophils (absolute and relative)
Hematocrit
Eosinophils (absolute and relative)
Red blood cells
Monocytes (absolute and relative)
Platelet count
Basophils (absolute and relative)
White blood cell count; total and differential
percentage
Lymphocytes (absolute and relative)
Urinalysis
A urine sample for urinalysis will be collected at the time points described in Table 1 (rich PK 
sample subset) and Table 2 (sparse PK sample subset). The following parameters will be 
assessed:
pH
Blood
Nitrites
Glucose
Ketones
Leukocyte esterase
Protein
Bilirubin
Specific gravity
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. 
7.2.2.6
Drug and Alcohol Screen
A urine screen for drugs of abuse and alcohol will be performed at the time point shown in 
Table 1 (rich PK sample subset) and Table 2 (sparse PK sample subset). Additional drug and 
alcohol screens may be performed at the investigator’s discretion.
Urine samples are to be tested for amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine, methadone, opiate metabolite, and phencyclidine.
Results of urine drug and alcohol screens will be reviewed and verified by the study monitor, but 
will not be collected in the CRF database.
Any positive result for drugs of abuse or alcohol at the first screening visit (with the exception of 
the subject’s current stimulant therapy) will exclude the subject from further participation in the 
study.
7.2.2.7
Electrocardiogram
Twelve-lead ECGs will be performed at the times specified in Table 1 (rich PK sample subset) 
and Table 2 (sparse PK sample subset). All ECGs will be performed after 5 minutes of rest using 
equipment approved by the central ECG laboratory and will be sent to the central ECG provider 
according to the instructions in the ECG manual provided by the ECG laboratory. 


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Additionally, ECGs will be performed in triplicate (with a 2 to 5 minute gap between traces) at 
screening. The subject should be asked to remove all clothing that covers the locations of lead 
placement. The subject must be resting in the supine position for at least 5 minutes prior to 
collecting the ECG.
In some cases, it may be appropriate to repeat abnormal ECGs to rule out improper lead
placement as contributing to the ECG abnormality. It is important that leads are placed in
approximately the same positions each time in order to achieve precise ECG recordings. A single
recording, including a 10 second rhythm strip, will be obtained for all assessments after the 
baseline. The time and date of each ECG obtained will be recorded on the CRF. A trace ECG 
recording will be printed and placed in the site’s study file for every ECG taken.
The initial interpretation of the ECG, normal or abnormal and clinical significance, will be 
performed by the Investigator immediately after collection to ensure the safety of each subject. 
An ECG tracing will then be evaluated by a pediatric 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, confirms 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.
7.2.2.8
Columbia-Suicide Severity Rating Scale
The C-SSRS (Posner, 2007) is a semistructured interview that captures the occurrence, severity, 
and frequency of suicide related thoughts and behaviors during the assessment period. The 
interview includes definitions and suggested questions to solicit the type of information needed 
to determine if a suicide-related thought or behavior occurred.
The C-SSRS contains 2 required items pertaining to suicidal ideation, 4 required items pertaining 
to suicidal behavior, and 1 required item pertaining to nonsuicidal but self-injurious behavior. In 
situations where there is a positive response to the screening questions, there are 8 additional 
suicidal ideation items and 4 additional suicidal behavior items which are completed. Thus, there 
is a maximum of 19 items to be completed.
The C-SSRS must be performed by an individual who is medically responsible for the subject. 
All individuals performing this assessment must be pre-approved by the sponsor or delegated 
vendor.


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The Pediatric/Cognitively Impaired Version of the scale will be used in the study. Two 
time-point versions of the C-SSRS are used in this study as follows:

The “baseline” version will be administered at the screening visit.

The “since last visit” version will be completed at all study visits after the screening visit.
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.
7.2.2.9
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 waking’s, parasomnias, sleep disordered breathing, and daytime 
sleepiness. The CSHQ will be conducted at each visit to the site starting with the baseline visit 
(predose on Day 1 of Week 1) and will be completed by the subject’s parent/LAR.
7.2.2.10
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 and will be 
conducted at each visit to the site starting with the baseline visit (predose on Day 1 of Week 1). 
The title, version, and date of the PSQ version used in this study are included in Appendix 3.
7.2.2.11
Suitability of the Subject to Remain in the Study
At each visit (except for early termination) starting with the baseline visit, 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 body 
mass index) and will evaluate for the presence of insomnia or decreased appetite potentially 
leading to weight loss. In cases where the subject has clinically significant decrease 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. 


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Any subject who has 1 or more positive responses must undergo further evaluation to ensure that 
they are not in any way at risk. As part of this assessment, if appropriate, the investigator should 
discuss risk factors for suicide with the subject. Where a subject has suffered an accidental 
injury, the investigator should ensure that this was a true accidental injury, rather than an episode 
of self-harming or a suicide attempt.
The investigator should pay particular attention to:

Any ‘yes’ response to Items 2, 3, 4, or 5 on the C-SSRS or any suicidal behavior
The subject’s source notes should clearly document that the assessment of continued suitability 
including assessment of the subject’s appetite, weight loss, insomnia and current potential risk of 
suicide, suicidal ideation, feelings of hopelessness, drug use, self-harm, or harm to others has 
taken place and should contain the decision on whether the subject is suitable to continue in the 
study.
7.2.3
Pharmacokinetic Procedures
The name and address of the bioanalytical laboratory for this study will be maintained in the 
investigator’s files at each site and in the Trial Master File at the CRO.
Actual PK blood sample collection times versus time of dosing will be monitored. The sponsor’s 
expectation is that the investigator will ensure that every effort is made to collect all PK blood 
samples at the precise protocol-scheduled time. Pharmacokinetic blood collection must not 
deviate from the nominal collection time set forth in the protocol by more than 5 minutes from 
samples drawn within 4 hours postdose or by more than 15 minutes for samples drawn beyond 
4 hours postdose. Samples drawn outside these parameters will be considered a protocol 
deviation. On Days 8 and 9 when subjects return to the CRC or for subjects who choose to 
remain in the CRC for the 24-hour and 48-hour postdose collection of PK samples, all efforts 
should be made to meet the 15 minute window; however, it will not be considered a protocol 
deviation unless the sample is collected more than ±60 minutes postdose for those collection 
times.
7.2.3.1
Blood Sample Collection and Handling Procedures
Blood samples will be collected at the time specified in Table 1 (rich PK sample subset) and 
Table 2 (sparse PK sample subset) to measure plasma concentrations of d-amphetamine and 
l-amphetamine. Potential metabolites may also be determined as appropriate.
Blood samples (2 mL) for PK analysis will be drawn by straight sticks or in-dwelling catheters 
into appropriately labelled K2EDTA Vacutainer® blood collection tubes (BD Vacutainer 
K2EDTA 2 mL tube, catalog number BD 367841, lavender top or equivalent) until the vacuum is 
exhausted and blood ceases to flow. Please refer to the Laboratory Manual for additional details.
The actual time that the sample was obtained will be recorded in the source document. In 
instances where more than 1 blood collection tube is used, the time of the initial blood draw will 
be recorded for all tubes collected at that time point in the source document.




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7.2.4
Volume of Blood to be Drawn from Each Subject
The volume of blood to be drawn from each subject is provided in Table 4 for the rich PK 
sample subset and Table 5 for the sparse PK sample subset.
Table 4:
Volume of Blood to be Drawn from Each Subject (Rich Pharmacokinetic 
Sample Subset)
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samplesa
2 or 3
9
18 - 27
Safety
Biochemistry
2
2
4
Hematology
1
2
2
Total (mL)
24 - 33
a
If a catheter is used, the first mL is to be discarded; the next 2 mL are to be collected into the appropriate tube for the 
pharmacokinetic sample. A total of 3 mL of blood drawn has been used in determination of sample volume.
Table 5:
Volume of Blood to be Drawn from Each Subject (Sparse Pharmacokinetic 
Sample Subset)
Assessment
Sample Volume (mL)
Number of 
Samples
Total Volume (mL)
Pharmacokinetic samples
2
4
8
Safety
Biochemistry
2
2
4
Hematology
1
2
2
Total (mL)
14
During this study, it is expected that approximately 24 mL to 33 mL of blood will be drawn from 
subjects in the rich PK sample subset and 14 mL of blood will be drawn from subjects in the 
sparse PK sample subset, regardless of sex. It is expected that a maximum of approximately 
18 mL will be drawn in any 24-hour period; the 18 mL corresponds to Day 7 of Week 4, where 
there will be 6 PK draws from predose to 16 hours postdose × 3 mL per draw if a catheter is 
used.
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 24 mL to 33 mL of blood will be drawn from subjects in the rich PK 
sample subset and 14 mL of blood will be drawn from subjects in the sparse PK sample subset. 
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.


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8
ADVERSE AND SERIOUS ADVERSE EVENTS ASSESSMENT
8.1
Definition of Adverse Events, Period of Observation, and 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 symptom, unfavorable and unintended sign (including an 
abnormal laboratory finding), or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not related to the medicinal (investigational) product 
(ICH Guideline E2A [1994]).
All AEs are collected from the time the informed consent form 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 and signs should be recorded. If a diagnosis 
has not been made, then each symptom and sign should be listed individually. All AEs should be 
captured in the source documents. In addition to untoward AEs, unexpected benefits outside the 
investigational product indication should also be captured.
All AEs must be followed to closure (the subject’s health has returned to his/her baseline status 
or all variables have returned to normal), regardless of whether the subject is still participating in 
the study. Closure indicates that an outcome is reached, stabilization achieved (the investigator 
does not expect any further improvement or worsening of the event), or the event is otherwise 
explained. When appropriate, medical tests and examinations are performed so that resolution of 
event(s) can be documented.
8.1.1
Severity Categorization
The severity of AEs must be recorded during the course of the event including the start and stop 
dates for each change in severity. An event that changes in severity should be captured as a new 
event. Worsening of pretreatment events, after initiation of investigational product, must be 
recorded as new AEs (for example, if a subject experiences mild intermittent dyspepsia prior to 
dosing of investigational product, but the dyspepsia becomes severe and more frequent after the 
dose of investigational product has been administered, a new AE of severe dyspepsia [with the 
appropriate date of onset] is recorded in the source document).
The medical assessment of severity is determined by using the following definitions:
Mild:
A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living.
Moderate:
A type of AE that is usually alleviated with specific therapeutic intervention. The 
event interferes with usual activities of daily living, causing discomfort but poses 
no significant or permanent risk of harm to the research subject.
Severe:
A type of AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention.


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8.1.2
Relationship Categorization
A physician/investigator must make the assessment of relationship to investigational product for 
each AE. The investigator should decide whether, in his or her medical judgment, there is a 
reasonable possibility that the event may have been caused by the investigational product. If 
there is no valid reason for suggesting a relationship, then the AE should be classified as “not 
related”. Otherwise, if there is any valid reason, even if undetermined or untested, for suspecting 
a possible cause-and-effect relationship between the investigational product and the occurrence 
of the AE, then the AE should be considered “related”. The causality assessment must be 
documented in the source 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 an 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 in the source documents. 
Outcomes are as follows:

Fatal

Not Recovered/Not Resolved

Recovered/Resolved

Recovered/Resolved With Sequelae

Recovering/Resolving

Unknown
8.1.4
Symptoms of the Disease under Study
Symptoms of the disease under study should not be classed as AEs as long as they are within the 
normal day-to-day fluctuation or expected progression of the disease and are part of the efficacy 
data to be collected in the study; however, significant worsening of the symptoms should be 
recorded as an AE.
8.1.5
Clinical Laboratory and Other Safety Evaluations
A change in the value of a clinical laboratory, vital sign, or ECG assessment can represent an 
AE if the change is clinically relevant or if, during treatment with the investigational product, 
a shift of a parameter is observed from a normal value to an abnormal value, or a further 
worsening of an already abnormal value. 


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When evaluating such changes, the extent of deviation from the reference range, the duration 
until return to the reference range, either while continuing treatment or after the end of treatment 
with the investigational product, and the range of variation of the respective parameter within its 
reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory, vital sign, or ECG 
values that were not present at the pretreatment value observed closest to the start of study 
treatment, further investigations should be performed until the values return to within the 
reference range or until a plausible explanation (eg, concomitant disease) is found for the 
abnormal values.
The investigator should decide, based on the above criteria and the clinical condition of a 
subject, whether a change in a clinical laboratory, vital sign, or ECG parameter is clinically 
significant and therefore represents an AE.
8.1.6
Abuse, Misuse, Overdose, and Medication Error
Abuse, misuse, overdose, or medication error (defined as follows) must be reported to the 
sponsor according to the SAE reporting procedure whether or not they result in an AE/SAE as 
described in Section 8.2. Note: The 24-hour reporting requirement for SAEs does not apply to 
reports of abuse, misuse, overdose, or medication errors unless these result in an SAE. 
The following categories are not mutually exclusive; the event can meet 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 investigational product higher
than the protocol-prescribed dose

Medication Error – An error made in prescribing, dispensing, administration, and/or use of
an investigational product. For studies, medication errors are reportable to the sponsor only
as defined as follows:

Cases of subjects missing doses of the investigational product are not considered
reportable as medication errors.

Medication errors should be collected/reported for all products under investigation.

The administration and/or use of 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.


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8.2
Serious Adverse Event Procedures
8.2.1
Reference Safety Information
The reference for safety information for this study is the IB which the sponsor has provided 
under separate cover to all investigators.
8.2.2
Reporting Procedures
All initial and follow-up SAE reports must be reported by the investigator to the Shire Global 
Pharmacovigilance and Risk Management Department and the CRO/Shire Medical Monitor 
within 24 hours of the first awareness of the event. Note: The 24-hour reporting requirement for 
SAEs does not apply to reports of abuse, misuse, overdose, or medication errors (Section 8.1.6) 
unless they result in an SAE.
The investigator must complete, sign, and date the Shire Clinical Study Serious Adverse Event 
and Nonserious AEs Required by the Protocol Form and verify the accuracy of the information 
recorded on the form with the corresponding source documents (Note: Source documents are not 
to be sent unless requested) and fax or e-mail the form to the Shire Global Pharmacovigilance 
and Risk Management Department. A copy of the Shire Clinical Study Serious Adverse Event 
and Nonserious AEs Required by the Protocol Form (and any applicable follow-up reports) must 
also be sent to the CRO/Shire Medical Monitor using the details specified in the emergency 
contact information section of the protocol.
8.2.3
Serious Adverse Event Definition
An SAE is any untoward medical occurrence (whether considered to be related to investigational 
product or not) that at any dose:

Results in death

Is life-threatening. Note: The term “life-threatening” in the definition of “serious” refers to an
event in which the subject was at risk of death at the time of the event; it does not refer to an
event which hypothetically might have caused death if it was more severe.

Requires inpatient hospitalization or prolongation of existing hospitalization. Note:
Hospitalizations that are the result of elective or previously scheduled surgery for
pre-existing conditions and 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 an 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.


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Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home; blood dyscrasias or convulsions that do not 
result in inpatient hospitalization; or the development of drug dependency or drug abuse.
8.2.4
Serious Adverse Event Collection Time Frame
All SAEs (regardless of relationship to study) are collected from the time the subject signs the 
informed consent until the defined follow-up period stated in Section 7.1.3 and must be reported 
to the Shire Global Pharmacovigilance and Risk Management Department and the CRO/Shire 
Medical Monitor within 24 hours of the first awareness of the event.
In addition, any SAE(s) considered “related” to the investigational product and discovered by the 
investigator at any interval after the study has completed must be reported to the Shire Global 
Pharmacovigilance and Risk Management Department within 24 hours of the first awareness of 
the event.
8.2.5
Serious Adverse Event Onset and Resolution Dates
The onset date of the SAE is defined as the date the event meets serious criteria. The resolution 
date is the date the event no longer meets serious criteria, the date the symptoms resolve, or the 
event is considered chronic. In the case of hospitalizations, the hospital admission and discharge 
dates are considered the onset and resolution dates, respectively.
In addition, any signs or symptoms experienced by the subject after signing the informed consent 
form, or leading up to the onset date of the SAE, or following the resolution date of the SAE, 
must be recorded as an AE, if appropriate.
8.2.6
Fatal Outcome
Any SAE that results in the subject’s death (ie, the SAE was noted as the primary cause of death) 
must have “fatal” checked as an outcome with the date of death recorded as the resolution date. 
For all other events ongoing at the time of death that did not contribute to the subject’s death, the 
outcome should be considered not resolved, without a resolution date recorded.
For any SAE that results in the subject’s death or any ongoing events at the time of death, unless 
another investigational product action was previously taken (eg, drug interrupted, reduced, or 
withdrawn), the action taken with the investigational product should be recorded as “dose not 
changed” or “not applicable” (if the subject never received investigational product). The 
investigational product action of “withdrawn” should not be selected solely as a result of the
subject’s death.
8.2.7
Regulatory Agency, Institutional Review Board, Ethics Committee, and Site 
Reporting
The sponsor and the clinical CRO are responsible for notifying the relevant regulatory authorities
and US central IRBs of related, unexpected SAEs.
In addition, the sponsor and clinical CRO are responsible for notifying active sites of all related, 
unexpected SAEs occurring during all interventional studies across the SHP465 program. 


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The investigator is responsible for notifying the local IRB, local ethics committee (EC), or the 
relevant local regulatory authority of all SAEs that occur at his or her site as required.
9
DATA MANAGEMENT AND STATISTICAL METHODS
9.1
Data Collection
The investigators’ authorized site personnel must enter the information required by the protocol 
on the source documents. A study monitor will visit each site in accordance with the monitoring 
plan and review the CRF data against the source data for completeness and accuracy. 
Discrepancies between source data and data entered on the CRF will be addressed by qualified 
site personnel. When a data discrepancy warrants correction, the correction will be made by 
authorized site personnel. Data collection procedures will be discussed with the site at the site 
initiation visit and/or at the investigator’s meeting. Once a subject is enrolled, it is expected that 
site personnel will complete the entries in the source documents within approximately 3 business 
days of the subject’s visit.
9.2
Clinical Data Management
Data are to be entered into a clinical database as specified in the CRO’s data management plan. 
Quality control and data validation procedures are applied to ensure the validity and accuracy of 
the clinical database.
Data are to be reviewed and checked for omissions, errors, and values requiring further 
clarification using computerized and manual procedures. Data queries requiring clarification are 
to be communicated to the site for resolution. Only authorized personnel will make corrections to 
the clinical database, and all corrections are documented in an auditable manner.
9.3
Statistical Analysis Process
The study will be analyzed by the sponsor or its agent.
The statistical analysis plan (SAP) will provide the statistical methods and definitions for the 
analysis of the PK, pharmacodynamic, and safety data, as well as describe the approaches to be 
taken for summarizing other study information such as subject disposition, demographics and 
baseline characteristics, investigational product exposure, and prior and concomitant 
medications. The SAP will also include a description of how missing, unused, and spurious data 
will be addressed.
To preserve the integrity of the statistical analysis and study conclusions, the SAP will be 
finalized prior to database lock.
All statistical analyses will be performed using SAS(SAS Institute, Cary, NC 27513). 


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9.4
Planned Interim Analysis, Adaptive Design, and Data Monitoring Committee
There is no planned interim analysis or adaptive design in this study.
9.4.1
Data Monitoring Committee
An external independent data monitoring committee (DMC) will be set up for the following 
studies: SHP465-112, SHP465-308, and SHP465-309. The DMC will review the data pertaining 
to safety, tolerability, and benefit/harm 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.
9.5
Sample Size Calculation and Power Considerations
To objectively justify the sample size for PK sampling and PK sampling scheme for this study, 
the following precision is recommended in the Food and Drug Administration (FDA) guidance, 
General Clinical Pharmacology: Considerations for Pediatric Studies for Drugs and Biological 
Products (DHHS, 2014).
The sample size for traditional rich PK sampling for noncompartmental analysis is calculated to 
achieve 80% probability (power), to assure the 95% confidence interval of the point estimate of 
the geometric mean of clearance is within 60% to 140% of the estimate of the clearance. 
Although the range (60%, 140%) is not symmetric to 1, the lower confidence interval bound is 
within (60%, 140%) (1/1.4=0.714), as long as the upper bound is ≤1.4.
The available data in Table 6 are from Shire’s completed study (SHP465-111) with an ADHD 
pediatric population and shows the reported apparent clearance (CL/F) and volume of 
distribution (Vz/F) for the d-amphetamine and l-amphetamine of SHP465 after oral 
administration of 12.5 mg in children aged 6 to 12 years and 25 mg in adolescents aged 
13 to 17 years.
Table 6:
Estimates of Clearance and Volume of Distribution for G-Amphetamine and 
O-Amphetamine
CV (%)
SHP465 12.5 mg
Children (6 to 12 years)
SHP465 25 mg
Adolescents (13 to 17 years)
CL/F (L/h)
Vz/F (L)
CL/F (L/h)
Vz/F (L)
d-Amphetamine
25.0
28.5
23.7
18.4
l-Amphetamine
26.9
32.2
28.4
22.0
CV=coefficient of variation 
Source: SHP465-111 Clinical Study Report Table 9-1 and Table 9-4.


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The sample size estimates uses the within-subject l-amphetamine variability of 32.2%, since it is 
numerically bigger. Applying the methods from the manuscript by Wang et al.,(2012), sample 
size estimations with related probability for corresponding coefficients of variation are provided 
as follows:
CV (%)
Number of Subjects Required
Probability of the Point Estimate 
Within the Prespecified Interval (%)
18.4
5
89
22.0
5
80
23.7
6
88
25.0
6
82
26.9
6
89
28.4
7
88
28.5
7
88
32.2
8
90
CV=coefficient of variation.
Based on these data, the PK analysis will need at least 8 subjects in total to provide reliable PK 
parameter estimates.
9.6
Study Population
The screened set will consist of all subjects who have provided consent.
The enrolled set will consist of all subjects who have been assigned a subject identification
number.
The safety set will consist of all enrolled subjects who have taken at least 1 dose of
investigational product.
The PK set will consist of all subjects in the safety set for whom at least 1 postdose PK blood 
sample was collected.
9.7
Pharmacokinetic Analyses
9.7.1
Pharmacokinetic Analysis
All the PK analyses will be performed using the PK set.
Pharmacokinetic parameters will be determined from the plasma concentration-time data for 
d-amphetamine and l-amphetamine by noncompartmental analysis using Phoenix® WinNonlin®
(Certara, Princeton, NJ) Version 6.4 or higher.


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The PK parameters will include, but not be limited to:

AUC0-∞
Area under the curve extrapolated to infinity

AUC0-t
Area under the curve from time 0 to the last time point of sample collection

AUC0-5
Area under the curve from time 0 predose to 5 hours postdose

AUC5-t
Area under the curve from time 5 hours to the last time point of sample collection

AUClast
Area under the curve from the time of dosing to the last measurable concentration

AUCtau
Area under the concentration curve over the dosing interval (24 hours) at steady
state

CL/F
Total body clearance for extravascular administration

Cmax
Maximum concentration occurring at tmax

Ctrough
Trough plasma concentration (the predose concentrations collected at steady 
state)

t1/2
Terminal half-life

tmax
Time of maximum observed concentration sampled during a dosing interval

VF/ss
Apparent volume of distribution at steady state

Vz/F
Volume of distribution associated with the terminal slope following extravascular 
administration

z
The first order rate constant associated with the terminal phase of elimination
9.7.1.1
Statistical Analysis of Pharmacokinetic Parameters
There will be no inferential statistical analysis of the PK data. Summary descriptive statistics 
(number of observations, mean, standard deviation, coefficient of variation, median, maximum, 
minimum and geometric mean) will be determined for all PK parameters. Plasma concentrations 
at each nominal sampling time will also be summarized using descriptive statistics.
9.8
Safety Analyses
Safety will be assessed by TEAEs, vital signs (systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature), 12-lead ECGs, weight, height, clinical laboratory tests 
(biochemistry, hematology, and urinalysis), PSQ, and a validated sleep questionnaire (CSHQ).
Additionally, the C-SSRS will capture the safety of SHP465 related to suicidality.
The safety endpoints will be summarized with descriptive statistics for the safety set.
Relevant safety endpoints as well as their changes from baseline will be summarized. 
Baseline is defined as the last assessment prior to the first dose of investigational product. 
Potentially clinically important findings will also be summarized or listed. The potentially 
clinically important values will be defined in the SAP.


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Weight, height, BMI, vital signs, ECG, PSQ, and CSHQ will be summarized. The C-SSRS 
results will be summarized and a listing of the C-SSRS data will be provided for subjects with a 
positive response.
Adverse events will be coded using the agreed-upon version of the Medical Dictionary for 
Regulatory Activities. Treatment-emergent AEs are defined as AEs that started or deteriorated 
on or after the date of the first dose of investigational product, and no later than 3 days following 
the first dose of investigational product. The number of events, incidence, and percentage of 
TEAEs will be calculated overall, by system organ class, and by preferred term. 
Treatment-emergent AEs will be further summarized by severity and relationship to 
investigational product. Adverse events related to investigational product, AEs leading to 
withdrawal, SAEs, and deaths will be similarly summarized/listed.
10
SPONSOR’S AND INVESTIGATOR’S RESPONSIBILITIES
This study is conducted in accordance with current applicable regulations, ICH, and local ethical 
and legal requirements.
The name and address of each third party vendor (eg, CRO) used in this study will be maintained 
in the investigator’s and sponsor’s files, as appropriate.
10.1
Sponsor’s Responsibilities
10.1.1
Good Clinical Practice Compliance
The study sponsor and any third party to whom aspects of the study management or monitoring 
have been delegated will undertake their assigned roles for this study in compliance with all 
applicable industry regulations, ICH GCP Guideline E6 (1996) and any updates, and all 
applicable national and local laws and regulations.
Visits to sites are conducted by representatives of the study sponsor and/or the company 
organizing/managing the research on behalf of the sponsor to inspect study data, subjects’ 
medical records, and source documents in accordance with current GCP and the respective local 
and inter/national government regulations and guidelines. Records and data may additionally be 
reviewed by auditors or by regulatory authorities.
The sponsor ensures that local regulatory authority requirements are met before the start of the 
study. The sponsor (or a nominated designee) is responsible for the preparation, submission, and 
confirmation of receipt of any regulatory authority approvals required 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.


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10.1.3
Submission of Summary of Clinical Study Report to Competent Authorities 
of Member States Concerned and Ethics Committees
The sponsor will provide a summary of the clinical study report to the competent authority of the 
member state(s) concerned as required by regulatory requirement(s) and to comply with the 
Community guideline on GCP. This requirement will be fulfilled within 6 months of the end of 
the study completion date for pediatric studies and within 1 year for nonpediatric studies as per 
guidance.
10.1.4
Study Suspension, Termination, and Completion
The sponsor may suspend or terminate the study, or part of the study, at any time for any reason. 
If the study is suspended or terminated, the sponsor will ensure that applicable sites, regulatory 
agencies, and IRBs/ECs are notified as appropriate. Additionally, the discontinuation of a 
registered clinical study which has been posted to a designated public website will be updated 
accordingly.
10.2
Investigator’s Responsibilities
10.2.1
Good Clinical Practice Compliance
The investigator must undertake to perform the study in accordance with ICH GCP Guideline E6 
(1996) and any updates, and applicable regulatory requirements and guidelines.
It is the investigator’s responsibility to ensure that adequate time, resources, and appropriately 
trained personnel are available at the site prior to commitment to participate in this study. The 
investigator should also be able to estimate or demonstrate a potential for recruiting the required 
number of suitable subjects within the agreed recruitment period.
The investigator will maintain a list of appropriately qualified persons to whom the investigator 
has delegated significant study-related tasks, and shall, upon request of the sponsor, provide 
documented evidence of any licenses and certifications necessary to demonstrate such 
qualification. Curriculum vitae for investigators and subinvestigators are provided to the study 
sponsor (or designee) before starting the study.
If a potential research subject has a primary care physician, the investigator should, with the 
subject’s consent, inform them of the subject’s participation in the study.
A co-ordinating 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 co-ordinating principal investigator, in compliance with ICH 
Guideline E3 (1995).
10.2.2
Protocol Adherence and Investigator Agreement
The investigator and any co-investigators must adhere to the protocol as detailed in this 
document. The investigator is responsible for enrolling only those subjects who have met 
protocol eligibility criteria. Investigators are required to sign an investigator agreement to 
confirm acceptance and willingness to comply with the study protocol.


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If the investigator suspends or terminates the study at their site, the investigator will promptly 
inform the sponsor and the IRB/EC and provide them with a detailed written explanation. The 
investigator will also return all investigational product, containers, and other study materials to 
the sponsor. Upon study completion, the investigator will provide the sponsor, IRB/EC, and 
regulatory agency with final reports and summaries as required by (inter)national regulations.
Communication with local IRBs/ECs, to ensure accurate and timely information is provided at 
all phases during the study, may be done by the sponsor, applicable CRO, investigator, or, for 
multicenter studies, the co-ordinating principal investigator, according to national provisions,
and will be documented in the investigator agreement.
10.2.3
Documentation and Retention of Records
10.2.3.1
Case Report Forms
Case report forms are supplied by the CRO and should be handled in accordance with 
instructions from the sponsor.
The investigator is responsible for maintaining adequate and accurate medical records from 
which accurate information is recorded onto CRFs, which have been designed to record all 
observations and other data pertinent to the clinical investigation. Case report forms must be 
completed by the investigator or designee as stated in the site delegation log.
All data will have separate source documentation; no data will be recorded directly onto the 
CRF.
All data sent to the sponsor must be endorsed by the investigator.
The CRA/study monitor will verify the contents against the source data per the monitoring plan. 
If the data are unclear or contradictory, queries are sent for corrections or verification of data.
10.2.3.2
Recording, Access, and Retention of Source Data and Study Documents
Original source data to be reviewed during this study will include, but are not limited to: 
subject’s medical file, subject’s diary, 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 IRB/EC, having access to source data (eg, subject’s medical file, 
appointment books, original laboratory reports, X-rays, etc).


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These records must be made available within reasonable times for inspection and duplication, if 
required, by a properly authorized representative of any regulatory agency (eg, the US FDA) or 
an auditor.
Essential documents must be maintained according to ICH GCP requirements and may not be 
destroyed without written permission from the sponsor.
10.2.3.3
Audit/Inspection
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of, eg, the US FDA (as well as other US national 
and local regulatory authorities), other regulatory authorities, the sponsor or its representatives, 
and the IRB/EC for each site.
10.2.3.4
Financial Disclosure
The investigator is required to disclose any financial arrangement during the study and for 1 year 
after, whereby the outcome of the study could be influenced by the value of the compensation for 
conducting the study, or other payments the investigator received from the sponsor. The 
following information is collected: any significant payments from the sponsor or subsidiaries 
such as a grant to fund ongoing research, compensation in the form of equipment, retainer for 
ongoing consultation or honoraria; any proprietary interest in investigational product; any 
significant equity interest in the sponsor or subsidiaries as defined in US Title 21 Code of 
Federal Regulations Part 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/Assent
It is the responsibility of the investigator to obtain written informed consent and assent from all 
study subjects and their parent/LAR prior to any study-related procedures including screening 
assessments. All consent and assent documentation must be in accordance with applicable 
regulations and GCP. Each subject 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
that was reviewed by the IRB/EC and received their favorable opinion/approval. A copy of the 
IRB/EC’s written favorable opinion/approval of these documents must be provided to the 
sponsor prior to the start of the study unless it is agreed to and documented (abiding by 
regulatory guidelines and national provisions) prior to study start that another party (ie, sponsor 
or co-ordinating 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 co-ordinating with IRBs/ECs is defined in the clinical trial agreement.
Prior to implementing changes in the study, the sponsor and the IRB/EC must approve any 
revisions of all informed consent documents and amendments to the protocol unless there is a 
subject safety issue.
Investigational product supplies will not be released until the CRO has received written IRB/EC 
approval of and copies of revised documents.
The investigator is responsible for keeping the IRB/EC appraised of the progress of the study 
and of any changes made to the protocol, but in any case at least once a year. 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 the Health Insurance Portability and Accountability Act (HIPAA) of 
1996. A site that is not a covered entity as defined by HIPAA must provide documentation of 
this fact to the CRO.
The confidentiality of records that may be able to identify subjects will be protected in 
accordance with applicable laws, regulations, and guidelines.


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After subjects have consented/assented to take part in the study, the sponsor and/or its 
representative 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/EC 
which gave approval for the study to proceed. The sponsor and/or its representative 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. 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 following paragraph, 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
Arnsten AF 2001. Modulation of prefrontal cortical-striatal circuits: relevance to therapeutic 
treatments for Tourette syndrome and attention-deficit hyperactivity disorder. Adv Neurol; 
85:333-41.
Bhutta AT, Anand KJ 2002. Vulnerability of the developing brain. Neuronal mechanisms. Clin 
Perinatol; 29(3):357-72.
Brown K 2003. Neuroscience. New attention to ADHD genes. Science; 301(5630):160-1.
Brown T 1996. Attention-Deficit Disorder Scales for Adolescents and Adults. The Psychological 
Corporation: San Antonio (TX).
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.
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.
Greenfield B, Hechman L 2005. Treatment of attention deficit hyperactivity disorder in adults. 
Expert Rev Neurother; 5(1):107-21.
Guy W. editor 1976. Clinical Global Impression (CGI). In: ECDEU Assessment Manual for 
Psychopharmacology. US Department of Health, Education, and Welfare. Rockville, MD, 
217-22.
Heal DJ, Smith SL, Gosden J, Nutt DJ 2013. Amphetamine, past and present – a 
pharmacological and clinical perspective. J Psychopharmacol; 27(6):479-96.
Kahn RS, Khoury J, Nichols WC, Lanphear BP 2003. Role of dopamine transporter genotype 
and maternal prenatal smoking in childhood hyperactive-impulsive, inattentive, and oppositional 
behaviors. J Pediatr; 143(1):104-10.
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.
Kratochvil CJ, Vaughan BS, Harrington MJ, Burke WJ 2003. Atomoxetine: a selective 
noradrenaline reuptake inhibitor for the treatment of attention-deficit/hyperactivity disorder. 
Expert Opin Pharmacother; 4(7):1165-74.


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Michelson D, Faries D, Wernicke 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 (NIH) 2004. The fourth report on the diagnosis, evaluation, and 
treatment of high blood pressure in children and adolescents. Pediatrics; 114(2 Suppl 4th 
report):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.
Safren SA, Sprich S, Chulvick S. Otto MW 2004. Psychosocial treatments for adults with 
attention-deficit/hyperactivity disorder. Psychiatr Clin North Am; 27(2):349-60.
Sheehan DV, Sheehan KH, Shytle RD, Janavs J, Bannon Y, Rogers JE, et al. 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, Wilens T, Harding M, O'Donnell D, Griffin S 1996. Pharmacotherapy 
of attention-deficit hyperactivity disorder across the life cycle. J Am Acad Child Adolesc 
Psychiatry; 35(4):409-32.
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.
US Department of Health and Human Services (DHHS), Food and Drug Administration, Center 
for Drug Evaluation and Research (CDER). Draft guidance. Guidance for industry. General 
clinical pharmacology considerations for pediatric studies for drugs and biological products.
Dec 2014.
Wang Y, Zheng Y, Du Y, Song DH, Shin YJ, Cho SC, et al. 2007. Atomoxetine versus 
methylphenidate in paediatric outpatients with attention deficit hyperactivity disorder: a 
randomized, double-blind comparison trial. Aust N Z J Psychiatry; 41(3):222-30.
Wang Y, Jadhav PR, Lala M, Gobburu JV 2012. Clarification on precision criteria to derive 
sample size when designing pediatric pharmacokinetic studies. J Clin Pharmacol; 
52(10):1601-6.
Weiss M, Murray C 2003. Assessment and management of attention-deficit hyperactivity 
disorder in adults. CMAJ; 168(6):715-22.


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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, 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.
Wilens TE, Spencer TJ, Biederman J 2002. A review of the pharmacotherapy of adults with 
attention-deficit/hyperactivity disorder. J Atten Disord; 5(4):189-202.


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APPENDICES




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


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


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


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APPENDIX 2.3
BLOOD PRESSURE LEVELS FOR BOYS BY AGE AND HEIGHT 
PERCENTILE
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; Appendix 2.2). For subjects who fall between the 
2 height percentiles, use the lower of the 2 percentiles. Once the subject’s age and height 
percentile for age are determined, use the following table to determine eligibility.
All blood pressure values listed as follows are 95th percentile for age and height percentile. The 
subject’s systolic and diastolic blood pressure readings at the screening visit and the baseline 
visit (predose on Day 1) must not exceed the following corresponding table value for their age 
and height percentile.
Age 
(Year)
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Percentile of Height
Percentile of Height
5%
10%
25%
50%
75%
90%
95%
5%
10%
25%
50%
75%
90%
95%
4
106
107
109
111
112
114
115
66
67
68
69
70
71
71
5
108
109
110
112
114
115
116
60
70
71
72
73
74
74
6
109
110
112
114
115
117
117
72
72
73
74
75
76
76
Source: National Heart Lung and Blood Institute; May 2004
http://www nhlbi nih.gov/guidelines/hypertension/child_tbl.htm 


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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
To determine the eligibility of a female 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; Appendix 2.4). For subjects who fall between 
the 2 height percentiles, use the lower of the 2 percentiles. Once the subject’s age and height 
percentile for age are determined, use the following table to determine eligibility.
All blood pressure values listed as follows are 95th percentile for age and height percentile. The 
subject’s systolic and diastolic blood pressure readings at the screening visit and the baseline 
visit (predose on Day 1) must not exceed the following corresponding table value for their age 
and height percentile.
Age 
(Year)
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Percentile of Height
Percentile of Height
5%
10%
25%
50%
75%
90%
95%
5%
10%
25%
50%
75%
90%
95%
4
105
106
107
108
110
111
112
68
68
69
70
71
71
72
5
107
107
108
110
111
112
113
70
71
71
72
73
73
74
6
108
109
110
111
113
114
115
72
72
73
74
74
75
76
Source: National Heart Lung and Blood Institute; May 2004
http://www nhlbi nih.gov/guidelines/hypertension/child_tbl.htm 


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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
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 in the previous table will be 
provided to the site. Updates to scales/assessments during the study (if applicable) will be 
documented in the previous table, and a new master file containing the revised scale/assessment 
will be provided to the site.

SAP_001.pdf: 


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TABLE OF CONTENTS
TABLE OF CONTENTS.................................................................................................................2
LIST OF TABLES...........................................................................................................................4
ABBREVIATIONS .........................................................................................................................5
1.
INTRODUCTION....................................................................................................................7
2.
STUDY DESIGN .....................................................................................................................8
2.1
General Study Design.................................................................................................8
2.2
Randomization ...........................................................................................................8
2.3
Blinding......................................................................................................................8
2.4
Schedule of Assessments ...........................................................................................9
2.5
Determination of Sample Size..................................................................................13
3.
OBJECTIVES.........................................................................................................................15
3.1
Primary Objective ....................................................................................................15
4.
STUDY POPULATION SETS...............................................................................................16
4.1
Screened Set .............................................................................................................16
4.2
Enrolled Set..............................................................................................................16
4.3
Safety Set..................................................................................................................16
4.4
Pharmacokinetic Set.................................................................................................16
5.
SUBJECT DISPOSITION......................................................................................................17
6.
PROTOCOL DEVIATIONS..................................................................................................18
7.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .................................19
7.1
Demographic and other Baseline Characteristics.....................................................19
7.2
Medical History........................................................................................................20
8.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE .......................................21
8.1
Exposure to Investigational product.........................................................................21
8.2
Measurement of Treatment Compliance..................................................................22
9.
PRIOR AND CONCOMITANT MEDICATIONS/TREATMENTS ....................................23
10. EFFICACY ANALYSES.......................................................................................................24
11. SAFETY ANALYSES ...........................................................................................................25
11.1
Adverse Events.........................................................................................................25
11.1.1 Adverse Events of Special Interest ........................................................................26
11.2
Clinical Laboratory Variables ..................................................................................29
11.3
Vital Signs (Including Height and Weight)..............................................................32
11.4
Electrocardiogram (ECG).........................................................................................34
11.5
Other Safety Variables .............................................................................................37
11.5.1 Columbia-Suicide Severity Rating Scale...............................................................37
11.5.2 Post Sleep Questionnaire .......................................................................................38


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11.5.3 Children’s Sleep Habits Questionnaire..................................................................38
12. CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES............40
12.1
Pharmacokinetic Methods........................................................................................40
12.1.1 Concentration Data ................................................................................................40
12.1.2 Handling BLQ Values............................................................................................40
12.1.3 Pharmacokinetic Parameters..................................................................................41
12.2
Summary of Pharmacokinetic Parameters ...............................................................42
12.3
Pharmacodynamic Methods (if applicable)..............................................................42
12.4
Statistical Analysis of Pharmacodynamic Data (if applicable)................................42
12.5
Analyses of Pharmacokinetic/Pharmacodynamic Relationships (If applicable)......42
12.6
Pharmacokinetic References ....................................................................................42
13. OTHER ANALYSES .............................................................................................................43
14. INTERIM ANALYSIS...........................................................................................................44
15. DATA MONITORING/REVIEW COMMITTEE.................................................................45
16. COMPUTER METHODS ......................................................................................................46
17. CHANGES TO ANALYSES SPECIFIED IN PROTOCOL.................................................47
18. DATA HANDLING CONVENTIONS..................................................................................48
18.1
General Data Reporting Conventions ......................................................................48
18.2
Derived Efficacy Endpoints .....................................................................................48
18.3
Association of Early Termination Assessments to Scheduled Visits.......................48
18.4
Repeated or Unscheduled Assessments of Safety Parameters.................................48
18.5
Missing Date of Investigational Product..................................................................49
18.6
Missing Date Information for Prior or Concomitant Medications...........................49
18.6.1 Incomplete Start Date ............................................................................................49
18.6.2 Incomplete Stop Date.............................................................................................50
18.7
Missing Date Information for Adverse Events ........................................................50
18.8
Missing Severity Assessment for Adverse Events...................................................50
18.9
Missing Relationship to Investigation Product for Adverse Events ........................51
18.10
Character Values of Clinical Laboratory Variables .................................................51
19. REFERENCES .......................................................................................................................52
20. TABLE OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS ..............................53


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LIST OF TABLES
Table 1: Schedule of Assessments for Rich Pharmacokinetic Sampling Portion.......................9
Table 2: Schedule of Assessments for Sparse Pharmacokinetic Sampling Portion..................11
Table 3: Estimates of Clearance and Volume of Distribution for d-Amphetamine and 
l-Amphetamine.......................................................................................................13
Table 4: Psychiatric Events.......................................................................................................27
Table 5: Criteria for Potentially Clinically Important Laboratory Tests ..................................31
Table 6: Criteria for Potentially Clinically Significant Vital Signs..........................................33
Table 7: Normal Range of Pulse Rate (beats/min) ...................................................................33
Table 8: 95th Percentile Cut-off Values of Blood Pressure Norms by Sex, Age, and Height 
Percentiles..............................................................................................................34
Table 9: Criteria for Potentially Clinically Important ECG Values .........................................36


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ABBREVIATIONS
ADHD
attention-deficit/hyperactivity disorder
ADHD-RS-5
ADHD Rating Scale Version 5
AE
adverse event
AUC
area under the concentration-time curve
AUClast
area under the concentration-time curve from the time of dosing to the last 
measurable concentration
AUC0-t
area under the concentration-time curve from the time 0 to the last time 
point of sample collection
AUC0-5
area under the concentration-time curve from time 0 to 5 hours postdose
AUC5-12
area under the concentration-time curve from 5 hours to 12 hours postdose
AUC12-16
area under the concentration-time curve from 12 hours to 16 hours 
postdose
AUC16-24
area under the concentration-time curve from 16 hours to 24 hours 
postdose
AUC5-t
area under the concentration-time curve from 5 hours postdose to the last 
time point of sample collection
AUCtau,ss
area under the concentration-time curve over the dosing interval (24 
hours), at steady-state
BLQ
below the limit of quantitation
BMI
body mass index
C12
the observed concentration at 12 hours after dose administration
C16
the observed concentration at 16 hours after dose administration
C24
the observed concentration at 24 hours after dose administration
CDC
Centers for Disease Control and Prevention
CGI-S
Clinical Global Impression - Severity of Illness
CI
confidence interval
CL/F
total body clearance for extravascular administration divided by the 
fraction of dose absorbed
Cmax
maximum concentration occurring at tmax
CRC
clinical research center
CSHQ
Children’s Sleep Habits Questionnaire
C-SSRS
Columbia-Suicide Severity Rating Scale
Ctrough,ss
trough plasma analyte concentration (the predose concentrations collected 
at steady-state)
CV
coefficient of variation
DINFC
date of informed consent


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DMC
data monitoring committee
DOB
date of birth
eCRF
electronic case report form
ECG
Electrocardiogram
ET
early termination
FoTA
final on-treatment assessment
IP
investigational product
LAR
legally authorized representative 
LLOQ
lower limit of quantitation
MINI-Kid
Mini International Neuropsychiatric Interview for Children and 
Adolescents
MedDRA
Medical Dictionary for Regulatory Activities
n
number of subjects
NQ
not quantitative
PCI
potentially clinically important
PK
pharmacokinetic(s)
PSQ
Post Sleep Questionnaire
PT
preferred term
SAS
Statistical Analysis System
SD
standard deviation
SOC
system organ class
TEAE 
treatment-emergent adverse event
t½
terminal half-life
tmax
time of maximum observed concentration sampled during a dosing 
interval
V/Fss
apparent volume of distribution at steady-state
WHO
World Health Organization


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1.
INTRODUCTION
This statistical analysis plan provides a technical and detailed elaboration of the statistical 
analyses of pharmacokinetic (PK), safety, and tolerability data as described in the final study 
protocol SHP465-112 version 1.0 dated 15 Sep 2017 and the protocol administrative change #1 
dated 31 Oct 2017. Specifications for tables, figures, and listings are contained in a separate 
document. 


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2.
STUDY DESIGN 
2.1
General Study Design
The study will be a Phase 1, open-label, multiple-dose, PK, safety, and tolerability study in 
children aged 4 to 5 years diagnosed with attention-deficit/ hyperactivity disorder (ADHD). 
Enrollment will be stratified by sex to ensure that at least 2 of the 10 subjects expected to 
complete the rich PK sampling portion of the study and at least 3 of the 10 subjects expected to 
complete the sparse PK sampling portion of the study are females.
Following the screening visit, eligible subjects will return to the clinical research center (CRC) 
on Day 1 of Week 1 to reconfirm eligibility criteria and enter into the treatment phase. Total 
duration for the treatment period is approximately 30 days for subjects in the rich PK sampling 
portion of the study and 29 days for subjects in the sparse PK sampling portion of the study. In 
the study, single 6.25 mg dose of SHP465 will be administered daily for 28 days (±1 day) at 8:00 
AM (±1 hour).
Rich PK Sample Scheme (9 Samples/Subject) Collection
Predose PK samples will be collected on Day 1 of Week 1, and serial blood samples for PK 
analysis will be drawn prior to dosing on Day 7 of Week 4 (within 60 minutes prior to dosing) 
and up to 48 hours after administration of the investigational product (IP).
On Day 7 of Week 4, subset of subjects in the rich PK sampling portion will be required to 
remain at the CRC through 8 hours postdose. Following completion of the 8-hour PK sample 
collection, per investigator’s discretion, subjects will have the option to remain at or leave the 
CRC. If they leave the CRC, subjects will either return to the CRC on Days 7, 8, and 9 of 
Week 4 for the 12-hour, 16-hour, 24-hour, and 48-hour postdose blood sample collections or, if 
the option is available at their clinical site, a qualified person may visit the subject for the 
12-hour, 16-hour, and 24-hour postdose blood sample collections, but they must return to the 
clinic for the 48-hour blood sample collection.
Sparse PK Sample Scheme (4 Samples/Subject) Collection
Predose PK samples will be collected on Day 1 of Weeks 1 to 3 and on Day 8 of Week 4 
(24 hours after dosing on Day 7 of Week 4) for subjects in the sparse PK sampling subset.
2.2
Randomization
Not applicable.
2.3
Blinding
This is an open-label study so blinding is not applicable.


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Statistical Analysis Plan
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2.4
Schedule of Assessments 
Table 1: Schedule of Assessments for Rich Pharmacokinetic Sampling Portion
Assessment Day
Screening and Washout
Week 1
to 3
Week 4
Follow-upa
D -32
to D -8
D -7
to D -1
Washout
D 1 D 2-7 D 1 D 2-6
D 7
D 8b
D 9
/ETb
Treatment Week 4 Time point (h)
Predosec
0
2
5
8
12
16
24
48
Informed Consent & Assent
X
Inclusion/Exclusion Criteria
X
Xd
Demographics
X
Medical & Medication History (Includes 
Prior Medications and Procedures)e
X
Physical Examination
X
Xf
Xf
Xg
Xh
Vital Signsi
X
X
X
X
X
Xh
Weightj
X
X
X
X
Xh
Heightj
X
Xh
Biochemistry, Hematology, and Urinalysis
X
Xh
TSH, T4, and T3
X
Xh
Urine Drug and Alcohol Screen
X
12-lead ECGi
X
X
X
X
Xh
C-SSRS Baseline Version
X
C-SSRS Since Last Visit Version
X
X
X
Xh
MINI-KID
X
ADHD-RS-5 Child, Home Version
X
Clinical Global Impressions – Severity of 
Illness
X
CSHQ
X
X
X
X
Xh
PSQ
X
X
X
X
Xh
Eligibility Confirmation
Xd
Investigational Product Dispensed
X
X
Investigational Product Administration 
Xk
Xl
Xk
Xl
Xk,m
Pharmacokinetic Sample Collection 
Xn
X
X
X
X
X
X
X
X
Concomitant Medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X


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Statistical Analysis Plan
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Table 1: Schedule of Assessments for Rich Pharmacokinetic Sampling Portion
Assessment Day
Screening and Washout
Week 1
to 3
Week 4
Follow-upa
D -32
to D -8
D -7
to D -1
Washout
D 1 D 2-7 D 1 D 2-6
D 7
D 8b
D 9
/ETb
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xh
X
ADHD-RS-5=Attention-Deficit/Hyperactivity Disorder Rating Scale-5; CRC=clinical research center; C-SSRS=Columbia-Suicide Severity Rating Scale; CSHQ=Children's Sleep 
Habits Questionnaire; D=day; ECG=electrocardiogram; ET=Early Termination; h=hours; MINI-KID=Mini International Neuropsychiatric Interview for Children and Adolescents; 
PSQ=Post Sleep Questionnaire; TSH=thyroid-stimulating hormone; T3=tri-iodothyronine; T4=thyroxine.
a 
Follow-up contact will be conducted approximately 1 week (7 days [±2 days]) following the last dose of investigational product.
b
Day 8 and Day 9 may be conducted on an out-patient basis.
c
These assessments should be performed within 2 hours prior to dose administration with the exception of the pharmacokinetic sample, which should be collected within 
60 minutes prior to dosing.
d
Inclusion/exclusion criteria and eligibility confirmation must be reviewed at the CRC on Day 1 of Week 1.
e
Medical and medication history will include a detailed description of the subject’s psychiatric diagnosis and a lifetime history of pharmacologic therapies for ADHD and other 
disorders.
f
A brief physical examination will be performed prior to dosing on Day 1.
g
A brief physical examination will be performed prior to dosing on Day 7 of Week 4.
h
An attempt to perform these assessments and procedures will be made for any subjects who withdraw or are removed from the study. 
i
Subjects should be resting in a sitting position for at least 5 minutes prior to collecting vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature). Subjects should be resting in a supine position for at least 5 minutes prior to collecting ECGs. If an invasive procedure was conducted prior to blood pressure, 
ECG and respiratory rate recording, the subject should be resting for 15 minutes.
Blood pressure and pulse will be measured at each visit. Measurements of blood pressure and pulse will be performed 3 times (with at least 2 minutes in between each 
collection) using the provided age-appropriate cuff. The average of each set of 3 measurements will be used to determine continued participation in the study.
Temperature and respiratory rate will be collected at the screening visit and ET visit only.
Measurement of blood pressure and pulse will be performed 3 times (with at least 2 minutes in between each collection) using the provided age-appropriate cuff.
j
Height and weight to be measured without shoes and with light clothing using a stadiometer for height and calibrated scale for weight.
k
Dosing will be done at the CRC.
l
Dosing will be done at the home.
m
Subjects should fast for 2 hours prior to dose administration on Day 7 of Week 4 and for 2 hours postdose. At 2 hours postdose on Day 7, subjects will be allowed to consume a 
light breakfast, ie, a single serving of cereal with up to 8 ounces of skim milk. Starting at 4 hours postdose on Day 1, for lunch and dinner, subjects will receive a standardized 
moderate fat meal. Subjects will be allowed snacks starting after lunch.
n
To be sampled predose on Week 1 only.
Whenever possible, the same individual should complete/rate consistently the following scales and questionnaires as appropriate: ADHD-RS-5 Child, Home Version; Clinical 
Global Impressions - Severity of Illness; Post Sleep Questionnaire; and Children’s Sleep Habits Questionnaire.


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Table 2: Schedule of Assessments for Sparse Pharmacokinetic Sampling Portion
Assessment Day
Screening and Washout
Week 1 to 3
Week 4
Follow-upa
D -32
to D -8
D -7 to D -1
Washout
D 1
D 2-7
D 1
D 2-7
D 8
/ET
Informed Consent & Assent
X
Inclusion/Exclusion Criteria
X
Xb
Demographics
X
Medical & Medication Historyc
X
Physical Examination
X
Xd
Xd
Xe
Vital Signsf
X
X
X
Xe
Weightg
X
X
X
Xe
Heightg
X
Xe
Biochemistry, Hematology, and Urinalysis
X
Xe
TSH, T4, and T3
X
Xe
Urine Drug and Alcohol Screen
X
12-lead ECGf
X
X
Xe
C-SSRS Baseline Version
X
C-SSRS Since Last Visit Version
X
X
Xe
MINI-KID
X
ADHD-RS-5 Child, Home Version
X
Clinical Global Impressions – Severity of Illness
X
CSHQ
X
X
X
Xe
PSQ
X
X
X
Xe
Eligibility Confirmation
Xb
Investigational Product Dispensed
X
X
Investigational Product Administration 
Xh
Xi
Xh
Xi
Pharmacokinetic Sample Collection - Predose
X
X
Concomitant Medications
X
X
X
X
X
X
Xe
X
Adverse Events
X
X
X
X
X
X
Xe
X


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Statistical Analysis Plan
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Table 2: Schedule of Assessments for Sparse Pharmacokinetic Sampling Portion
Assessment Day
Screening and Washout
Week 1 to 3
Week 4
Follow-upa
D -32
to D -8
D -7 to D -1
Washout
D 1
D 2-7
D 1
D 2-7
D 8
/ET
ADHD-RS-5=Attention-Deficit/Hyperactivity Disorder Rating Scale-5; CRC=clinical research center; C-SSRS=Columbia-Suicide Severity Rating Scale; CSHQ=Children's Sleep 
Habits Questionnaire; D=day; ECG=electrocardiogram; ET=Early Termination; h=hours; MINI-KID=Mini International Neuropsychiatric Interview for Children and 
Adolescents; PSQ=Post Sleep Questionnaire; TSH=thyroid-stimulating hormone; T3=tri-iodothyronine; T4=thyroxine.
a
Follow-up contact will be conducted approximately 1 week (7 days [±2 days]) following the last dose of investigational product.
b
Inclusion/exclusion criteria and eligibility confirmation must be reviewed at the CRC on Day 1 of Week 1.
c
Medical and medication history will include a detailed description of the subject’s psychiatric diagnosis and a lifetime history of pharmacologic therapies for ADHD and other 
disorders.
d
A brief physical examination will be performed prior to dosing on Day 1 of Weeks 1 to 4.
e
An attempt to perform these assessments and procedures will be made for any subjects who withdraw or are removed from the study.
f
Subjects should be resting in a sitting position for at least 5 minutes prior to collecting vital signs (systolic and diastolic blood pressure, pulse rate, respiratory rate, and body 
temperature). Subjects should be resting in a supine position for at least 5 minutes prior to collecting ECGs. If an invasive procedure was conducted prior to blood pressure, 
ECG and respiratory rate recording, the subject should be resting for 15 minutes.
Blood pressure and pulse will be measured at each visit.
Temperature and respiratory rate will be collected at the screening visit and ET visit only.
g
Height and weight to be measured without shoes and with light clothing using a stadiometer for height and calibrated scale for weight.
h
Dosing will be done at the CRC.
i
Dosing will be done at the home


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Statistical Analysis Plan
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2.5
Determination of Sample Size
To objectively justify the sample size for PK sampling and PK sampling scheme for this study, 
the precision below (in accordance with FDA guidance) is used.
The sample size for traditional rich PK sampling for noncompartmental analysis is calculated to 
achieve 80% probability (power), to ensure that the 95% confidence interval (CI) of the point 
estimate of the geometric mean of clearance is within 60% to 140% of the estimate of the 
clearance. Although the range (60-140%) is not symmetric to 1, the lower CI bound is within the 
minimum and maximum (60%, 140%) (1/1.4=0.714), provided that the upper bound is ≤1.4.
The data presented in Table 3 are from Shire’s completed study (SHP465-111) in pediatric 
subjects with ADHD and show that the reported apparent clearance (CL/F) and volume of 
distribution (Vz/F) for the d-amphetamine and l-amphetamine of SHP465 after oral 
administration of SHP465 12.5 mg in children aged 6 to 12 years and 25 mg in adolescents aged 
13 to 17 years.
Table 3: Estimates of Clearance and Volume of Distribution for d-Amphetamine and 
l-Amphetamine
SHP465 12.5 mg
Children (6 to 12 years)
SHP465 25 mg
Adolescents (13 to 17 years)
CV (%)
CL/F (L/h)
Vz/F (L)
CL/F (L/h)
Vz/F (L)
d-amphetamine
25.0
28.5
23.7
18.4
l-amphetamine
26.9
32.2
28.4
22.0
CL/F=body clearance; CV=coefficient of variation; Vz/F=volume of distribution
Source: SHP465-111 Clinical Study Report (06 May 2016) Tables 9-1 and 9-4.
The sample size estimates use the within-subject l-amphetamine variability of 32.2%, since it is 
numerically bigger. Applying the methods from the manuscript by Wang et al. (2012), sample 
size estimations with related probability for corresponding coefficients of variation are provided 
as follows:
CV (%)
Number of Subjects Required
Probability of the Point Estimate 
Within the Prespecified Interval (%)
18.4
5
89
22.0
5
80
23.7
6
88
25.0
6
82
26.9
7
89
28.4
7
88
28.5
7
88
32.2
8
90
CV=coefficient of variation


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Based on these data, the PK sampling analysis will need at least 8 subjects in total to provide 
reliable PK results.
Approximately 24 subjects are expected to be enrolled to ensure that 10 subjects will complete 
the rich PK sampling portion of the study and an additional 10 subjects will complete the sparse 
PK sampling portion of the study. Enrollment will be stratified by sex to ensure that at least 2 of 
the 10 subjects in the rich PK sampling portion of the study and at least 3 of the 10 subjects in 
the sparse PK sampling portion of the study expected to complete the study are females.


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3.
OBJECTIVES
3.1
Primary Objective
To evaluate the PK, safety, and tolerability of SHP465 in children aged 4 to 5 years with ADHD 
after SHP465 multiple daily doses of 6.25 mg.


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4.
STUDY POPULATION SETS 
4.1
Screened Set 
The screened set will consist of all subjects who have provided informed consent.
4.2
Enrolled Set
The enrolled set will consist of all subjects who have been assigned a subject identification 
number and enrolled at baseline (predose on Day 1) visit.
4.3
Safety Set 
The safety set will consist of all enrolled subjects who have taken at least 1 dose of 
investigational product.
4.4
Pharmacokinetic Set 
The PK set will consist of all subjects in the safety set for whom at least 1 PK blood sample was 
collected.


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5.
SUBJECT DISPOSITION
The number of subjects included in each subject set (i.e. enrolled, safety and PK) will be 
summarized. 
The number and percentage of subjects who completed and discontinued the study will be 
presented for the enrolled set. Reasons for discontinuation as recorded on the termination page of 
the electronic case report form (eCRF) will be summarized (number and percentage) for the 
enrolled set. All enrolled subjects who discontinued from the study will be listed and the reason 
for discontinuation will be provided. The subjects who completed the study will be those who 
completed the final scheduled visit on Day 9 of Week 4 for the rich PK sample subset or on Day 
8 of Week 4 for the sparse PK sample subset.
Subject disposition and study analysis sets will be listed for the enrolled set.  


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6.
PROTOCOL DEVIATIONS
All 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 study deviation tools. The Shire study team will review the protocol deviations and their 
classification throughout the study and before the 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 the database lock.
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 the safety set. Protocol deviations/violations will be listed for the enrolled 
set.


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7.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
7.1
Demographic and other Baseline Characteristics
Descriptive summaries of demographic and other baseline characteristics will be presented for 
the safety set and PK set. 
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 (Child, Home Version) total score, and baseline Clinical Global Impressions -
Severity of Illness (CGI-S) score will be summarized.  
The ADHD-RS-5, which measures the behavior of children, 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 (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 to 54. The ADHD-RS-5 total score will be calculated as the sum of 
the individual items from the ADHD-RS-5. 
The CGI-S is performed 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).
Continuous variables, such as age, weight, height, BMI, years since diagnosis of ADHD, and 
baseline ADHD-RS-5 total score will be summarized using descriptive statistics including 
number of subjects (n), mean, standard deviation (SD), median, minimum, and maximum. 
Categorical variables such as sex, ethnicity, race, ADHD Subtype, and baseline CGI-S score will 
be summarized by reporting the number and percentage of subjects in each category. All 
summarized values will be taken from the Screening Visit or Predose assessments (for baseline 
weight and BMI). 
Age will be calculated as the difference between date of birth (DOB) and date of informed 
consent (DINFC), truncated to years, using the following formula:
Age = floor((intck('month',DOB,DINFC) - (day(DINFC) < day(DOB))) / 12)
For PK analyses age will also be calculated without truncation as the difference between DOB 
and DINFC.
Height and weight will be summarized in international system of units.
Height and weight at predose assessment will be used to calculate BMI using the formula below:
BMI = Weight in kilograms / (Height in meters)2
Number of years since diagnosis of ADHD will be based on DINFC. 


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Demographics and baseline characteristics will be listed for the safety set.
7.2
Medical History
At the Screening Visit demographic information, a complete medical and medication history will 
be collected including recent ingestion of medication (30 days prior to entering the screening 
period) and history of respiratory, cardiovascular, renal, gastrointestinal, hepatic, endocrine, 
hematological, neurological, psychiatric, and other diseases. 
Medical history will be listed for the safety set.
The Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) 
version 7.0.2 collected at the Screening Visit 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.
For ADHD medication history collected at the Screening Visit (Visit 1), version September 1, 
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 for the 
Safety Set. ADHD medication history will be listed for the safety set.


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8.
EXTENT OF EXPOSURE AND TREATMENT COMPLIANCE
8.1
Exposure to Investigational product 
A listing will be created by subject number and will show the date and time of dose 
administration and investigational product accountability for the safety set.
Exposure to SHP465 6.25 mg will be summarized for the safety set.
For the investigational product SHP465 all dosing information (total dose, average daily dose 
and cumulative dose) will be listed and the following statistics will be calculated by study visit:

Days of dosing: number of days on which dose information was available and non-zero

Total dose (mg): total number of capsules taken × dose level (6.25 mg)

Average daily dose (mg/day): the total dose / total days of dosing

Cumulative dose (mg): sum of total dose since start of treatment

Duration of exposure in weeks: the total days of dosing / 7
A 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 6.25mg. It is 
calculated as total number of days in which SHP465 6.25mg was taken for each subject (total 
days of dosing for the treatment period), and then sum over all subjects for the treatment period.
If a subject is lost to follow up without returning the leftover of 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 
(predose on Day 1), it will not be assumed that any of the investigational product 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.


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8.2
Measurement of Treatment Compliance
Treatment compliance will be calculated as follows:
For whole capsules:
Compliance = 
Total Capsules Taken × 100
Capsules Prescribed per Protocol
For capsule contents sprinkled in applesauce:
Compliance = Total Sprinkled Doses Taken × 100
Capsules Prescribed per Protocol
Where,

if the subject completed the treatment period: capsules prescribed per protocol = 28;

if the subject discontinued early in the treatment period, capsules prescribed per protocol
= date of treatment discontinuation – date of first dose +1.
Descriptive statistics for investigational product compliance will be presented for the safety set. 
Individual subject treatment compliance will be listed by category. The investigation product 
treatment compliance will be categorized as <80%, 80-120%, or >120%. The category 80-120%
will be considered compliant for analysis purpose. 


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9.
PRIOR AND CONCOMITANT MEDICATIONS/TREATMENTS 
The WHO Drug Dictionary version September 1, 2017 will be used to classify prior and 
concomitant medications by preferred drug name.  
Prior medication or treatment is defined as any medication (including but not limited to herbal 
treatments, vitamins, nonpharmacological treatment, such as behavioral treatment) received 
within 30 days (or PK equivalent of 5 half-lives, whichever is longer) prior to the date of the 
administration of investigational product. 
Concomitant medication or treatment is defined as any medication or treatment 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 for the safety set. 
Medications can be counted both as prior and concomitant medication. For the purpose of 
summaries multiple medication usage by a subject in the same category will be counted only 
once.
All prior, concomitant and post-treatment medications/treatments will be listed for the safety set.


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10.
EFFICACY ANALYSES
Not applicable.


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11.
SAFETY ANALYSES
The safety analysis will be performed using the safety set. Safety endpoints include the 
occurrence of treatment-emergent AEs (TEAEs), vital signs (systolic and diastolic blood 
pressure, pulse rate, respiratory rate, and body temperature), weight, height, electrocardiogram 
(ECG) results, the Columbia-Suicide Severity Rating Scale (C-SSRS), clinical laboratory tests 
(biochemistry, hematology, and urinalysis), the parent/ legally authorized representative (LAR)-
completed Children’s Sleep Habits Questionnaire (CSHQ) and the Post Sleep Questionnaire 
(PSQ). 
For each safety endpoint, unless otherwise specified, the last value collected before the first dose 
of the administration of investigational product will be used as baseline for all analyses of that 
safety endpoint. 
Except for AE data, only baseline assessments from baseline visit (predose on Day 1 of Week 1)
and post-baseline assessment up to the final scheduled visit (Day 9 of Week 4 for rich PK sample 
subset or Day 8 of Week 4 for sparse PK sample subset) that were collected on or before 2 days 
after the last dose of the investigational product will be analyzed. 
A Final on-Treatment Assessment (FoTA) will be defined as the last valid assessment obtained 
after baseline and whilst on investigational product (on or before 2 days after the last dose date).
11.1
Adverse Events 
Adverse events will be coded using Version 20.1 of the Medical Dictionary for Regulatory 
Activities (MedDRA). 
Treatment-emergent AEs are defined as AEs that started or deteriorated on or after the date of 
the first dose of investigational product, and no later than 3 days following the last dose of 
investigational product. If more than 1 AE with the same preferred term is reported before the 
date of the first dose of the investigational product, then the AE with the greatest severity will be 
used as the benchmark for comparison to the AEs occurring during the treatment period under 
the preferred term.
An overall summary of the number of subjects with TEAEs will be presented, including the 
number and percentage of subjects with any TEAEs, serious TEAEs, TEAEs related to 
investigational product, TEAEs leading to discontinuation from the study, and TEAEs leading to 
death. 
The number and percentage of subjects reporting TEAEs will be tabulated by system organ class 
(SOC) and preferred term (PT); by SOC, PT, and maximum severity.  TEAEs considered related 
to investigational product will also be summarized by SOC and PT. If more than 1 AE occurs 
with the same PT for the same subject, then the subject will be counted only once for that PT 
using the most severe and most related occurrence for the summarization by severity and by 
relationship to investigational product.


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For subjects on SHP465 the incidence of all TEAEs will be summarized by preferred term, and 
sorted by decreasing frequency. Serious TEAEs, TEAEs related to investigational product, and 
TEAEs leading to discontinuation from the study will be summarized by SOC and PT for the 
safety set. Listings will be presented for all AEs, serious TEAEs, TEAEs related to 
investigational product, and TEAEs leading to discontinuation from the study.
11.1.1
Adverse Events of Special Interest
Adverse events of special interest will include psychiatric events of interest (categorized as 
psychosis/mania, suicidal, aggression and other miscellaneous psychiatric events) listed in Table 
4. 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 4: 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
Gunshot 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
Miscellaneous psychiatric events (include 
events with serious outcome only)
Abnormal behavior
Agitation
Amnesia
Confusional state
Depressed mood
Depression
Disorientation
Emotional disorder


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Table 4: Psychiatric Events
Category
Preferred Term/Verbatim term
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 
INSOMNIA'), weight decrease and decreased appetite.
For each of these 3 AEs, the following information will be presented:

Number and percentage of subjects reporting the TEAE

Number of TEAEs

Summary of onset day of first TEAE: The onset day of first TEAE is calculated as 
(onset date of first TEAE – date of first dose) + 1 for subjects who experienced the 
TEAE

Summary of duration of TEAE while on study drug: The duration of each event is the 
number of days from the onset of the TEAE, while on study drug 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 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.


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
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:
o
Resolved while on study drug
o
Ongoing
o
Dose interrupted
o
Dose withdrawn (and other action categories related to dose)
o
TEAEs leading to discontinuation
o
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

Number and percentage of mild, moderate and severe TEAEs. If a subject has more than 
one TEAE in the same week, then the worst severity is counted.
In addition, for each subject, all occurrences of each of these 3 AEs will be listed separately by 
subject, start date and stop date. The information presented will include: subject, sex, age, race, 
ethnicity, preferred term/reported term, start date, stop date, onset day, study visit, last dose date, 
duration/imputed duration of TEAE (days), SAE, severity, and effect on doing.
11.2
Clinical Laboratory Variables
Descriptive statistics for clinical laboratory values (in SI units) and changes from baseline to 
Week 4/ET as well as shift tables from baseline to Week 4/ET for quantitative variables will be 
presented for the following clinical laboratory variables.
Hematology
Hemoglobin, hematocrit, red blood cells, platelet count, white blood cell count 
– total and differential, total neutrophils (absolute and relative), eosinophils 
(absolute and relative), monocytes (absolute and relative), basophils (absolute 
and relative), and lymphocytes (absolute and relative).
Biochemistry
Sodium, potassium, glucose, blood urea nitrogen, creatinine, calcium, chloride, 
thyroid-stimulating hormone, thyroxine, tri-iodothyronine, phosphorus, total 
protein, total CO2 (bicarbonate), albumin, aspartate transaminase, alanine 
transaminase, gamma glutamyl transferase, alkaline phosphatase, total 
bilirubin, and uric acid.
Urinalysis
pH, glucose, protein, blood, ketones, bilirubin, nitrites, leukocyte esterase, and 
specific gravity.
Microscopic examination will be conducted if protein and/or blood is/are detected during 
urinalysis. At a minimum the microscopic examination will consist of red blood cells, white 
blood cells, casts, and bacteria.


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Clinical laboratory test values are potentially clinically important (PCI) if they meet either the 
low or high PCI criteria listed in Table 5. 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 5: Criteria for Potentially Clinically Important Laboratory Tests
Parameter
SI Unit
Lower Limit
Higher Limit
Biochemistry
Albumin
g/L
< 30g/L
-
Alkaline phosphatase
≥ 2.5 x ULN
Aspartate transaminase 
-
-
≥ 3 x ULN
Alanine transaminase 
-
-
≥ 3 x ULN
Blood urea nitrogen
mmol/L
-
> 10.71 mmol/L or > 2.5 x 
ULN
Calcium, total
mmol/L
2
2.88
Creatinine
µmol/L
-
> 176.80 µmol/L or > 1.5 x 
ULN
Gamma glutamyl transferase
-
-
≥ 2.5 x ULN
Glucose
mmol/L
< 3.05
> 8.88
Phosphorus, inorganic
mmol/L
< 0.81
2.26
Potassium
mmol/L
< 3.0 
> 5.5
Thyroid stimulating hormone
-
< LLN
> 2 x ULN
Sodium
mmol/L
< 130
> 150
Uric acid
µmol/L
-
> 594.85
Bilirubin, total
µmol/L
-
> 34.21
Protein. total
g/L
< 50
> 90
Hematology
Basophils
-
-
10%
Hemoglobin
g/L
90
160
Hematocrit
%
< 30%
> 50%
Platelet count
109/L
75
600
Red blood cells
X 1012/L
2.5
7.5
White blood cell count
X 109/L
3.0
> 16.0 
Neutrophils
X 109/L OR %
1x109/L OR < 30%
> 6.2 x 109/L OR > 70 %  
Eosinophils 
109/L   OR %
NA
0.5 x 109/L   OR 10%
Lymphocytes 
%
10%
> 70%
Monocytes 
%
-
20%
URINALYSIS
Glucose
-
-
Positive Value (excluding 
trace)
Protein
-
-
Positive Value (excluding 
trace)
Blood
-
-
Positive Value (excluding 
trace)


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Table 5: Criteria for Potentially Clinically Important Laboratory Tests
Parameter
SI Unit
Lower Limit
Higher Limit
Ketones
-
-
Positive Value (excluding 
trace)
Bilirubin
-
-
Positive Value (excluding 
trace)
Leukocyte esterase
-
-
Positive Value (excluding 
trace)
Nitrites
-
-
Positive Value (excluding 
trace)
LLN:  Lower limit of normal value provided by the laboratory
ULN:  Upper limit of normal value provided by the laboratory
All clinical laboratory data will be listed for the safety set.  
11.3
Vital Signs (Including Height and Weight)
Descriptive statistics for vital signs (e.g. systolic and diastolic blood pressure, pulse rate, 
respiratory rate, and body temperature) and their changes from baseline at each post-baseline 
assessment time point and at FoTA will be presented. 
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 time 
point 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 time point and at the FoTA. 
In addition, z-scores for height, weight, and BMI will be based on the subject’s age at each time 
point 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 both the observed value criteria and the 
change from baseline criteria listed in Table 6. The number and percentage of subjects with PCI 
post-baseline values will be tabulated. 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, baseline, 
and post-baseline PCI values. 
The averaged values of the 3 measurements for sitting systolic, diastolic blood pressure and 
pulse at each time point will be used for all summaries and determination of PCIs.


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Table 6: Criteria for Potentially Clinically Significant Vital Signs
Vital Sign Parameter
Flag
Criteriaa
Observed Value
Change from Baseline
Sitting Systolic blood pressure
(mmHg)
High
120
Increase of >10
Low
<75
Decrease of >10
Sitting Diastolic blood pressure 
(mmHg)
High
85
Increase of >10
Low
<40
Decrease of >10
Pulse rate
(beats per minute)
High
130
Increase of >15
Low
55
Decrease of >15
Weight (kg)
High
-
Increase of 7%
Low
-
Decrease of 7%
Temperature (deg. C)
High
>39
-
Low
<35
-
BMI (kg/m2)
High
>95th percentile for age and 
sex
-
Low
<5th percentile for age and 
sex
-
a A post-baseline value is considered as a PCI value if its meets either the criteria for observed value or the criteria for change 
from baseline.
Measurements of oral or tympanic temperature, sitting respiratory rate will be performed at the 
screening visit and ET visit only.
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 7.
Table 7: Normal Range of Pulse Rate (beats/min)
1st Percentile
99th Percentile
Males, 4-5 years
69
120
Females, 4-5 years
70
132
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 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 sex) 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.


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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 8.
Table 8: 95th Percentile Cut-off Values of Blood Pressure Norms by Sex, Age, and Height 
Percentiles
Systolic Blood Pressure (mmHg)
Diastolic Blood Pressure (mmHg)
Age 
(y)
Percentile of Height
Percentile of Height
Boys
5%
10%
25%
50%
75%
90%
95%
5%
10%
25%
50%
75%
90%
95%
4
106
107
109
111
112
114
115
66
67
68
69
70
71
71
5
108
109
110
112
114
115
116
69
70
71
72
73
74
74
Girls
4
105
106
107
108
110
111
112
68
68
69
70
71
71
72
5
107
107
108
110
111
112
113
70
71
71
72
73
73
74
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 sex. The denominator will be the number of 
subjects in the safety set (per sex) with at least 1 post-baseline blood pressure measurement. The 
numerator will be the total number of subjects with at least 1 blood pressure value higher than 
the 95th percentile. A supportive listing of all subjects with abnormal blood pressure values will 
be provided.
All vital signs data will be listed for the safety set.
11.4
Electrocardiogram (ECG)
Descriptive statistics for ECG variables (eg, heart rate, RR interval, PR interval, QRS interval, 
QT interval, and QTc interval) and their changes from baseline at each assessment time point
will be presented. QTc interval will be calculated using both Bazett (QTcB=QT/(RR)1/2) and 
Fridericia (QTcF=QT/(RR)1/3) corrections; and if RR is not available, it will be replaced with 
60/heart rate in the correction formula. Electrocardiogram interpretation will be summarized by 
assessment time point for all scheduled assessments. A shift table from baseline to each 
assessment time point for qualitative ECG results will be presented. 


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For the ECG interval parameters, baseline is defined as the average of the triplicate ECG 
measurements obtained at the baseline visit (predose on Day 1) prior to the administration of the 
investigational product. For the ECG interpretation, baseline will be the ECG with the worst 
interpretation obtained at the baseline visit (predose on Day 1), providing this is prior to the 
administration of the investigational product. The ECG interpretation of normal will be 
considered better than abnormal, and not clinically significant abnormal will be considered better 
than clinically significant abnormal. 
Electrocardiogram variable values will be considered PCI if they meet or exceed the upper limit 
values listed in Table 9. 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 non-PCI baseline and at least 1 post-baseline assessment. The numerator is the total 
number of subjects with at least 1 PCI post-baseline ECG value. A listing of all subjects with 
post-baseline PCI value will be provided including the subject number, baseline, and post-
baseline PCI values.


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Table 9: Criteria for Potentially Clinically Important ECG Values
ECG 
Parameter
Unit
Observed Value
Change from Baseline
Lower 
Limit
Higher Limit
Lower 
Limit
Higher 
Limit
ECG Result
-
-
Abnormal (core lab) and clinically 
significant from investigator
-
-
Heart Rate
beats/minute
<55
>130
Decrease 
>15
Increase >15
PR Interval
msec
-
200
-
-
QT Interval
msec
-
≥440
-
≥30 and <60
60
QTcF Interval
msec
-
≥440 and <480
≥480 and <500
500
-
≥30 and <60
60
QTcB Interval
msec
-
≥440 and <480
≥480 and <500
500
-
≥30 and <60
60
QRS Interval
msec
-
≥90
-
-
Rhythm
-
-
Any rhythm other than sinus rhythm
ECG evaluation –abnormal rhythm
•
Complete Heart Block
•
Tachycardia
•
Bradycardia
•
Wandering Atrial Pacemaker
•
Ectopic Atrial Rhythm
•
Atrial Fibrillation
•
Atrial Flutter
•
Multifocal Atrial Tachycardia
•
Supraventricular Tachycardia
•
Atrial Bigeminy
•
Ventricular Bigeminy
•
Atrial Couplets
•
Ventricular Couplets
•
Ventricular Tachycardia
•
Torsade des Pointes
•
Ventricular Fibrillation
•
Junctional Rhythm
•
Idioventricular Rhythm
•
Escape Beat
•
Atrial Pacemaker
-
-


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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 time point and at the FoTA will be produced. A shift table showing the change 
in evaluation from baseline to the FoTA by treatment group will also be produced.
All ECG data will be listed for the safety set. Listings of ECG data including the central reader’s 
assessment and investigator's interpretation by individual subject will also be produced. 
11.5
Other Safety Variables
11.5.1
Columbia-Suicide Severity Rating Scale
The Pediatric/Cognitively Impaired Version of the C-SSRS will be used in the study. The 
C-SSRS (Posner 2007) is a semi-structured interview that captures the occurrence, severity, and 
frequency of suicide-related thoughts and behaviors during the assessment period. The interview 
includes definitions and suggested questions to solicit the type of information needed to 
determine if a suicide-related thought or behavior occurred.
The C-SSRS contains 2 required items pertaining to suicidal ideation, 4 required items pertaining 
to suicidal behavior, and 1 required item pertaining to non-suicidal self-injurious behavior. In 
situations where there is a positive response to the screening questions, there are 8 additional 
suicidal ideation items and 2 additional suicidal behavior items which are completed. There are 
also 2 items for suicide and suicide behavior present during the interview. Thus, there is a 
maximum of 19 items to be completed. 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 will be used in this study as follows:

The Pediatric/Cognitively Impaired - Lifetime Recent-Clinical version will be administered 
at the screening visit.

The Pediatric/Cognitively Impaired -Since Last Visit - Clinical version will be completed at 
all study visits after the screening visit.
The number and percentage of subjects with positive responses for each suicidal ideation item, 
intensity of ideation item, suicidal behavior item, actual attempts item will be presented for 
overall and at each time point. Descriptive statistics for number of attempts of suicidal behavior 
will also be summarized.
Listings of the C-SSRS data will be provided for subjects with a positive response for the safety 
set.


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11.5.2
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 and will be 
conducted at each time point to the site starting with the baseline visit (predose on Day 1 of 
Week 1). 
Items with continuous responses, such as length of time to fall sleep per night, number of times 
woke up per night, length of time awake per night, length of time sleeping per night will be 
summarized using descriptive statistics (n, mean, SD, minimum, median, and maximum). Items 
with categorical responses such as woke up during the night, number of times woke up per night, 
overall quality of sleep during the past week, typical week, reason the past week was not typical, 
overall quality of sleep during the past school week will be summarized by reporting the number 
and percentage of subjects in each category.
All PSQ data will be listed for the safety set.
11.5.3
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. Each scored question except for 
Watching TV and Riding in car are rated on a 3-point scale depending on the frequency of 
occurring:

“usually” ( 5–7 times within the past week): score = 3

“sometimes” (2–4 times within the past week): score = 2

“rarely” (never or 1 time within the past week): score = 1 
The following six questions should be reversed in scoring for calculation of subscale score and 
total sleep disturbance score so that higher score reflects more disturbed sleep behavior: “Goes 
to bed at same time”, “Falls asleep in own bed”, “Falls asleep in 20 minutes”, “Sleeps the right 
amount”, “Sleeps same amount each day”, “Wakes by himself”. These six questions are rated on 
3-point scale depending on the frequency of occurring:

“usually” ( 5–7 times within the past week): score = 1

“sometimes” ( 2–4 times within the past week): score = 2

“rarely” (never or 1 time within the past week): score = 3
Questions of Watching TV and Riding in car is rated on a 3-point scale (more than 1 occurrences 
can apply for each question; highest score contributes as the question score):

“not sleepy”: score = 0

“very sleepy”: score = 1


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
“falls asleep”: score = 2
The instrument evaluates the child’s sleep based on behavior within 8 different subscales: 
1. Bedtime resistance (sum of the responses for Goes to bed at same time, Falls asleep in 
own bed, Falls asleep in other’s bed, Needs parent in room to sleep, Struggles at bedtime 
and Afraid of sleeping alone)
2. Sleep-onset delay (Falls asleep in 20 minutes)
3. Sleep duration (sum of the responses for Sleeps too little, Sleeps the right amount and 
Sleeps same amount each day)
4. Sleep anxiety (sum of the responses for Needs parent in room to sleep, Afraid of sleeping 
in the dark, Afraid of sleeping alone and Trouble sleeping away)
5. Night wakings (sum of the responses for Moves to other’s bed in night, Awakes once 
during night and Awakes more than once)
6. Parasomnias (sum of the responses for Wets the bed at night, Talks during sleep, Restless 
and moves a lot, Sleepwalks, Grinds teeth during sleep, Awakens screaming, sweating 
and Alarmed by scary dream)
7. Sleep-disordered breathing (sum of the responses for Snores loudly, Stops breathing and 
Snorts and gasps)
8. Daytime sleepiness (sum of the responses for Wakes by himself, Wakes up in negative 
mood, Others wake child, Hard time getting out of bed, Takes long time to be alert, 
Seems tired, Watching TV and Riding in car) 
The CSHQ will be conducted at each visit to the site starting with the baseline visit (predose on 
Day 1 of Week 1) and will be completed by the subject’s parent/LAR.
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 time point. 
All CSHQ data will be listed for the safety set.


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12.
CLINICAL PHARMACOKINETIC AND PHARMACODYNAMIC ANALYSES
12.1
Pharmacokinetic Methods
All summaries and analyses of the PK data will be based on the PK set.
12.1.1
Concentration Data
During this study blood samples for the determination of plasma d- and l-amphetamine
concentrations will be drawn from each subject. For subjects enrolled onto the Rich PK sample 
portion blood samples will be collected on Day 1 of Week 1 at predose, and on Day 7 of Week 4 
at predose, and at 2, 5, 8, 12, 16, 24, and 48 hours after administration of the investigational 
product. For subjects enrolled onto the Sparse PK sample portion blood samples will be collected 
on Day 1 of Weeks 1 to 3, and on Day 8 of Week 4 at predose only. Plasma d- and l-
amphetamine concentrations will be measured using the most current validated bioanalytical 
method.
Individual plasma d- and l-amphetamine concentrations will be listed by subject, week, day, and 
time based on the PK set and summarized by time based on the PK set with the following 
descriptive statistics: n, arithmetic mean, SD, coefficient of variation (CV%), median, minimum, 
maximum, and geometric mean. The individual and mean plasma d- and l-amphetamine 
concentration versus time profiles will be presented in figures on both linear and semi-
logarithmic concentration scales for the Rich PK sampling portion. Mean (±SD) plasma d- and 
l-amphetamine concentration versus time profiles will be presented using nominal time and 
individual plasma d- and l-amphetamine concentration versus time profiles will be presented 
using actual time based on the PK set. Individual and mean (±SD) plasma d- and l-amphetamine 
trough concentrations versus day will be presented in figures on linear concentration scale.
12.1.2
Handling BLQ Values
The following conventions will be used for reporting plasma analyte concentrations that are 
below the lower limit of quantitation (LLOQ) (reported as not quantitative [NQ]):

Plasma samples with analyte concentrations that are below the limit of quantitation (BLQ) 
are reported as zero on the data listings.

Plasma samples with analyte concentrations that are BLQ will be treated as zero in the 
calculation of summary statistics (eg, mean, SD, etc.) for the plasma analyte concentrations 
at individual time points.

If analyte concentrations is BLQ in all plasma samples, mean plasma analyte concentrations 
will be reported as zero, and no descriptive statistics will be reported. 

If the calculated mean (± SD) plasma analyte concentration is less than the LLOQ, the value 
will be reported as calculated. The mean values derived using these conventions will be used 
to create the mean plasma analyte concentration versus time plots.


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12.1.3
Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by non-compartmental analysis using Phoenix®
WinNonlin® from the plasma d- and l-amphetamine concentration-time data in subjects from the 
Rich PK sampling portion only. All calculations will be based on actual sampling times.
For calculation of area under the concentration-time curve (AUC), BLQ values are set equal to 
zero in the PK dataset loaded into WinNonlin. For concentration greater than the LLOQ at the 
first time point WinNonlin uses the zero values, but for all later time points WinNonlin excludes 
the zero values from the AUC calculation.
The following primary PK parameters will be reported:
Cmax
Maximum concentration occurring at tmax
Ctrough,ss
Plasma analyte trough concentration (the predose concentrations 
collected at steady-state)
tmax
Time of maximum observed plasma analyte concentration sampled 
during a dosing interval
AUC0-t
Area under the concentration-time curve from the time 0 to the last time 
point of sample collection
AUC0-5
AUC from time 0 to 5 hours postdose
AUC5-t
AUC from 5 hours postdose to the last-point of sample collection
AUClast
AUC from the time of dosing to the last measurable concentration
AUCtau,ss
AUC over the dosing interval (24 hours) at steady-state
z
First order rate constant associated with the terminal phase of elimination
t½
Terminal half-life
CL/F
Total body clearance for extravascular administration
V/Fss
Apparent volume of distribution at steady-state calculated as:
V/Fss = Dose/ (AUCtau,ss • z)
AUC-Area under the concentration time curve
The following secondary PK parameters will also be reported:
C12
The observed plasma analyte concentration at 12 hours after dose 
administration
C16
The observed plasma analyte concentration at 16 hours after dose 
administration
C24
The observed plasma analyte concentration at 24 hours after dose 
administration
AUC5-12
Area under the concentration-time curve from 5 hours to 12 hours 
postdose
AUC12-16
Area under the concentration-time curve from 12 hours to 16 hours 
postdose
AUC16-24
Area under the concentration-time curve from 16 hours to 24 hours 
postdose


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12.2
Summary of Pharmacokinetic Parameters
PK parameters will be summarized based on the PK set. The PK parameters of d- and 
l-amphetamine will be summarized with descriptive statistics (n, arithmetic mean, SD, CV%, 
median, minimum, maximum, and geometric mean. Individual PK parameters versus age will be 
presented in figures on both linear and semi-logarithmic PK parameter scales for AUC0-t, 
AUCtau,ss, Cmax, CL/F, and V/Fss.
12.3
Pharmacodynamic Methods (if applicable)
Not applicable.
12.4
Statistical Analysis of Pharmacodynamic Data (if applicable)
Not applicable.
12.5
Analyses of Pharmacokinetic/Pharmacodynamic Relationships (If applicable)
Not applicable.
12.6
Pharmacokinetic References
Not applicable.


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


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14.
INTERIM ANALYSIS
No interim analysis is planned for this study.


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15.
DATA MONITORING/REVIEW COMMITTEE
An external independent data monitoring committee (DMC) will be set up for the following 
studies: SHP465-112, SHP465-308, and SHP465-309. The DMC will review the data pertaining 
to safety, tolerability, and benefit/harm 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 contract research organization. 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.


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16.
COMPUTER METHODS 
Statistical analyses will be performed using Version 9.3 or higher of SAS(SAS Institute, Cary, 
NC 27513) on a suitably qualified environment. Pharmacokinetic parameters will be determined 
using a validated version of Phoenix TM WinNonlin® Version 6.4 or higher.


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17.
CHANGES TO ANALYSES SPECIFIED IN PROTOCOL
The PK parameters AUC0-∞and Vz/F for d- and l-amphetamine have been omitted from the PK 
analysis, given that only steady-state PK concentrations will be available. These parameters are 
not appropriate for calculation and interpretation in multiple dosing scenarios. There are no other 
changes from the PK analysis methods stated in the protocol.
Protocol section 9.8 (Safety Analyses) states: Treatment-emergent AEs are defined as AEs that 
started or deteriorated on or after the date of the first dose of investigational product, and no later 
than 3 days following the first dose of investigational product. Since this is a multiple-dose study 
and the dose will be administered daily as a single dose for 28 days, the definition of TEAE in 
the protocol will exclude the AEs started or deteriorated on or after the fourth dose, which will 
not be appropriate for safety analysis. The following definition for TEAEs is used in the 
Statistical Analysis Plan: Treatment-emergent AEs are defined as AEs that started or deteriorated 
on or after the date of the first dose of investigational product, and no later than 3 days following 
the last dose of investigational product.


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18.
DATA HANDLING CONVENTIONS
18.1
General Data Reporting Conventions
Continuous variables will be summarized using the following descriptive statistics: n, mean, 
median, standard deviation, minimum, 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 will 
be presented to 2 more decimal places than the raw data.
Body mass index, averaged laboratory results e.g. diastolic/systolic blood pressure and pulse 
(when taken in triplicate), and derived questionnaire scores will be rounded to 1 decimal place 
for reporting.
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 as whole numbers. 
18.2
Derived Efficacy Endpoints 
Not applicable.
18.3
Association of Early Termination Assessments to Scheduled Visits
For purposes of reporting early termination assessments during the study, each early termination 
visit will be assigned the next nominal visit number after the last completed visit. This rule 
applies to all safety variables (e.g. vital signs) except for the lab data, which will be analyzed
and/or summarized by visit.
18.4
Repeated or Unscheduled Assessments of Safety Parameters 
If a subject has repeated or unscheduled assessments before the start of investigational product, 
then the results from the final assessment made prior to the start of investigational product will 
be used as baseline.  For the ECG interval parameters, this will be the average of the triplicate 
ECG measurements obtained at the baseline visit (predose on Day 1) 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 (predose on Day 1), providing this is prior to the first 
dose of the investigational product.
If a subject has repeated assessments at any post-baseline assessment time point, the first 
recorded assessment will be assigned to the assessment time point for generating descriptive 
statistics. For vital signs (sitting systolic blood pressure, diastolic blood pressure, and pulse), this 
will be the average of the 3 measurements from the first recorded assessment. For the ECG 
interpretation, if there are multiple assessments at any assessment time point, the worst 
interpretation will be used for generating descriptive statistics.


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If end of study assessments are repeated or unscheduled, the last post-baseline assessment will be 
used as the end of study 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, including unscheduled and repeated assessments, will be presented in the data 
listings.
18.5
Missing Date of Investigational Product 
When the date of the last dose of investigational product is missing for a subject in the safety set, 
all efforts should be made to obtain this date from the investigator. If after all efforts the date of 
the last dose of IP is still missing, then the last visit date when investigational product was 
returned will be used in the calculation of treatment duration.  
18.6
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, including rescue medications, incomplete (ie, partially 
missing) start date and/or stop date will be imputed. When the start date and the stop date are 
both incomplete for a subject, impute the start date first.
18.6.1
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 
IP, then the day and month of the date of the first dose of IP 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 IP, 
then December 31 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 IP, 
then 01 January will be assigned to the missing fields.
Missing month only

The day will be treated as missing and both month and day will be replaced according to 
the above procedure.
Missing day only

If the month and year of the incomplete start date are the same as the month and year of the 
date of the first dose of IP, then the day of the date of the first dose of IP will be assigned 
to the missing day.

If either the year is before the year of the date of the first dose of IP or if both years are the 


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same but the month is before the month of the date of the first dose of IP, 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 IP or if both years are the 
same but the month is after the month of the date of the first dose of IP, then the first day 
of the month will be assigned to the missing day.
18.6.2
Incomplete Stop Date 
The following rules will be applied to impute the missing numerical fields. If the date of the last 
dose of investigational product is missing, then replace it with the last visit date. If the imputed 
stop date is before the start date (imputed or non-imputed start date), then the imputed stop date 
will be equal to the start date.
Missing day and month

If the year of the incomplete stop date is the same as the year as of the date of the last dose 
of IP, then the day and month of the date of the last dose of IP 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 IP, 
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 IP, 
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 IP, then the day of the date of the last dose of IP will be assigned to 
the missing day.

If either the year is before the year of the date of the last dose of IP or if both years are the 
same but the month is before the month of the date of the last dose of IP, 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 IP or if both years are the same but the 
month is after the month of the date of the last dose of IP, then the first day of the month 
will be assigned to the missing day.
18.7
Missing Date Information for Adverse Events 
For AEs, incomplete (i.e., partially missing) start dates will be imputed and will follow the same 
rules as in Section 18.6.1. Incomplete stop dates will not be imputed.  
18.8
Missing Severity Assessment for Adverse Events
If severity is missing for an AE starting prior to the date of the first dose of IP, then a severity of 
“Mild” will be assigned. If the severity is missing for an AE starting on or after the date of the 


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first dose of IP, then a severity of “Severe” will be assigned. The imputed values for severity 
assessment will be used for incidence summaries, while the actual values will be used in data 
listings.
18.9
Missing Relationship to Investigation Product for Adverse Events
If the relationship to IP is missing for an AE starting on or after the date of the first dose of IP, a 
causality of “Related” will be assigned. The imputed values for relationship to the IP will be 
used for incidence summaries, while the actual values will be presented in data listings.
18.10
Character Values of Clinical Laboratory Variables 
The actual values of clinical laboratory variables as reported in the database will be presented in 
data listings. No coded values (e.g. when a character string is reported for a numerical variable) 
are necessary.


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19.
REFERENCES
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).
Posner K. Suicidality Issues in Clinical Trials: Columbia Suicidal Adverse Event Identification 
in FDA Safety Analyses Division of Metabolism and Endocrinology Products Advisory 
Committee Meeting, Food and Drug Administration, 2007.
Wang Y, Jadhav PR, Lala M, Gobburu JV. 2012. Clarification on precision criteria to derive 
sample size when designing pediatric pharmacokinetic studies. J Clin Pharmacol; 
52(10): 1601-6.


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20.
TABLE OF CONTENTS FOR TABLES, FIGURES, AND LISTINGS
Table
Title
14.1.1.1
Disposition by Treatment Group (Enrolled Set)
14.1.1.2
Summary of Subject Completion Status by Visit (Safety Set)
14.1.2.1
Protocol Deviations by Site and Treatment Group (Safety Set)
14.1.2.2
Protocol Violations by Site and Treatment Group (Safety Set)
14.1.3.1
Enrollment Duration by Site (Enrolled Set)
14.1.4.1.1
Demographic Characteristics by Treatment Group (Safety Set)
14.1.4.1.2
Demographic Characteristics by Treatment Group (Pharmacokinetic Set)
14.1.4.2.1
Baseline Characteristics by Treatment Group (Safety Set)
14.1.4.2.2
Baseline Characteristics by Treatment Group (Pharmacokinetic Set)
14.1.4.3
Prior Medications by Treatment Group (Safety Set)
14.1.4.4
Concomitant Medications by Treatment Group (Safety Set)
14.2.5.1
Summary of Plasma d-amphetamine Concentrations versus Time 
(Pharmacokinetic Set)
14.2.5.2
Summary of Plasma l-amphetamine Concentrations versus Time (Pharmacokinetic 
Set)
14.2.5.3
Summary of Plasma d-amphetamine Pharmacokinetic Parameters 
(Pharmacokinetic Set)
14.2.5.4
Summary of Plasma l-amphetamine Pharmacokinetic Parameters (Pharmacokinetic 
Set)
14.3.1.1
Overall Treatment-Emergent Adverse Events (TEAEs) by Treatment Group 
(Safety Set)
14.3.1.2
Treatment-Emergent Adverse Events by System Organ Class, Preferred Term, and 
Treatment Group (Safety Set)
14.3.1.3
Treatment-Emergent Adverse Events by Descending Order of Frequency (Safety 
Set)


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Table
Title
14.3.2.1
Treatment-Emergent Adverse Events by Maximum Severity, System Organ Class, 
Preferred Term, and Treatment Group (Safety Set)
14.3.2.2
Treatment-Emergent Adverse Events Considered Related to Investigational 
Product by System Organ Class, Preferred Term, and Treatment Group (Safety 
Set)
14.3.3.1
Treatment-Emergent Adverse Events Leading to Discontinuation (Safety Set)
14.3.3.2
Serious Treatment-Emergent Adverse Events (Safety Set)
14.3.3.3
Treatment-Emergent Psychiatric Adverse Events of Special Interest by Sex (Safety 
Set)
14.3.3.4.1
Summary of Treatment-Emergent Insomnia Adverse Events (Safety Set)
14.3.3.4.2
Incidence of Treatment-Emergent Insomnia Adverse Events by Week (Safety Set)
14.3.3.5.1
Summary of Treatment-Emergent Weight Decreased Adverse Events (Safety Set)
14.3.3.5.2
Incidence of Treatment-Emergent Weight Decreased Adverse Events by Week
(Safety Set)
14.3.3.6.1
Summary of Treatment-Emergent Decreased Appetite Adverse Events (Safety Set)
14.3.3.6.2
Incidence of Treatment-Emergent Decreased Appetite Adverse Events by Week
(Safety Set)
14.3.4.1
Quantitative Clinical Laboratory Results by Treatment Group: Hematology (SI 
Units) (Safety Set)
14.3.4.2
Shift from Baseline in Clinical Laboratory Results by Treatment Group: 
Hematology (SI Units) (Safety Set)
14.3.4.3
Potentially Clinically Important (PCI) Laboratory Results by Treatment Group: 
Hematology (Safety Set)
14.3.4.4
Quantitative Clinical Laboratory Results by Treatment Group: Biochemistry (SI 
Units) (Safety Set)
14.3.4.5
Shift from Baseline in Clinical Laboratory Results by Treatment Group: 
Biochemistry (SI Units) (Safety Set)


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Table
Title
14.3.4.6
Potentially Clinically Important (PCI) Laboratory Results by Treatment Group: 
Biochemistry (Safety Set)
14.3.4.7
Quantitative Clinical Laboratory Results by Treatment Group: Urinalysis (SI 
Units) (Safety Set)
14.3.4.8
Qualitative Clinical Laboratory Results by Treatment Group: Urinalysis (Safety 
Set)
14.3.4.9
Shift from Baseline in Clinical Laboratory Results by Treatment Group: Urinalysis 
(SI Units) (Safety Set)
14.3.4.10
Potentially Clinically Important (PCI) Laboratory Results by Treatment Group: 
Urinalysis (Safety Set)
14.3.5.1
Actual Values and Change from Baseline in Vital Signs by Treatment Group 
(Safety Set)
14.3.5.2
Potentially Clinically Important (PCI) Vital Sign Results by Visit and Treatment 
Group (Safety Set)
14.3.5.3
Summary of Height, Weight and BMI Percentiles and Z-score Categories by Visit 
and Treatment Group (Safety Set)
14.3.5.4
Shift from Baseline in Height Percentile Category by Visit and Treatment Group 
(Safety Set)
14.3.5.5
Shift from Baseline in Weight Percentile Category by Visit and Treatment Group 
(Safety Set)
14.3.5.6
Shift from Baseline in BMI Percentile Category by Visit and Treatment Group 
(Safety Set)
14.3.5.7
Summary of Subjects with Abnormal Pulse Rate and Blood Pressure by Treatment 
Group (Safety Set)
14.3.6.1
Actual Values and Change from Baseline in ECG by Time point and Treatment 
Group (Safety Set)
14.3.6.2
ECG Interpretation by Time point and Treatment Group (Safety Set)
14.3.6.3
Shift from Baseline to Post-baseline Time point in Qualitative ECG Results by 
Treatment Group (Safety Set)


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Table
Title
14.3.6.4
Potentially Clinically Important (PCI) ECG Results by Visit and Treatment Group 
(Safety Set)
14.3.6.5
Summary of Post Sleep Questionnaire (Safety Set)
14.3.6.6
Summary of Children’s Sleep Habits Questionnaire (CSHQ) Total Score and 
Subscales (Safety Set)
14.3.6.7
Summary of Children’s Sleep Habits Questionnaire (CSHQ) Individual Items by 
Visit (Safety Set)
14.3.6.8
Columbia-Suicide Severity Rating Scale by Treatment Group: Suicidal Ideation 
and Suicidal Behavior (Safety Set)
14.3.6.9
Columbia-Suicide Severity Rating Scale by Treatment Group: Suicidal Behavior -
Number of Attempts (Safety Set)
14.3.7.1
Investigational Product Exposure by Treatment Group and Visit (Safety Set)
14.3.7.2
Investigational Product Exposure During Treatment Period by Treatment Group 
(Safety Set)


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Figure
Title
14.2.5.1
Mean (±SD) Plasma d-amphetamine Concentrations versus Time 
(Pharmacokinetic Set)
14.2.5.2
Mean (±SD) Plasma l-amphetamine Concentrations versus Time 
(Pharmacokinetic Set)
14.2.5.3
Mean (±SD) Plasma d-amphetamine and l-amphetamine Trough Concentrations 
versus Day (Pharmacokinetic Set)
14.2.5.4
Individual Plasma d-amphetamine Concentrations versus Time (Pharmacokinetic 
Set)
14.2.5.5
Individual Plasma l-amphetamine Concentrations versus Time (Pharmacokinetic 
Set)
14.2.5.6
Individual Plasma d-amphetamine and l-amphetamine Trough Concentrations 
versus Day (Pharmacokinetic Set)
14.2.5.7
Individual Plasma d-amphetamine Concentrations versus Time (Spaghetti Plot) 
(Pharmacokinetic Set)
14.2.5.8
Individual Plasma l-amphetamine Concentrations versus Time (Spaghetti Plot) 
(Pharmacokinetic Set)
14.2.5.9
Individual Plasma d-amphetamine and l-amphetamine Cmax values versus Age 
(Pharmacokinetic Set)
14.2.5.10
Individual Plasma d-amphetamine and l-amphetamine AUC0-t values versus Age 
(Pharmacokinetic Set)
14.2.5.11
Individual Plasma d-amphetamine and l-amphetamine AUCtau,ss values versus 
Age (Pharmacokinetic Set)
14.2.5.12
Individual Plasma d-amphetamine and l-amphetamine CL/F values versus Age 
(Pharmacokinetic Set)
14.2.5.13
Individual Plasma d-amphetamine and l-amphetamine V/Fss values versus Age 
(Pharmacokinetic Set)


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Listing
Title
16.2.1.1
Subject Disposition (Enrolled Set)
16.2.1.2
Subjects Who Terminated from the Study (Enrolled Set)
16.2.1.3
Study Analysis Set Classification (Enrolled Set)
16.2.2.1
Listing of Protocol Deviations (Enrolled Set)
16.2.4.1
Subject Demographics (Safety Set)
16.2.4.2
Subject Baseline Characteristics (Safety Set)
16.2.4.3
Medical History (Safety Set)
16.2.4.4
Prior and Concomitant Medications (Safety Set)
16.2.4.5
Prior ADHD Medications (Safety Set)
16.2.4.6
ADHD Rating Scale (ADHD-RS-5) Questions
16.2.4.7
ADHD-RS-5 Records by Individual Subject (Safety Set)
16.2.4.8
Clinical Global Impression - Severity (Safety Set)
16.2.4.9
Mini International Neuropsychiatric Interview for Children and Adolescents – Part 
1 (Safety Set)
16.2.4.10
Mini International Neuropsychiatric Interview for Children and Adolescents – Part 
2 (Safety Set)
16.2.5.1
Investigational Product Accountability (Safety Set)
16.2.5.2
Investigational Product Summary Information (Safety Set)
16.2.5.3
Pharmacokinetic Blood Plasma Draw Times and d-amphetamine Concentration 
Data (Pharmacokinetic Set)
16.2.5.4
Pharmacokinetic Blood Plasma Draw Times and l-amphetamine Concentration 
Data Time (Pharmacokinetic Set)
16.2.5.5
Individual Plasma d-amphetamine Pharmacokinetic Parameters (Pharmacokinetic 
Set)


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Listing
Title
16.2.5.6
Individual Plasma l-amphetamine Pharmacokinetic Parameters (Pharmacokinetic 
Set)
16.2.7.1
Adverse Events (Safety Set)
16.2.7.2
Serious Adverse Events (Safety Set)
16.2.7.3
Adverse Events Leading to Discontinuation from the Study (Safety Set)
16.2.7.4
Adverse Events Considered Related to Investigational Product (Safety Set)
16.2.7.5
Adverse Events Leading to Death (Safety Set)
16.2.7.6
Subjects Reporting Psychiatric Treatment-Emergent Adverse Events (Safety Set)
16.2.7.7
Treatment-Emergent Insomnia Adverse Events (Safety Set)
16.2.7.8
Treatment-Emergent Weight Decreased Adverse Events (Safety Set)
16.2.7.9
Treatment-Emergent Decreased Appetite Adverse Events (Safety Set)
16.2.8.1.1
Clinical Laboratory Test Results (Safety Set)
16.2.8.1.2
Subjects with Potentially Clinically Important Laboratory Test Results (Safety Set)
16.2.8.2.1
Vital Signs (Safety Set)
16.2.8.2.2
Subjects with Potentially Clinically Important Vital Signs (Safety Set)
16.2.8.2.3
Height, Weight and BMI Percentiles and Z-scores (Safety Set)
16.2.8.2.4
Pulse Rate and Blood Pressure Values for Subjects with an Abnormal Post-
Baseline Value (Safety Set)
16.2.8.3.1
12-lead ECG Results and Interpretation (Safety Set)
16.2.8.3.2
Subjects with Potentially Clinically Important ECG Results (Safety Set)
16.2.8.3.3
12-Lead ECG: Investigator’s Interpretation (Safety Set)
16.2.8.4.1
Columbia-Suicide Severity Rating Scale – Suicide Ideation (Safety Set)
16.2.8.4.2
Columbia-Suicide Severity Rating Scale – Intensity of Ideation (Safety Set)
16.2.8.4.3
Columbia-Suicide Severity Rating Scale – Suicidal Behavior (Safety Set)


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Listing
Title
16.2.8.4.4
Columbia-Suicide Severity Rating Scale – Actual Attempts (Safety Set)
16.2.8.5
Post Sleep Questionnaire (Safety Set)
16.2.8.6
Children's Sleep Habits Questionnaire
16.2.8.7
Children's Sleep Habits Questionnaire Responses (Safety Set)